High rate of spontaneous inhibitor clearance during the long term observation study of a single cohort of 524 haemophilia a patients not undergoing immunotolerance

Background: The natural history of inhibitors in patients with haemophilia A not undergoing immune tolerance induction (ITI) is largely unknown. A recent randomized controlled trial suggests that the higher the FVIII dose used for ITI, the faster the clearance and the lower the rate of bleeding, without any difference in the rate of tolerance. We aimed at assessing the rate of spontaneous inhibitor clearance in a large cohort of patients not undergoing ITI. Methods: A retrospective analysis of anti-FVIII inhibitors of long-term registry data in a single centre cohort of 524 haemophilia A patients considered for synovectomy was performed. Patients were tested for inhibitors before and 15 days after any and each surgical episode and thereafter did not undergo immune tolerance at any time. Results: The cumulative incidence of inhibitors overall was 34% (180 out of 524) with the highest percentage of 39% (168 out of 434) in severe patients which represented 83% of the cohort. Among the 180 inhibitor patients: 63 had permanent inhibitors; 70 fulfilled current criteria for transient inhibitors but a third category of 47 additional patients cleared the alloantibody spontaneously in >6 months. At logistic regression, both the inhibitor titre and the gene mutation were shown to predict time to clearance. Conclusions: Spontaneous clearance of inhibitors over variable time in the absence of ITI treatment was found in up to 2/3 of the cases.

via Journal of Hematology & Oncology

Predictors of postoperative renal functional damage after nephron-sparing surgery

Background: Although nephron-sparing surgery has been reported not to affect total renal function, it is a non-negligible fact that functional damage of the operated kidney usually results, for various reasons. This study aimed to explore the effects of preoperative baseline characteristics, tumor characteristics, and function protection methods on postoperative renal damage. Methods: This study was a retrospective review of 51 patients who underwent open nephron-sparing surgery. The mean age of the patients (39 men, 12 women) was 54.2 +/- 13.9 years, range 32 to 71 years. The glomerular filtration rate (GFR) was measured preoperatively and 6th months after the operation. Univariate analysis was used to screen indicators with significant differences in different levels of renal function damage. All variables found to be significant on univariate analysis were entered into a multiple logistic regression model to predict risk factors for renal function damage. Results: Univariate analysis showed that there was a significant difference in age, GFR of operated kidney, tumor diameter, tumor depth, and ischemic protection type between patients with little damage and those with heavy damage (P < 0.05). Forward stepwise logistic regression analysis suggested that age (odds ratio, 3.08; 95% confidence interval 1.78 to 7.04; P = 0.037), preoperative GFR of operated kidney (odds ratio, 0.51; 95% confidence interval 0.11 to 0.73; P = 0.033), and tumor diameter (odds ratio, 5.49; 95% confidence interval 2.14 to 7.88; P = 0.012) and depth (odds ratio, 5.82; 95% confidence interval 2.66 to 8.06; P = 0.010) were independent risk factors for postoperative renal function damage. Conclusions: Patients with older age, poor renal function, and large tumor diameter and depth might be at higher risk of renal function damage after nephron-sparing surgery.

via World Journal of Surgical Oncology

Fibroblast growth factor-2 (FGF2) and syndecan-1 (SDC1) are potential biomarkers for putative circulating CD15+/CD30+ cells in poor outcome Hodgkin lymphoma patients

Background: High risk, unfavorable classical Hodgkin lymphoma (cHL) includes those patients with primary refractory or early relapse, and progressive disease. To improve the availability of biomarkers for this group of patients, we investigated both tumor biopsies and peripheral blood leukocytes (PBL) of untreated (chemo-naive, CN) Nodular Sclerosis Classic Hodgkin Lymphoma (NS-cHL) patients for consistent biomarkers that can predict the outcome prior to frontline treatment.Methods and materials: Bioinformatics data mining was used to generate 151 candidate biomarkers, which were screened against a library of 10 HL cell lines. Expression of FGF2 and SDC1 by CD30+ cells from HL patient samples representing good and poor outcomes were analyzed by qRT-PCR, immunohistochemical (IHC), and immunofluorescence analyses. Results: To identify predictive HL-specific biomarkers, potential marker genes selected using bioinformatics approaches were screened against HL cell lines and HL patient samples. Fibroblast Growth Factor-2 (FGF2) and Syndecan-1 (SDC1) were overexpressed in all HL cell lines, and the overexpression was HL-specific when compared to 116 non-Hodgkin lymphoma tissues. In the analysis of stratified NS-cHL patient samples, expression of FGF2 and SDC1 were 245 fold and 91 fold higher, respectively, in the poor outcome (PO) group than in the good outcome (GO) group. The PO group exhibited higher expression of the HL marker CD30, the macrophage marker CD68, and metastatic markers TGFbeta1 and MMP9 compared to the GO group. This expression signature was confirmed by qualitative immunohistochemical and immunofluorescent data. A Kaplan-Meier analysis indicated that samples in which the CD30+ cells carried an FGF2+/SDC1+ immunophenotype showed shortened survival. Analysis of chemo-naive HL blood samples suggested that in the PO group a subset of CD30+ HL cells had entered the circulation. These cells significantly overexpressed FGF2 and SDC1 compared to the GO group. The PO group showed significant down-regulation of markers for monocytes, T-cells, and B-cells. These expression signatures were eliminated in heavily pretreated patients. Conclusion: The results suggest that small subsets of circulating CD30+/CD15+ cells expressing FGF2 and SDC1 represent biomarkers that identify NS-cHL patients who will experience a poor outcome (primary refractory and early relapsing).

via Journal of Hematology & Oncology

SU6668 suppresses proliferation of triple negative breast cancer cells through down-regulating MTDH expression

Background: The multiple tyrosine kinase inhibitors SU6668 have a promising therapeutic effect on the progression of hematological malignancies and some solid tumors. Here, we determined its effect on triple negative breast cancer (TNBC) cells and explored the potential molecular mechanism. Methods: In this study, MDA-MB-231 cells were treated with SU6668 (15 muM, 30 muM) for 72 h and the change of proliferation was examined by MTT and tablet cloning. DNA ploidy was detected by flow cytometric analysis with PI staining. Double-label immunofluorescence method was used to detect the expression and distribution of MTDH proteins. VEGFR2, HIF-1alpha, MTDH, E-cadhrein, and SMA expressions were detected by Western bolt assay. Results: This study showed that SU6668 inhibited the proliferation and induced polyploidization of MDA-MB-231 cells in a dose dependent form. SU6668 exposure increased the distribution of MTDH in cytoplasm and decreased its distribution in nuclei. After the treatment of SU6668, VEGFR2, HIF-1alpha, MTDH and SMA proteins were down-regulated, while E-cadhrein was up-regulated in MDA-MB-231 cells. Conclusions: In conclusion, SU6668 exposure maybe induces polyploidization, inhibit EMT and influence the expression of MTDH, which suppresses the proliferation in TNBC cells. MTDH is a key signal protein in downstream of VEGF/HIF-1alphapathway in MDA-MB-231 cells, which may be used as the potential target in the treatment of TNBC.

via Cancer Cell International

Albumin-bound paclitaxel has favorable risk–benefit profile in NSCLC

Albumin-bound paclitaxel plus carboplatin is an effective and well-tolerated first-line treatment in patients with advanced non-small-cell lung cancer, irrespective of histology, study results show.

via Med Wire News

Simultaneous laparoscopic splenectomy and right hemihepatectomy for littoral cell angiosarcoma accompanied with liver metastases

Despite the wide acceptance of laparoscopic resection for treatment of abdominal tumors, only few cases of simultaneous laparoscopic removal of the spleen and the right liver have been reported to date. Littoral cell angiosarcoma (LCAS), which arises from the littoral cells lining the sinus channels of the splenic red pulp, is a rare condition, and there is limited literature on littoral cell angiosarcoma with liver metastases. We present the case of a 28-year-old woman with postoperative pathologically-proven LCAS with right liver metastases. The patient's surgery was safely performed, and her postoperative course was uneventful until now. This case suggests that concomitant laparoscopic splenectomy (LS) and right hemihepatectomy is a suitable surgical option for selected patients.

via World Journal of Surgical Oncology

Invasive adenocarcinoma arising from a mixed hyperplastic/adenomatous polyp and synchronous transverse colon cancer

An admixture of hyperplastic and adenomatous components within the same polyp is unusual. Adenocarcinoma arising from a mixed hyperplastic/adenomatous polyp (MHAP) occurs even more rarely. We report the first case of a 59-year-old male who presented with invasive adenocarcinoma originating from a MHAP at a sigmoid colon and synchronous transverse colon cancer.

via World Journal of Surgical Oncology

Muscle density improves mRCC prognosis prediction

Patients with metastatic renal cell carcinoma treated with targeted therapies have a better prognosis if they also have a high quality of muscle, study findings indicate.

via Med Wire News

Tumor vessel density linked to mRCC treatment response

Changes in tumor vessel density correlate with response and resistance to anti-angiogenic therapy in patients with metastatic renal cell carcinoma, study findings suggest.

via Med Wire News

Findings support partial nephrectomy for T1b RCC

Partial nephrectomy and radical nephrectomy provide comparable cancer control for T1b renal cell carcinoma, yet use of the less radical approach has remained limited in the USA over recent years, study results show.

via Med Wire News

Time to RCC recurrence prognostic threshold challenged

A large study confirms the prognostic value of time to recurrence after surgery for renal cell carcinoma, and also suggests the need to reduce the threshold for early recurrence.

via Med Wire News

Impact of breast cancer surgery on angiogenesis circulating biomarkers: a prospective longitudinal study

Background: Debate about the potential effects that surgery might have on cancer cells dormancy and angiogenesis prompted us to investigate the impact of breast surgery on circulating angiogenesis modulating gene transcripts and proteins. Methods: Blood samples from 10 female patients diagnosed with breast cancer and 6 with fibroadenoma were collected before surgery and post-operatively on days 3 and 7 (breast cancer patients only). A set of 84 angiogenesis-associated transcripts were assessed using quantitative PCR arrays, and circulating protein levels (vascular endothelial growth factor A (VEGFA), IL8 and fibroblast growth factor 2 (FGF2) were measured using ELISA in the same samples. The results were investigated against clinicopathological data and patient outcome. Results: Plasma levels of VEGFA and IL8 after surgery were significantly elevated in the breast cancer group compared to the control group (P = 0.038 and P = 0.021, respectively). In the cohort of breast cancer patients, VEGFA increased on day 3 (P = 0.038) and declined on day 7 (P= 0.017), while IL8 did not change on day 3 but showed a significant decline on day 7 (P = 0.02). FGF2 levels did not change significantly over time. Regarding gene transcripts, we detected upregulation of a significant number of angiogenesis-specific genes in patients with breast cancer versus controls: sphingosine kinase 1(SPHK1), epidermal growth factor (EGF), vascular endothelial growth factor C (VEGFC), neuropilin 1 (NRP1), fibroblast growth factor (FGF1), laminin alpha 5 (LAMA5), collagen type IV alpha 3 (COL4A3), IL8, ephrin B2 (EFNB2), ephrin A3 (EFNA3), tyrosine endothelial kinase (TEK), integrin beta 3 (ITGB3), AKT1, thrombospondin 1 (THBS1), chemokine (C-C motif) ligand 11 (CCL11) and TIMP metallopeptidase inhibitor 3 (TIMP3). Surgery induced an altered expression in several keygenes in breast cancer patients. We identified an upregulation of COL4A3 and downregulation of chemokine (C-X-C motif) ligand 9 (CXCL9), EGF, FGF1, Kinase insert domain receptor (KDR), Placental growth factor (PGF), TIMP3 and VEGFC. Conclusion: Breast cancer patients have a different expression profile of circulating angiogenesis biomarkers compared to patients with fibroadenoma. Moreover, mastectomy promotes a transient increase of VEGFA and a shift in the expression patterns of a broad panel of angiogenesis-related circulating gene transcripts.

via World Journal of Surgical Oncology

Personalized medicine: Lung Cancer leads the way

P Parikh, T Puri



Indian Journal of Cancer 2013 50(2):77-79





via Indian Jounal of Cancer

A year of anaplastic large cell kinase testing for lung carcinoma: Pathological and technical perspectives

SS Desai, AS Shah, K Prabhash, NA Jambhekar



Indian Journal of Cancer 2013 50(2):80-86



Background: An in-frame fusion protein between echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic large cell kinase (ALK) genes is seen in some non-small cell lung cancer (NSCLC). EML4-ALK demonstrates constitutive kinase activity. These ALK-positive lung carcinomas have been shown to respond to ALK kinase inhibitors. ALK gene rearrangement is commonly detected using fluorescent in situ hybridization (FISH). Aims: To study the pathological features of ALK positive and negative NSCLC and evaluate the causes of uninterpretable FISH results. Materials and Methods: This is a retrospective, observational study. The molecular pathology records of patients on whom test for ALK had been performed in a period of 1 year (February 2012 to February 2013) were accessioned. A total 224 cases were identified. Histological features were reviewed. The in situ hybridization was performed using Vysis ALK Dual Color Break Apart Rearrangement Probe (Abbott Molecular Inc.). Signal interpretation under the fluorescent microscope was performed in accordance with College of American Pathologists guidelines. Results: Five patients showed ALK gene rearrangement, 182 were negative and 37 cases were uninterpretable. Five patients with ALK gene rearrangement had a mean age of 48 years and the male to female ratio was 2:3. In the ALK negative cases, the mean age was 54 years and male to female ratio was 3.2:1. Histologically, amongst the rearranged cases, three showed solid pattern, one showed acinar and one showed acinar with signet ring cells on histology. Conclusion: The percentage of ALK gene rearrangement was 2.7% (excluding the uninterpretable cases). These ALK positive patients were relatively younger than ALK negative patients. Solid pattern on histology was associated with ALK positivity. In a quarter of the uninterpretable results, the material submitted was fixed and processed outside.

via Indian Jounal of Cancer

Epidermal growth factor receptor mutation in non-small-cell lung carcinomas: A retrospective analysis of 1036 lung cancer specimens from a network of tertiary cancer care centers in India

VH Veldore, RM Rao, S Kakara, S Pattanayak, R Tejaswi, R Sahoo, E Venkataswamy, SA Prabhudesai, N Krishnamoorthy, BN Tejaswini, D Hazarika, SA Gangoli, SM Rahman, R Naik, RB Diwakar, CT Satheesh, SP Shashidhar, Shekar G Patil, BS Ajai Kumar



Indian Journal of Cancer 2013 50(2):87-93



Background: Epidermal growth factor receptor (EGFR) mutation plays a vital role in the prognosis of patients with lung cancer. However, there is a dearth of studies on EGFR mutation in Indian population. In this retrospective study conducted at a network of tertiary cancer care centers across India, we evaluated the proportion of EGFR mutation in patients with non-small-cell lung carcinomas (NSCLC). Materials and Methods: A total of 1036 cases of non-small lung cancer were assessed for EGFR mutation status using Scorpion amplified refractory mutation system real time polymerase chain reaction method from fine needle aspiration cytology core biopsy, pleural fluid and cell blocks. For a few cases, macro dissection of tumor from H and E slides was also performed for EGFR analysis. EGFR Status was assessed for the most commonly known driver mutations in Exons 18, 19, 20 and 21, which contributes to a total of 29 somatic mutations including the resistance mutation T790M. Results: Around 39% of the cohort was female and 61% were male. Mutation was positive in 40.3% and negative (wild type) in 59.7%. There was 1.8% mutation in exon 18, 24.6% in exon 19, 1.6% in exon 20 and 12.8% in exon 21. 38.2% had a mutation in a single site and 1.1% had a mutation in two sites. Overall mutation was significant in females (50.5% vs. 33.9%) compared with males (&#967;2 = 28.3, P < 0.001). Mutation was significant in exon 21 (16.8% vs. 10.3%, &#967;2 = 9.44, P = 0.002) and exon 19 (30.7% vs. 20.7%, &#967;2 = 13.2, P < 0.001) in females compared with males. Conclusion: EGFR is expressed differentially/mutated in patients with NSCLC. Further studies to unravel the predictors for acquired genetic alterations of EGFR are needed.

via Indian Jounal of Cancer

Clinicopathologic features of non-small cell lung cancer in India and correlation with epidermal growth factor receptor mutational status

AD Bhatt, R Pai, G Rebekah, G Arun Nehru, S Dhananjayan, A Samuel, A Singh, A Joel, A Korula, RT Chacko



Indian Journal of Cancer 2013 50(2):94-101



Introduction: We performed retrospective analysis of 106 patients with lung cancer for which formalin-fixed paraffin-embedded tissues was available. Their epidermal growth factor receptor (EGFR) mutation status and treatment outcomes are described. Materials and Methods: All patients with confirmed non - small cell lung cancer (NSCLC) during Jan 2008 to Dec 2010 were included. EGFR sequencing was performed with ABI PRISM 310 genetic analyzer. Results: Forty-two (39.6%) patients had mutation in one of the four exons characterized. Patients whose EGFR mutational status was not available at presentation before the start of treatment were started on chemotherapy, n = 46 (43.39%). If EGFR mutational analysis was available and mutations were present, the patients were started on either upfront tyrosine kinase inhibitor (TKI), n = 15 (14.15%) or if on chemotherapy arm were allowed to finish six cycles and then start with maintenance TKIs, n = 26 (24.52%). The median progression free survival for patients with and without mutations was 11 months (95% CI,7-14) and 9 months (95% CI,7-10) respectively. A median PFS of 14 months (95%CI, 12-16) was seen in the mutation-positive group that received both chemotherapy followed by switch maintenance with TKIs versus 8 months (95%CI, 7-8 months) in the group that received only TKI. Conclusion: The prevalence of EGFR mutations in this population of NSCLC patients was 39.6% with exon 19 mutation being the most common. The observed benefit of addition of chemotherapy over TKI in EGFR mutation-positive group raises the question, can we offer the therapy of chemotherapy-TKI combination to EGFR mutation-positive lung cancer patients as shown in the present study.

via Indian Jounal of Cancer

Molecular epidemiology of epidermal growth factor receptor mutations in lung cancers in Indian population

J Mehta



Indian Journal of Cancer 2013 50(2):102-106



Background: Lung cancer is the leading cause of cancer related mortality world-wide and amongst males in India. The discovery of tyrosine kinase inhibitors holds a ray of hope for a subset of lung cancer patients, which have activating epidermal growth factor receptor (EGFR) mutations. Much of the preliminary data on frequency of EGFR mutations emanated from Western studies, which reported EGFR mutation rates of 10-15%. However, studies from Asian countries report a much higher frequency of EGFR mutations, not only in the male population, but also in females. AIM: The object of this study was to share the author's experience of EGFR mutation testing in 402 lung cancer patients as no large-scale study addressing the issue has been published from India. Materials and Methods: Formalin fixed paraffin embedded tissues were analyzed for EGFR exon 19 deletions and exon 21 point mutation by length analysis of fluorescently labeled polymerase chain reaction products on Applied Biosystems Inc. 310 genetic analyzer. Results: Out of 402 samples, 35 samples could not be analyzed because of poor deoxyribonucleic acid material. Thus of the remaining 367 cases analyzed, EGFR mutations were found in 118 patients (32%). Mutations were equally distributed between males (50%) and females (50%). Majority of the mutations were seen in adenocarcinoma subtype (90%). Exon 19 mutations accounted for 76% while exon 21 mutations accounted for 24% of the mutations. Summary: EGFR mutation frequency is higher in Indian population vis-&#224;-vis Caucasian population, but lower than that reported in the East Asian population. A significantly higher number of males also harbor EGFR mutations.

via Indian Jounal of Cancer

Epidermal growth factor receptor mutation subtypes and geographical distribution among Indian non-small cell lung cancer patients

A Choughule, V Noronha, A Joshi, S Desai, N Jambhekar, S Utture, A Thavamanni, K Prabhash, A Dutt



Indian Journal of Cancer 2013 50(2):107-111



Background: The Medical Oncology Department at Tata Memorial Hospital, the single largest tertiary cancer care center in Asia, receives in-house registered and referral patient samples from all parts of the country. Our recent studies establish 23% EGFR mutation frequency among Indian population. Here, we extend our study and report further analysis of distribution of different types of EGFR mutations in 1018 non small cell lung cancer patient, and its co-relation with clinical parameters and geographical variations across the country. Material and Methods: This study is a retrospective analysis on all the patients who were referred for EFGR testing as a routine service over a 1.5 year period. This was part of standard care. EGFR kinase domain mutations in exon 18-21 were probed by TaqMan probe-based assays in 1018 NSCLC patients. Results and Discussion: While EGFR exon 19 mutations, the most frequent EGFR mutation, were found be higher among non smokers females, we find surprisingly higher incidence of exon 21 mutations among EGFR mutation positive male smokers of Indian ethnicity. Furthermore, as Indian population is known to be composed of a gradient admixture of Ancestral North Indian (with genetic influence from Middle Easterners, Central Asians, and Europeans harboring variant EGFR mutation frequency) and Ancestral South Indians, as a paradox our study indicates comparable EGFR mutation frequency across different geographical locations within India Conclusion: Geographically there is uniform distribution in the EGFR mutation frequency within India. Further more, while exon 19 mutations are predominant among non smokers, higher incidence of exon 21 mutations exists among EGFR mutation positive male smokers of Indian ethnicity.

via Indian Jounal of Cancer

Metronomics in low and middle income countries: India showing the way!

N André, E Pasquier



Indian Journal of Cancer 2013 50(2):112-114





via Indian Jounal of Cancer

Association between baseline VEGF/sVEGFR-2 and VEGF/TSP-1 ratios and response to metronomic chemotherapy using cyclophosphamide and celecoxib in patients with advanced breast cancer

HA Perroud, MJ Rico, CM Alasino, SM Pezzotto, VR Rozados, OG Scharovsky



Indian Journal of Cancer 2013 50(2):115-121



Background: Metronomic chemotherapy (MCT) with cyclophosphamide (Cy) and celecoxib (Cel) has therapeutic efficacy and low toxicity profile in advanced breast cancer patients (ABCP), but no reliable biomarkers of response have been found yet that allow patient selection for treatment. AIM: To investigate the potential role as biomarkers of pro- and antiangiogenic parameters and evaluate their response in ABCP receiving metronomic Cy 50 mg p.o./day + Cel 400 mg p.o./day. Materials and Methods: Serum levels of vascular endothelial growth factor-C (VEGF-C), soluble VEGF receptors 2 and 3 (sVEGFR-2, sVEGFR-3), were measured at different time points in 13/15 patients included in a phase II trial of MCT with Cy+Cel. Results: Serum levels of sVEGFR-2 and sVEGFR-3 increased significantly during treatment (P = 0.0392; P = 0.0066, respectively). VEGF-C showed no significant modifications. Previous determinations of VEGF and TSP-1 in the same patients were utilized. VEGF/sVEGFR-2, VEGF/TSP-1, and VEGF-C/sVEGFR-3 ratios decreased significantly along the treatment (P = 0.0092; P = 0.0072; P = 0.0141, respectively). Nonsignificant variations were observed for VEGF-C/sVEGFR-2 ratio. Baseline values of VEGF/sVEGFR-2 and VEGF/TSP-1 ratios were associated with time to progression (TTP) (P = 0.0407; P = 0.0394, respectively) meanwhile baseline VEGF was marginally significant (P = 0.0716). Patients with values lower than the 50 th percentile for both ratios showed longer TTP. Conclusions: We have identified the baseline VEGF/sVEGFR-2 and VEGF/TSP-1 ratios as potential biomarkers of response in ABCP treated metronomically with Cy+Cel. This finding warrants its confirmation in a higher number of patients.

via Indian Jounal of Cancer

Efficacy and safety of metronomic administration of paclitaxel for advanced recurrent non-small-cell lung cancer

V Noronha, VM Patil, A Joshi, K Prabhash



Indian Journal of Cancer 2013 50(2):122-127



Context: There are limited effective therapeutic options in the relapsed setting for non-small cell lung cancer (NSCLC) or in the first line for platinum-ineligible patients. Aim: To evaluate the safety and efficacy of a metronomic schedule of paclitaxel administered weekly in relapsed refractory NSCLC or upfront in patients not eligible for platinum-based chemotherapy. Settings and Design: Retrospective analysis of a prospectively collected database from the medical oncology department at Tata Memorial Hospital in Mumbai, India. Materials and Methods: Patients with recurrent and treatment-na&#239;ve platinum-ineligible advanced NSCLC were treated with weekly paclitaxel at 80 mg/m 2 with palliative intent. Restaging scans were obtained every two months. Chemotherapy was continued until progressive disease, intolerable side effects, or decision of the patient. Statistical Analysis Used: SPSS version 16 was used for analysis. Simple percentages were used for descriptive statistics. Progression-free survival (PFS) was calculated from date of start of paclitaxel till the date of progression, change of therapy due to any reason, or death due to any cause. Overall survival (OS) was calculated from date of start of paclitaxel to death. The Kaplan Meier method was used for estimation of survival. Results: There were 37 patients over eight months. The median age was 59 years, with a male-to-female ratio of 5:1. Two patients received paclitaxel in the first line, 18 patients in second line, nine in third line, five in fourth line, and three were in fifth line. 73% patients had received prior platinum and 48.6% patients had Eastern Cooperative Oncology Group performance status (ECOG PS) >2. The median number of weekly cycles delivered was 14. The response rate was 35% [complete remission (CR): 2.7%, partial remission (PR): 32.4%, stable disease (SD): 32.4%, progressive disease (PD): 27%], the median PFS was four months, and the estimated median OS was seven months. Chemotherapy was well tolerated. The most frequent grade 3 toxicities included anemia: 8%, neutropenia: 5.4%, and sensory neuropathy: 8%. There were no grade 4 toxicities and no episodes of febrile neutropenia. Conclusions: Weekly low-dose continuous metronomic-type scheduling of paclitaxel is safe and effective for relapsed refractory NSCLC and in the first line in platinum-ineligible patients.

via Indian Jounal of Cancer

Metronomics in low and middle income countries: India showing the way!

V Noronha, V Patil, B Bhosale, A Joshi, N Purandare, K Prabhash



Indian Journal of Cancer 2013 50(2):128-134



Context: Advanced esophageal cancer is aggressive with an expected median survival of 6-7 months. Combination chemotherapy regimens provide effective palliation, but result in substantial toxicity. Materials and Methods: Retrospective analysis of prospectively collected data of patients with advanced esophageal cancer, not amenable to definitive intent therapy who were treated with intravenous weekly paclitaxel. Results: Between October 2010 and August 2011, 51 patients were included. Median age was 56 years, with a male: female ratio of 2.9:1. 29% were mid esophageal and 55% were lower third and gastroesophageal junction tumors. 65% of the tumors had squamous histology. Performance status was > 2 in 45%. 61% patients had received prior therapy, either definitive or palliative. 51% patients were platinum-pre-treated and 29% had received prior 3 weekly paclitaxel. 76% patients had distant metastases. Median number of cycles of weekly paclitaxel delivered was 11. 71% of patients had improvement in dysphagia, with a median time to symptom improvement of 9 days. In 72% patients, the feeding nasogastric tube could be removed. Overall response rate was 49% (complete remission: 4%, partial remission: 45%, stable disease: 13%). Median progression free survival was 4.7 months (confidence interval [95% CI: 3.7-5.7 months]) and median overall survival was 7.5 months (95% CI: 3.1-11.8 months). Histopathology, performance status and pre-treatment albumin significantly affected survival. The most common grade 3/4 toxicities included hyponatremia (14%), fatigue (16%), diarrhea (12%), anemia (31%), neutropenia (10%) and febrile neutropenia (4%). Conclusions: Metronomic weekly paclitaxel chemotherapy may provide palliative benefit in advanced unresectable metastatic esophageal cancer with minimal toxicity.

via Indian Jounal of Cancer

Oral metronomic scheduling of anticancer therapy-based treatment compared to existing standard of care in locally advanced oral squamous cell cancers: A matched-pair analysis

PS Pai, AD Vaidya, K Prabhash, SD Banavali



Indian Journal of Cancer 2013 50(2):135-141



Context: Head and neck cancers in developing countries present with advanced disease, compounded by poor access to tertiary care centers. Aim: We evaluated oral metronomic scheduling of anticancer therapy (MSAT) in advanced operable oral cancers, in conjunction with standard therapy. Settings and Design: This was a retrospective matched-pair analysis carried out in a tertiary referral cancer center. Materials and Methods: Advanced operable oral cancer patients having a waiting period for surgery > 3 weeks were administered MSAT. Patients then underwent standard therapy (surgery +/- adjuvant radiation/chemoradiation) as warranted by the disease, followed by MSAT maintenance therapy. Outcomes of the MSAT group were compared with stage-matched controls with similar waiting periods. Statistical Analysis: Survivals were found using the Kaplan-Meier method and compared between groups using the log rank test. Results: Response was seen in 75% of 32 patients. Two-year disease-free survivals (DFS) in MSAT and control groups were 86.5 and 71.6%, respectively. Two-year DFS in MSAT group who received at least three months of MSAT was 94.6% (P = 0.03). Conclusions: Oral MSAT is an economical, effective, and safe adjuvant therapy for oral cancers. It has the potential for preventing progression of the disease and improving DFS.

via Indian Jounal of Cancer

Metronomic therapy: Chemotherapy revisited

V Noronha, V Wamsi, V Patil, A Joshi, SD Banavali, K Prabhash



Indian Journal of Cancer 2013 50(2):142-148



Cytotoxic antiproliferative chemotherapeutic agents are the mainstay of treatment in cancers. Chemotherapy is usually administered every 2-3 weeks. Along with acute toxicity and long-term effects of cumulative doses, this strategy potentially allows regrowth of the tumor in the interval period and leads to the emergence of resistant populations of tumor cells. Moreover, even with intense chemotherapy, the outcome is stagnating for most of the tumors. There has been recent interest in the use of chemotherapy in fractionated doses which is far below the maximum tolerated dose. This is called metronomic scheduling of chemotherapy. Here, we review the biology and evidence for metronomic chemotherapy.

via Indian Jounal of Cancer

Can combination metronomic therapy overcome chemoresistance in cholangiocarcinoma? A literature review

SD Banavali, NR Patil, VS Nirabhawane, BB Bhosale, SB Desai



Indian Journal of Cancer 2013 50(2):149-153



Cholangiocarcinoma (CCa) is relatively resistant to chemotherapy as well as radiation therapy, and complete resection is the main curative therapy for these patients. The prognosis for patients with unresectable intrahepatic CCa (iCCa) is extremely poor. A 55-year-old woman presented at our hospital with abdominal pain. After evaluation, she was diagnosed to have multifocal iCCa. She did not opt for standard chemotherapy and therefore received oral metronomic therapy with a combination of celecoxib, etoposide, and cyclophosphamide for a total of 30 months. Presently, she is 57 months post diagnosis and 27 months post cessation of all treatment and continues to be in complete radiological remission. In the present report, we review the literature and discuss whether metronomic scheduling of biologic agents and anticancer drugs will be able to overcome chemoresistance and improve the outcome in cholangiocarcinoma. References for the review were identified through searches of Pubmed for the last 10 years as well as searches of the files of the authors themselves. The final list was generated on the basis of originality and relevance to this review.

via Indian Jounal of Cancer

Erratum

Indian Journal of Cancer 2013 50(2):153-153





via Indian Jounal of Cancer

Is there a role for metronomic induction (and maintenance) therapy in elderly patients with acute myeloid leukemia? A literature review

N Tandon, S Banavali, H Menon, S Gujral, PA Kadam, A Bakshi



Indian Journal of Cancer 2013 50(2):154-158



Acute myeloid leukemia (AML) in older adults differs biologically and clinically from that in younger patients and is characterized by adverse chromosomal abnormalities, stronger intrinsic resistance, and lower tolerance to chemotherapy. In patients over age 60 with AML, cure rates are under 10% despite intensive chemotherapy, and most of them die within a year of diagnosis. Over the last decade, metronomic chemotherapy has emerged as a potential strategy to control advanced/refractory cancer. Here, we report a case of a 68-year-old gentleman having AML with high-risk cytogenetic features, who achieved complete remission on our oral metronomic PrET (PrET: Prednisolone, etoposide, thioguanine) protocol on an outpatient basis. He was later treated with standard high-dose (HD) cytosine arabinoside (Ara-C) consolidation followed by maintenance with etoposide, thioguanine, and sodium valproate. Presently, the patient is nearly 35 months since diagnosis and 21 months off treatment. This case report and review highlights that the combination of oral low-intensity metronomic therapy, followed by standard HD consolidation therapy and metronomic maintenance therapy may be well tolerated by elderly patients especially with less proliferative, high (cytogenetic)-risk AML who are otherwise deemed to be unfit for intensive intravenous induction chemotherapy regimens. References for this review were identified through searches of Pubmed for recent publications on the subject as well as searches of the files of the authors themselves. The final list was generated on the basis of originality and relevance to this review.

via Indian Jounal of Cancer

Personalized medicine: Lung Cancer leads the way

P Parikh, T Puri



Indian Journal of Cancer 2013 50(2):77-79







via Indian Journal of Cancer

A year of anaplastic large cell kinase testing for lung carcinoma: Pathological and technical perspectives

SS Desai, AS Shah, K Prabhash, NA Jambhekar



Indian Journal of Cancer 2013 50(2):80-86



Background: An in-frame fusion protein between echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic large cell kinase (ALK) genes is seen in some non-small cell lung cancer (NSCLC). EML4-ALK demonstrates constitutive kinase activity. These ALK-positive lung carcinomas have been shown to respond to ALK kinase inhibitors. ALK gene rearrangement is commonly detected using fluorescent in situ hybridization (FISH). Aims: To study the pathological features of ALK positive and negative NSCLC and evaluate the causes of uninterpretable FISH results. Materials and Methods: This is a retrospective, observational study. The molecular pathology records of patients on whom test for ALK had been performed in a period of 1 year (February 2012 to February 2013) were accessioned. A total 224 cases were identified. Histological features were reviewed. The in situ hybridization was performed using Vysis ALK Dual Color Break Apart Rearrangement Probe (Abbott Molecular Inc.). Signal interpretation under the fluorescent microscope was performed in accordance with College of American Pathologists guidelines. Results: Five patients showed ALK gene rearrangement, 182 were negative and 37 cases were uninterpretable. Five patients with ALK gene rearrangement had a mean age of 48 years and the male to female ratio was 2:3. In the ALK negative cases, the mean age was 54 years and male to female ratio was 3.2:1. Histologically, amongst the rearranged cases, three showed solid pattern, one showed acinar and one showed acinar with signet ring cells on histology. Conclusion: The percentage of ALK gene rearrangement was 2.7% (excluding the uninterpretable cases). These ALK positive patients were relatively younger than ALK negative patients. Solid pattern on histology was associated with ALK positivity. In a quarter of the uninterpretable results, the material submitted was fixed and processed outside.



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Epidermal growth factor receptor mutation in non-small-cell lung carcinomas: A retrospective analysis of 1036 lung cancer specimens from a network of tertiary cancer care centers in India

VH Veldore, RM Rao, S Kakara, S Pattanayak, R Tejaswi, R Sahoo, E Venkataswamy, SA Prabhudesai, N Krishnamoorthy, BN Tejaswini, D Hazarika, SA Gangoli, SM Rahman, R Naik, RB Diwakar, CT Satheesh, SP Shashidhar, Shekar G Patil, BS Ajai Kumar



Indian Journal of Cancer 2013 50(2):87-93



Background: Epidermal growth factor receptor (EGFR) mutation plays a vital role in the prognosis of patients with lung cancer. However, there is a dearth of studies on EGFR mutation in Indian population. In this retrospective study conducted at a network of tertiary cancer care centers across India, we evaluated the proportion of EGFR mutation in patients with non-small-cell lung carcinomas (NSCLC). Materials and Methods: A total of 1036 cases of non-small lung cancer were assessed for EGFR mutation status using Scorpion amplified refractory mutation system real time polymerase chain reaction method from fine needle aspiration cytology core biopsy, pleural fluid and cell blocks. For a few cases, macro dissection of tumor from H and E slides was also performed for EGFR analysis. EGFR Status was assessed for the most commonly known driver mutations in Exons 18, 19, 20 and 21, which contributes to a total of 29 somatic mutations including the resistance mutation T790M. Results: Around 39% of the cohort was female and 61% were male. Mutation was positive in 40.3% and negative (wild type) in 59.7%. There was 1.8% mutation in exon 18, 24.6% in exon 19, 1.6% in exon 20 and 12.8% in exon 21. 38.2% had a mutation in a single site and 1.1% had a mutation in two sites. Overall mutation was significant in females (50.5% vs. 33.9%) compared with males (&#967;2 = 28.3, P < 0.001). Mutation was significant in exon 21 (16.8% vs. 10.3%, &#967;2 = 9.44, P = 0.002) and exon 19 (30.7% vs. 20.7%, &#967;2 = 13.2, P < 0.001) in females compared with males. Conclusion: EGFR is expressed differentially/mutated in patients with NSCLC. Further studies to unravel the predictors for acquired genetic alterations of EGFR are needed.



via Indian Journal of Cancer

Clinicopathologic features of non-small cell lung cancer in India and correlation with epidermal growth factor receptor mutational status

AD Bhatt, R Pai, G Rebekah, G Arun Nehru, S Dhananjayan, A Samuel, A Singh, A Joel, A Korula, RT Chacko



Indian Journal of Cancer 2013 50(2):94-101



Introduction: We performed retrospective analysis of 106 patients with lung cancer for which formalin-fixed paraffin-embedded tissues was available. Their epidermal growth factor receptor (EGFR) mutation status and treatment outcomes are described. Materials and Methods: All patients with confirmed non - small cell lung cancer (NSCLC) during Jan 2008 to Dec 2010 were included. EGFR sequencing was performed with ABI PRISM 310 genetic analyzer. Results: Forty-two (39.6%) patients had mutation in one of the four exons characterized. Patients whose EGFR mutational status was not available at presentation before the start of treatment were started on chemotherapy, n = 46 (43.39%). If EGFR mutational analysis was available and mutations were present, the patients were started on either upfront tyrosine kinase inhibitor (TKI), n = 15 (14.15%) or if on chemotherapy arm were allowed to finish six cycles and then start with maintenance TKIs, n = 26 (24.52%). The median progression free survival for patients with and without mutations was 11 months (95% CI,7-14) and 9 months (95% CI,7-10) respectively. A median PFS of 14 months (95%CI, 12-16) was seen in the mutation-positive group that received both chemotherapy followed by switch maintenance with TKIs versus 8 months (95%CI, 7-8 months) in the group that received only TKI. Conclusion: The prevalence of EGFR mutations in this population of NSCLC patients was 39.6% with exon 19 mutation being the most common. The observed benefit of addition of chemotherapy over TKI in EGFR mutation-positive group raises the question, can we offer the therapy of chemotherapy-TKI combination to EGFR mutation-positive lung cancer patients as shown in the present study.



via Indian Journal of Cancer

Molecular epidemiology of epidermal growth factor receptor mutations in lung cancers in Indian population

J Mehta



Indian Journal of Cancer 2013 50(2):102-106



Background: Lung cancer is the leading cause of cancer related mortality world-wide and amongst males in India. The discovery of tyrosine kinase inhibitors holds a ray of hope for a subset of lung cancer patients, which have activating epidermal growth factor receptor (EGFR) mutations. Much of the preliminary data on frequency of EGFR mutations emanated from Western studies, which reported EGFR mutation rates of 10-15%. However, studies from Asian countries report a much higher frequency of EGFR mutations, not only in the male population, but also in females. AIM: The object of this study was to share the author's experience of EGFR mutation testing in 402 lung cancer patients as no large-scale study addressing the issue has been published from India. Materials and Methods: Formalin fixed paraffin embedded tissues were analyzed for EGFR exon 19 deletions and exon 21 point mutation by length analysis of fluorescently labeled polymerase chain reaction products on Applied Biosystems Inc. 310 genetic analyzer. Results: Out of 402 samples, 35 samples could not be analyzed because of poor deoxyribonucleic acid material. Thus of the remaining 367 cases analyzed, EGFR mutations were found in 118 patients (32%). Mutations were equally distributed between males (50%) and females (50%). Majority of the mutations were seen in adenocarcinoma subtype (90%). Exon 19 mutations accounted for 76% while exon 21 mutations accounted for 24% of the mutations. Summary: EGFR mutation frequency is higher in Indian population vis-&#224;-vis Caucasian population, but lower than that reported in the East Asian population. A significantly higher number of males also harbor EGFR mutations.



via Indian Journal of Cancer

Epidermal growth factor receptor mutation subtypes and geographical distribution among Indian non-small cell lung cancer patients

A Choughule, V Noronha, A Joshi, S Desai, N Jambhekar, S Utture, A Thavamanni, K Prabhash, A Dutt



Indian Journal of Cancer 2013 50(2):107-111



Background: The Medical Oncology Department at Tata Memorial Hospital, the single largest tertiary cancer care center in Asia, receives in-house registered and referral patient samples from all parts of the country. Our recent studies establish 23% EGFR mutation frequency among Indian population. Here, we extend our study and report further analysis of distribution of different types of EGFR mutations in 1018 non small cell lung cancer patient, and its co-relation with clinical parameters and geographical variations across the country. Material and Methods: This study is a retrospective analysis on all the patients who were referred for EFGR testing as a routine service over a 1.5 year period. This was part of standard care. EGFR kinase domain mutations in exon 18-21 were probed by TaqMan probe-based assays in 1018 NSCLC patients. Results and Discussion: While EGFR exon 19 mutations, the most frequent EGFR mutation, were found be higher among non smokers females, we find surprisingly higher incidence of exon 21 mutations among EGFR mutation positive male smokers of Indian ethnicity. Furthermore, as Indian population is known to be composed of a gradient admixture of Ancestral North Indian (with genetic influence from Middle Easterners, Central Asians, and Europeans harboring variant EGFR mutation frequency) and Ancestral South Indians, as a paradox our study indicates comparable EGFR mutation frequency across different geographical locations within India Conclusion: Geographically there is uniform distribution in the EGFR mutation frequency within India. Further more, while exon 19 mutations are predominant among non smokers, higher incidence of exon 21 mutations exists among EGFR mutation positive male smokers of Indian ethnicity.



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Metronomics in low and middle income countries: India showing the way!

N André, E Pasquier



Indian Journal of Cancer 2013 50(2):112-114







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Association between baseline VEGF/sVEGFR-2 and VEGF/TSP-1 ratios and response to metronomic chemotherapy using cyclophosphamide and celecoxib in patients with advanced breast cancer

HA Perroud, MJ Rico, CM Alasino, SM Pezzotto, VR Rozados, OG Scharovsky



Indian Journal of Cancer 2013 50(2):115-121



Background: Metronomic chemotherapy (MCT) with cyclophosphamide (Cy) and celecoxib (Cel) has therapeutic efficacy and low toxicity profile in advanced breast cancer patients (ABCP), but no reliable biomarkers of response have been found yet that allow patient selection for treatment. AIM: To investigate the potential role as biomarkers of pro- and antiangiogenic parameters and evaluate their response in ABCP receiving metronomic Cy 50 mg p.o./day + Cel 400 mg p.o./day. Materials and Methods: Serum levels of vascular endothelial growth factor-C (VEGF-C), soluble VEGF receptors 2 and 3 (sVEGFR-2, sVEGFR-3), were measured at different time points in 13/15 patients included in a phase II trial of MCT with Cy+Cel. Results: Serum levels of sVEGFR-2 and sVEGFR-3 increased significantly during treatment (P = 0.0392; P = 0.0066, respectively). VEGF-C showed no significant modifications. Previous determinations of VEGF and TSP-1 in the same patients were utilized. VEGF/sVEGFR-2, VEGF/TSP-1, and VEGF-C/sVEGFR-3 ratios decreased significantly along the treatment (P = 0.0092; P = 0.0072; P = 0.0141, respectively). Nonsignificant variations were observed for VEGF-C/sVEGFR-2 ratio. Baseline values of VEGF/sVEGFR-2 and VEGF/TSP-1 ratios were associated with time to progression (TTP) (P = 0.0407; P = 0.0394, respectively) meanwhile baseline VEGF was marginally significant (P = 0.0716). Patients with values lower than the 50 th percentile for both ratios showed longer TTP. Conclusions: We have identified the baseline VEGF/sVEGFR-2 and VEGF/TSP-1 ratios as potential biomarkers of response in ABCP treated metronomically with Cy+Cel. This finding warrants its confirmation in a higher number of patients.



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Efficacy and safety of metronomic administration of paclitaxel for advanced recurrent non-small-cell lung cancer

V Noronha, VM Patil, A Joshi, K Prabhash



Indian Journal of Cancer 2013 50(2):122-127



Context: There are limited effective therapeutic options in the relapsed setting for non-small cell lung cancer (NSCLC) or in the first line for platinum-ineligible patients. Aim: To evaluate the safety and efficacy of a metronomic schedule of paclitaxel administered weekly in relapsed refractory NSCLC or upfront in patients not eligible for platinum-based chemotherapy. Settings and Design: Retrospective analysis of a prospectively collected database from the medical oncology department at Tata Memorial Hospital in Mumbai, India. Materials and Methods: Patients with recurrent and treatment-na&#239;ve platinum-ineligible advanced NSCLC were treated with weekly paclitaxel at 80 mg/m 2 with palliative intent. Restaging scans were obtained every two months. Chemotherapy was continued until progressive disease, intolerable side effects, or decision of the patient. Statistical Analysis Used: SPSS version 16 was used for analysis. Simple percentages were used for descriptive statistics. Progression-free survival (PFS) was calculated from date of start of paclitaxel till the date of progression, change of therapy due to any reason, or death due to any cause. Overall survival (OS) was calculated from date of start of paclitaxel to death. The Kaplan Meier method was used for estimation of survival. Results: There were 37 patients over eight months. The median age was 59 years, with a male-to-female ratio of 5:1. Two patients received paclitaxel in the first line, 18 patients in second line, nine in third line, five in fourth line, and three were in fifth line. 73% patients had received prior platinum and 48.6% patients had Eastern Cooperative Oncology Group performance status (ECOG PS) >2. The median number of weekly cycles delivered was 14. The response rate was 35% [complete remission (CR): 2.7%, partial remission (PR): 32.4%, stable disease (SD): 32.4%, progressive disease (PD): 27%], the median PFS was four months, and the estimated median OS was seven months. Chemotherapy was well tolerated. The most frequent grade 3 toxicities included anemia: 8%, neutropenia: 5.4%, and sensory neuropathy: 8%. There were no grade 4 toxicities and no episodes of febrile neutropenia. Conclusions: Weekly low-dose continuous metronomic-type scheduling of paclitaxel is safe and effective for relapsed refractory NSCLC and in the first line in platinum-ineligible patients.



via Indian Journal of Cancer

Metronomics in low and middle income countries: India showing the way!

V Noronha, V Patil, B Bhosale, A Joshi, N Purandare, K Prabhash



Indian Journal of Cancer 2013 50(2):128-134



Context: Advanced esophageal cancer is aggressive with an expected median survival of 6-7 months. Combination chemotherapy regimens provide effective palliation, but result in substantial toxicity. Materials and Methods: Retrospective analysis of prospectively collected data of patients with advanced esophageal cancer, not amenable to definitive intent therapy who were treated with intravenous weekly paclitaxel. Results: Between October 2010 and August 2011, 51 patients were included. Median age was 56 years, with a male: female ratio of 2.9:1. 29% were mid esophageal and 55% were lower third and gastroesophageal junction tumors. 65% of the tumors had squamous histology. Performance status was > 2 in 45%. 61% patients had received prior therapy, either definitive or palliative. 51% patients were platinum-pre-treated and 29% had received prior 3 weekly paclitaxel. 76% patients had distant metastases. Median number of cycles of weekly paclitaxel delivered was 11. 71% of patients had improvement in dysphagia, with a median time to symptom improvement of 9 days. In 72% patients, the feeding nasogastric tube could be removed. Overall response rate was 49% (complete remission: 4%, partial remission: 45%, stable disease: 13%). Median progression free survival was 4.7 months (confidence interval [95% CI: 3.7-5.7 months]) and median overall survival was 7.5 months (95% CI: 3.1-11.8 months). Histopathology, performance status and pre-treatment albumin significantly affected survival. The most common grade 3/4 toxicities included hyponatremia (14%), fatigue (16%), diarrhea (12%), anemia (31%), neutropenia (10%) and febrile neutropenia (4%). Conclusions: Metronomic weekly paclitaxel chemotherapy may provide palliative benefit in advanced unresectable metastatic esophageal cancer with minimal toxicity.



via Indian Journal of Cancer

Oral metronomic scheduling of anticancer therapy-based treatment compared to existing standard of care in locally advanced oral squamous cell cancers: A matched-pair analysis

PS Pai, AD Vaidya, K Prabhash, SD Banavali



Indian Journal of Cancer 2013 50(2):135-141



Context: Head and neck cancers in developing countries present with advanced disease, compounded by poor access to tertiary care centers. Aim: We evaluated oral metronomic scheduling of anticancer therapy (MSAT) in advanced operable oral cancers, in conjunction with standard therapy. Settings and Design: This was a retrospective matched-pair analysis carried out in a tertiary referral cancer center. Materials and Methods: Advanced operable oral cancer patients having a waiting period for surgery > 3 weeks were administered MSAT. Patients then underwent standard therapy (surgery +/- adjuvant radiation/chemoradiation) as warranted by the disease, followed by MSAT maintenance therapy. Outcomes of the MSAT group were compared with stage-matched controls with similar waiting periods. Statistical Analysis: Survivals were found using the Kaplan-Meier method and compared between groups using the log rank test. Results: Response was seen in 75% of 32 patients. Two-year disease-free survivals (DFS) in MSAT and control groups were 86.5 and 71.6%, respectively. Two-year DFS in MSAT group who received at least three months of MSAT was 94.6% (P = 0.03). Conclusions: Oral MSAT is an economical, effective, and safe adjuvant therapy for oral cancers. It has the potential for preventing progression of the disease and improving DFS.



via Indian Journal of Cancer

Metronomic therapy: Chemotherapy revisited

V Noronha, V Wamsi, V Patil, A Joshi, SD Banavali, K Prabhash



Indian Journal of Cancer 2013 50(2):142-148



Cytotoxic antiproliferative chemotherapeutic agents are the mainstay of treatment in cancers. Chemotherapy is usually administered every 2-3 weeks. Along with acute toxicity and long-term effects of cumulative doses, this strategy potentially allows regrowth of the tumor in the interval period and leads to the emergence of resistant populations of tumor cells. Moreover, even with intense chemotherapy, the outcome is stagnating for most of the tumors. There has been recent interest in the use of chemotherapy in fractionated doses which is far below the maximum tolerated dose. This is called metronomic scheduling of chemotherapy. Here, we review the biology and evidence for metronomic chemotherapy.



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Can combination metronomic therapy overcome chemoresistance in cholangiocarcinoma? A literature review

SD Banavali, NR Patil, VS Nirabhawane, BB Bhosale, SB Desai



Indian Journal of Cancer 2013 50(2):149-153



Cholangiocarcinoma (CCa) is relatively resistant to chemotherapy as well as radiation therapy, and complete resection is the main curative therapy for these patients. The prognosis for patients with unresectable intrahepatic CCa (iCCa) is extremely poor. A 55-year-old woman presented at our hospital with abdominal pain. After evaluation, she was diagnosed to have multifocal iCCa. She did not opt for standard chemotherapy and therefore received oral metronomic therapy with a combination of celecoxib, etoposide, and cyclophosphamide for a total of 30 months. Presently, she is 57 months post diagnosis and 27 months post cessation of all treatment and continues to be in complete radiological remission. In the present report, we review the literature and discuss whether metronomic scheduling of biologic agents and anticancer drugs will be able to overcome chemoresistance and improve the outcome in cholangiocarcinoma. References for the review were identified through searches of Pubmed for the last 10 years as well as searches of the files of the authors themselves. The final list was generated on the basis of originality and relevance to this review.



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Erratum

Indian Journal of Cancer 2013 50(2):153-153







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Is there a role for metronomic induction (and maintenance) therapy in elderly patients with acute myeloid leukemia? A literature review

N Tandon, S Banavali, H Menon, S Gujral, PA Kadam, A Bakshi



Indian Journal of Cancer 2013 50(2):154-158



Acute myeloid leukemia (AML) in older adults differs biologically and clinically from that in younger patients and is characterized by adverse chromosomal abnormalities, stronger intrinsic resistance, and lower tolerance to chemotherapy. In patients over age 60 with AML, cure rates are under 10% despite intensive chemotherapy, and most of them die within a year of diagnosis. Over the last decade, metronomic chemotherapy has emerged as a potential strategy to control advanced/refractory cancer. Here, we report a case of a 68-year-old gentleman having AML with high-risk cytogenetic features, who achieved complete remission on our oral metronomic PrET (PrET: Prednisolone, etoposide, thioguanine) protocol on an outpatient basis. He was later treated with standard high-dose (HD) cytosine arabinoside (Ara-C) consolidation followed by maintenance with etoposide, thioguanine, and sodium valproate. Presently, the patient is nearly 35 months since diagnosis and 21 months off treatment. This case report and review highlights that the combination of oral low-intensity metronomic therapy, followed by standard HD consolidation therapy and metronomic maintenance therapy may be well tolerated by elderly patients especially with less proliferative, high (cytogenetic)-risk AML who are otherwise deemed to be unfit for intensive intravenous induction chemotherapy regimens. References for this review were identified through searches of Pubmed for recent publications on the subject as well as searches of the files of the authors themselves. The final list was generated on the basis of originality and relevance to this review.



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Correlation analysis of preoperative serum alpha-fetoprotein (AFP) level and prognosis of hepatocellular carcinoma (HCC) after hepatectomy

Background: To investigate the prediction value of preoperative serum alpha-fetoprotein (AFP) level for the prognosis of hepatocellular carcinoma (HCC), by comparing pathological characteristics, recurrence rate and survival rate after hepatectomy. Methods: 108 cases of HCC patients who received liver resection in our hospital from 2005 to 2011 were enrolled in this study. According to preoperative serum AFP level, the patients were divided into AFP <=20 ng/mL group, AFP 20 to 400 ng/mL group and AFP >400 ng/mL group, and the clinicopathological and cytopathological features were compared. All the patients were followed up for 24 months, the postoperative recurrence rates and survival rates were compared and analyzed, and the risk factors for HCC postoperative survival rate were studied by multifactor regression analysis. Results: Of the 108 cases of HCC patients, there were 42 cases in AFP <=20 ng/mL group, 28 cases in AFP 20--400 ng/mL group and 39 cases in AFP >400 ng/mL group. It was shown that cell differentiation degrees (chi2 = 20.198, P = 0.000) and microvascular invasion rates (chi2 = 20.358, P = 0.000) were significantly different among the three groups. The AFP <=20 ng/mL group showed higher cell differentiation degrees and significantly lower microvascular invasion rates compared to the other groups (P <0.05). The follow-up data showed that postoperative 2-year recurrence rate (chi2 = 6.164, P = 0.046), 18-month survival rate (chi2 = 7.647, P = 0.022) and 24-month survival rate(chi2 = 6.725, P = 0.035) of the three groups were significantly different, and we found that the AFP <=20 ng/mL group had lower postoperative 2-year recurrence rate, and higher 18-month survival rate and 24-month survival rate than the other two groups (P <0.05). Multiple logistic regression analysis indicated that tumor diameter (>=5 cm) and preoperative serum AFP level (>400 ng/mL) were closely correlated with HCC postoperative survival rate (P <0.05). Conclusions: It is shown that preoperative serum AFP level has considerable predictive value for the malignant feature and prognosis of HCC. It is suggested that HCC patients with no contraindication of operation and serum AFP <=20 ng/mL can benefit most from primary treatment of hepatectomy. While HCC patients with serum AFP higher than 20 ng/mL need comprehensive therapy besides surgical resection and close follow up.

via World Journal of Surgical Oncology

Molecular crosstalk between apoptosis and autophagy induced by a novel 2-methoxyestradiol analogue in cervical adenocarcinoma cells

Background: 2-Methoxyestradiol has been shown to induce both autophagy and apoptosis in various carcinogenic cell lines. Although a promising anti-cancer agent, it has poor bioavailability and rapid in vivo metabolism which decreases its efficiency. In order to improve 2-methoxyestradiol's anti-proliferative properties, a novel 2-methoxyestradiol analogue, 2-ethyl-3-O-sulphamoyl-estra-1,3,5 (10)16-tetraene (ESE-16), was previously in silico-designed in our laboratory. This study investigated ESE-16 for its anti-proliferative potential on a cervical adenocarcinoma cell (HeLa) cell line. Additionally, the possible intracellular crosstalk mechanisms between the two types of cell death were investigated.Methods and results: HeLa cells exposed to 0.5 muM ESE-16 for 24 hours showed morphological evidence of both apoptotic and autophagic death pathways as assessed by polarization-optical transmitted light differential interference contrast microscopy, fluorescent microscopy and transmission electron microscopy. Flow cytometric cyclin B1 quantification revealed induction of programmed cell death after halting cell cycle progression in metaphase. Confocal microscopy demonstrated that ESE-16 caused microtubule fragmentation. Flow cytometric analysis of cell cycle progression and phosphatidylserine flip determination confirmed induction of apoptosis. Moreover, an increase in aggresome formation and microtubule-associated protein light chain, LC3, was demonstrated indicative of autophagy. Both caspase 8 and 3 were upregulated in a spectrophotometric analysis, indicating the involvement of the extrinsic pathway of apoptotic induction. Conclusions: We conclude that the novel in silico-designed compound, ESE-16, exerts its anti-proliferative effect on the tumorigenic human epithelial cervical (HeLa) cells by sequentially targeting microtubule integrity, resulting in a metaphase block, causing induction of both autophagic and apoptotic cell death via a crosstalk mechanism that involves the extrinsic pathway. Future investigations will expand on signal transduction pathways involved in both apoptosis and autophagy for assessment of ESE-16 effects on microtubule dynamic instability parameters.

via Cancer Cell International

Candidate microRNA biomarkers in human epithelial ovarian cancer: systematic review profiling studies and experimental validation

Despite advances in detection and therapy, epithelial ovarian cancer (EOC) still represents the most lethal gynecologic malignancy in women worldwide. The high mortality of EOC is mainly due to late-stage diagnosis for more than 70% of patients. There is an urgent need to search for specific and sensitive biomarkers for early diagnosis of EOC. Recently, the cumulative data indicated an essential role for microRNA (miRNA), a class of small non-coding RNAs targeting multiple mRNAs and triggering translation repression and/or RNA degradation, in ovarian caner carcinogenesis and progression. Here, we reviewed the published miRNA expression profiling studies that compared the miRNA expression profiles between EOC tissues or cell lines and normal ovarian tissues or benign ovarian tumor or human primary cultured ovarian surface epithelial cells. A miRNA ranking system that takes the number of comparisons in agreement and direction of differential expression into the consideration was devised and used. Finally, five promising differentially miRNAs (miR-200a, miR-100, miR-141, miR-200b, and miR-200c) were reported with the consistent direction in four or more studies. MiR-200a, miR-200b, miR-200c, and miR-141, all of them belong to miR-200 family, were reported with consistently up-regulated in at least 4 studies, whereas miR-100 was reported with down-regulated in 4 studies. Furthermore, we validated these miRNAs in a clinical setting using qRT-PCR and their dysregulations in EOC tissues confirmed the findings. Conclusively, the five most consistently expressed miRNAs might provide some clues of the potential biomarkers in EOC. Further mechanistic and precise validation studies are needed for their clinical significances and roles in the progression of EOC.

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Definition of compartment-based radical surgery in uterine cancer: radical hysterectomy in cervical cancer as 'total mesometrial resection (TMMR)' by Michael Hockel translated to robotic surgery (rTMMR)

Background: Radical hysterectomy has been developed as a standard treatment in Stage I and II cervical cancers with and without adjuvant therapy. However, there have been several attempts to standardize the technique of radical hysterectomy required for different tumor extension with variable success. Total mesometrial resection as ontogenetic compartment-based oncologic surgery - developed by open surgery - can be standardized identically for all patients with locally defined tumors. It appears to be promising for patients in terms of radicalness as well as complication rates. Robotic surgery may additionally reduce morbidity compared to open surgery. We describe robotically assisted total mesometrial resection (rTMMR) step by step in cervical cancer and present feasibility data from 26 patients. Methods: Patients (n = 26) with the diagnosis of cervical cancer were included. Patients were treated by robotic total mesometrial resection (rTMMR) and pelvic or pelvic/periaortic robotic therapeutic lymphadenectomy (rtLNE) for FIGO stage IA-IIB cervical cancer. Results: No transition to open surgery was necessary. No intraoperative complications were noted. The postoperative complication rate was 23%. Within follow-up time (mean: 18 months) we noted one distant but no locoregional recurrence of cervical cancer. There were no deaths from cervical cancer during the observation period. Conclusions: We conclude that rTMMR and rtLNE is a feasible and safe technique for the treatment of compartment-defined cervical cancer.

via World Journal of Surgical Oncology

Primary malignant melanoma of the esophagus: a rare and aggressive disease

Primary malignant melanoma of the esophagus is an uncommon tumor, with approximately 300 cases having been reported thus far. The purpose of this study was to describe a case of a 60 year-old man with a 10 month history of progressive dysphagia and thoracic pain, the investigations of which led to a diagnosis of primary malignant melanoma of the esophagus. The patient underwent a transhiatal esophagectomy with subcarinal lymphadenectomy, and isoperistaltic gastric tube replacement of the esophagus. Nine months after surgery, he developed ischemic colitis, and metastasis in the mesentery was diagnosed. His disease progressed and he died one year after the esophagectomy. A review of the literature was performed.

via World Journal of Surgical Oncology

Safety of intracorporeal circular stapling esophagojejunostomy using trans-orally inserted anvil (OrVilTM) following laparoscopic total or proximal gastrectomy - comparison with extracorporeal anastomosis

Background: There have been several attempts to develop a unique and easier way to perform esophagojejunostomy during laparoscopy-assisted total gastrectomy or laparoscopy-assisted proximal gastrectomy. The OrVilTM system (Covidien, Mansfield, MA, USA) is one of those methods, but its technical and oncologic feasibility have not been proven and need to be observed. Methods: Among 87 patients who underwent laparoscopy-assisted total gastrectomy (LATG; 79 cases) and laparoscopy-assisted proximal gastrectomy with double tract anastomosis (LAPG_DT; 8 cases) from April 2004, 47 patients underwent the conventional extracorporeal method (Group I; 2004--2008) were compared with 40 patients treated with the intracorporeal OrVilTM system (Group II; 2009--2012). Results: There was no significant difference in clinicopathologic characteristics between the two groups except tumor location; more cardia lesions were involved in group II (p = 0.012). The mean time for esophagojejunostomy (E-J), defined as the time from anvil insertion to closure of the jejunal entry site has no significant difference (Group I vs II: 22.2 +/- 3.2 min vs 18.6 +/- 3.5 min, p = 0.623). In terms of anastomotic complication, there was no significant difference in E-J leakage and stricture. E-J leakage occurred in 2 out of 47 (4.3%) cases in group I and 2 out of 40 (5%) in group II (p = 0.628); half of them were treated conservatively in each group and the others underwent reoperation. E-J stricture occurred in 2 (4.3%) cases in group I and 1 (2.5%) in group II (p = 0.561), which required postoperative gastrofiberscopic balloon dilatation. Conclusions: Esophagojejunostomy using the OrVilTM system was a feasible and safe technique compared with the conventional extracorporeal method through mini-laparotomy in terms of anastomotic complications. Moreover, it can help to reduce surgeon's stress regarding esophagojejunostomy because it needs no purse-string procedure and serves a secure operation view laparoscopically.

via World Journal of Surgical Oncology

An evolving new paradigm: endothelial cells -- conditional innate immune cells

Endothelial cells (ECs) are a heterogeneous population that fulfills many physiological processes. ECs also actively participate in both innate and adaptive immune responses. ECs are one of the first cell types to detect foreign pathogens and endogenous metabolite-related danger signals in the bloodstream, in which ECs function as danger signal sensors. Treatment with lipopolysaccharide activates ECs, causing the production of pro-inflammatory cytokines and chemokines, which amplify the immune response by recruiting immune cells. Thus, ECs function as immune/inflammation effectors and immune cell mobilizers. ECs also induce cytokine production by immune cells, in which ECs function as immune regulators either by activating or suppressing immune cell function. In addition, under certain conditions, ECs can serve as antigen presenting cells (antigen presenters) by expressing both MHC I and II molecules and presenting endothelial antigens to T cells. These facts along with the new concept of endothelial plasticity suggest that ECs are dynamic cells that respond to extracellular environmental changes and play a meaningful role in immune system function. Based on these novel EC functions, we propose a new paradigm that ECs are conditional innate immune cells. This paradigm provides a novel insight into the functions of ECs in inflammatory/immune pathologies.

via Journal of Hematology & Oncology

TORS ‘viable’ and preserves QoL in oropharyngeal cancer

Patients with oropharyngeal squamous cell carcinoma who are treated with transoral robotic surgery maintain a high quality of life at 1-year post-surgery, a prospective study indicates

via Med Wire News

Primary chondrosarcoma of the breast: a case presentation and review of the literature

Mammary sarcomas are uncommon tumors. When tumors like malignant cystosarcomaphyllodes and metaplastic carcinoma, where malignant cartilaginous areas may be present, are excluded, only nine cases have been reported to date.We report another case of primary chondrosarcoma of the breast here. A 24-year-old Mediterranean woman presented with a painful mass in the right breast and a physical examination revealed a palpable mass. An incisional biopsy was performed and primary chondrosarcoma was diagnosed based on histological examination. Our patient underwent a mastectomy. A preoperative clinical and cytological diagnosis of chondrosarcoma, even though possible in a few cases, is usually not attained due to its similarclinical behavior with other breast tumors.

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Disrupting the CXCL12/CXCR4 axis disturbs the characteristics of glioblastoma stem-like cells of rat RG2 glioblastoma

Background: Glioblastoma stem-like cells (GSC) have been shown to promote tumor growth, tumor-associated neovascularization, therapeutic resistance, and metastasis. CXCR4 receptors have been found involved in the proliferation, metastasis, angiogenesis, and drug-resistant characteristics of glioblastoma. However, the role of CXCR4 in modulating the stem-like cell properties of rat glioblastoma remains ambiguous. Methods: To explore the role of the CXCL12/CXCR4 axis in maintaining rat GSC properties, we disrupted the CXCR4 signaling by using small hairpin interfering RNA (shRNA). To investigate the role of the CXCL12/CXCR4 axis in maintaining rat GSC properties, we used a spheroid formation assay to assess the stem cell self-renewal properties. A western blot analysis and PCR arrays were used to examine the genes involved in proliferation, self-renewal, and cancer drug resistance. Finally, DNA content and flow cytometry, an immunohistochemical analysis, and methylcellulose colony formation, in vitro invasive and intracranial injection xenograft assays were employed to examine the disruptive effect of CXCR4 on the characteristics of GSCs of the RG2 cell line. Results: Disrupting CXCR4 inhibited the proliferation of RG2 cells both in vitro and in vivo. The spheroid formation assay indicated that CXCR4 was vital for the self-renewal of RG2 GSCs. Disrupting the CXCL12/CXCR4 pathway also reduced the expression of GSC cell markers, including Nestin, ABCG2, and musashi (Msi), and the expression of genes involved in regulating stem cell properties, including Oct4, Nanog, maternal embryonic leucine zipper kinase (MELK), MGMT, VEGF, MMP2, and MMP9. Conclusion: The chemokine receptor CXCR4 is crucial for maintaining the self-renewal, proliferation, therapeutic resistance, and angiogenesis of GSCs of rat RG2 glioblastoma.

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Correction: Functional disruption of macrophage migration inhibitory factor (MIF) suppresses proliferation of human h460 lung cancer cells by caspase-dependent apoptosis

After publication of the original article [1] it came to the authors attention that an incomplete version of figure three was published with the article. The complete figure and new figure legend are presented in this correction article.

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Spindle and kinetochore associated complex subunit 1 regulates the proliferation of oral adenosquamous carcinoma CAL-27 cells in vitro

Background: The prognosis of oral squamous cell carcinoma is very poor due to local recurrence and metastasis. This study explores the molecular events involved in oral carcinoma with the goal of developing novel therapeutic strategies. The mitotic spindle is a complex mechanical apparatus required for the accurate segregation of sister chromosomes during mitosis. Spindle and kinetochore associated complex subunit 1 (SKA1) is a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation. In recent years, much attention has been focused on determining how SKA proteins interact with each other, as well as their biological role in cancer cells. However, the precise role of SKA1 in oral carcinoma remains unknown. Methods: In order to investigate the role of SKA1 in oral cancer, we employed lentivirus-mediated shRNA to silence SKA1 expression in the CAL-27 human oral adenosquamous carcinoma cell line. Results: Depletion of SKA1 in CAL-27 cells significantly decreased cell proliferation, as determined by MTT and colony formation assays. These results strongly demonstrate that reduced SKA1 protein levels may cause inhibition of tumor formation. The shRNA-mediated depletion of SKA1 also led to G2/M phase cell cycle arrest and apoptosis. Conclusion: This is the first report to show that SKA1 plays an important role in the progression of oral adenosqamous carcinoma. Thus, silencing of SKA1 by RNAi might be a potential therapy for this disease.

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Mixed epithelial and stromal tumor of the kidney: report of eight cases and literature review

Mixed epithelial and stromal tumor of the kidney (MESTK) is the term given to a class of uncommon biphasic tumors of the kidney, with few reported cases. We describe eight cases of MESTK with detailed clinicopathological data and follow-up information. With this report, we hope to increase clinical awareness that MESTK should be considered as one of the possible diagnoses for cystic renal mass, especially in peri-menopausal women or those who receive hormone therapy. In addition, regular follow-up is necessary for the any cases with malignant potential.

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PAX8: a sensitive and specific marker to identify cancer cells of ovarian origin for patients prior to neoadjuvant chemotherapy

Background: Neoadjuvant chemotherapy followed by cytoreduction surgery has been used where an accurate cytologic or pathologic diagnosis is usually required before the initiation of neoadjuvant chemotherapy. However, it is difficult to make definitive diagnosis of presence of cancer cells, particularly gynecologic versus non-gynecologic origin, from those ascites specimens due to the absence of specific biomarkers of gynecologic cancers. In the present study, we evaluated if, in addition to the routine morphologic diagnosis, the biomarker PAX8 could be useful in recognition of ovarian epithelial cancer cells prior to the neoadjuvant chemotherapy. Methods: Two hundred and two cytology specimens including 120 pretreatment ovarian cancer samples, 60 benign controls, and 22 malignant non-gynecologic cases were studied. All cytology slides were morphologically reviewed in a blinded fashion without knowing corresponding pathology diagnosis, if present. A total of 168 cytology specimens with a cell block were stained with PAX8 and Calretinin. These included patients with potential for ovarian cancer neoadjuvant chemotherapy (n = 96), metastatic cancers (n = 22), and benign controls (n = 50). Results: Among the 96 ascitic samples prior to neoadjuvant chemotherapy, 76 (79%) showing morphologic features consistent with cancers of ovarian primary were all PAX+/Calretinin-. The remaining 20 (21%) cases were positive for adenocarcinoma, but morphologically unable to be further classified. Among the 22 metastatic cancers into the pelvis, one case with PAX8+/Calretinin- represented a renal cell carcinoma and the remaining 21 PAX8-/Calretinin- metastatic cancers were either breast metastasis (n = 4) and the metastasis from gastrointestinal tract (n = 17). Among the 50 benign control pelvic washing cases, 5 PAX8+/Calretinin-cases represented endosalpingiosis (n = 4) and endometriosis (n = 1), 25 PAX8-/Calretinin + cases showed reactive mesothelial cells, and the remaining 20 specimens with PAX8-/Calretinin- phenotype typically contained inflammatory or blood cells without noticeable diagnostic epithelia. Conclusions: PAX8 identifies all Mullerian derived benign or malignant epithelia. When combining with Calretinin, PAX8 is a sensitive marker to diagnose the carcinomas of ovarian origin, which will be ideal to be used for those patients with a possible advanced ovarian cancer prior to receiving neoadjuvant chemotherapy.

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Ibrutinib and novel BTK inhibitors in clinical development

Small molecule inhibitors targeting dysregulated pathways (RAS/RAF/MEK, PI3K/AKT/mTOR, JAK/STAT) have significantly improved clinical outcomes in cancer patients. Recently Bruton's tyrosine kinase (BTK), a crucial terminal kinase enzyme in the B-cell antigen receptor (BCR) signaling pathway, has emerged as an attractive target for therapeutic intervention in human malignancies and autoimmune disorders. Ibrutinib, a novel first-in-human BTK-inhibitor, has demonstrated clinical effectiveness and tolerability in early clinical trials and has progressed into phase III trials. However, additional research is necessary to identify the optimal dosing schedule, as well as patients most likely to benefit from BTK inhibition. This review summarizes preclinical and clinical development of ibrutinib and other novel BTK inhibitors (GDC-0834, CGI-560, CGI-1746, HM-71224, CC-292, and ONO-4059, CNX-774, LFM-A13) in the treatment of B-cell malignancies and autoimmune disorders.

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Inflammatory myofibroblastic tumor with extensive involvement of the bladder in an adolescent: a case report

Inflammatory myofibroblastic tumor (IMT) is a rare lesion of unclear pathogenesis that shows a wide, highly variable spectrum of clinical behavior. We describe the case of a 17-year-old boy with a large IMT that infiltrated the bladder, ileocecal junction, peritoneum and pelvic retroperitoneal space. The tumor was associated with extensive toughening and thickening of the bladder, and, although it showed a tendency for invasive growth, it affected mainly the bladder and adjacent tissue. To the best of our knowledge, this case report is the first to describe an IMT involving the entire bladder and several adjacent pelviabdominal organs. The bladder wall was tough and could hardly be cut by scalpel. Levels of inflammatory response markers such as C-reactive protein fell after surgery.

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Enhanced levels of asymmetric dimethylarginine in a serum of middle age patients with myelodysplastic syndrome

Myelodysplastic syndromes (MDS) are hematological malignancies of unclear etiology where oxidative stress may contribute to the pathogenesis. Methylarginines, naturally occurring inhibitors of NO synthase, can increase superoxide generation from uncoupled NO synthase. We found significant increase in concentrations of asymmetric dimethylarginine (0.84 +/- 0.32 mumol/L, p = 0.0022) and malondialdehyde (0.77 +/- 0.11 mumol/L, p < 0.001) in sera of MDS patients vs controls (asymmetric dimethylarginine: 0.56 +/- 0.16 mumol/L, malondialdehyde: 0.52 +/- 0.07 mumol/L). On the contrary, nitrites concentrations were significantly decreased in MDS patients (1.71 +/- 0.46 micromol/L, p = 0.0028) vs controls (2.16 +/- 0.38 micromol/L). We suppose that the oxidative stress in MDS is enhanced due to methylated arginines influence on NO synthase activity impairment.

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Combined large cell neuroendocrine carcinoma with giant cell carcinoma of the lungs: a case report

Combined large cell neuroendocrine carcinoma of the lungs (combined LCNEC) with giant cell carcinoma is extremely rare. A 65-year-old man was found to have an abnormal shadow in his left lung field. Computed tomography revealed a solid, round mass measuring 2.8 x 2.2 cm that was located in the left S9. The patient underwent left lower lobectomy and mediastinal lymph node dissection. Histopathological examination revealed an LCNEC, combined with giant cell carcinoma. The patient received by S-1 (TS-1, an oral fluoropyrimidine) chemotherapy, and he has been disease-free for over 8 months. Combined LCNEC with giant cell carcinoma is an extremely rare tumor with high malignant potential, and thus, multidisciplinary therapy and close follow-up are advised.

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Gastric and duodenal squamous cell carcinoma: metastatic or primary?

Either metastatic or primary squamous cell carcinoma in the gastrointestinal tract is extremely rare, with very few cases reported in the literature. In this paper, we report a case in which the patient presented with dysphagia during the course of radiotherapy for recurrent lung cancer in a mediastinal lymph node. Although the dysphagia mimicked radiation esophagitis, the ultimate cause proved to be gastric and duodenal metastases from primary lung squamous cell carcinoma. Taking into account the value of identification of metastatic or primary SCC in the stomach and duodenum on the prognosis and treatment options, it is imperative that the correct diagnosis be established. This report is followed by a discussion of the differential diagnosis between metastatic and primary squamous cell carcinoma in the stomach and duodenum.

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Selective growth inhibition of human malignant melanoma cells by syringic acid-derived proteasome inhibitors

Background: It has been shown that proteasome inhibition leads to growth arrest in the G1 phase of the cell cycle and/or induction of apoptosis. However, it was found that some of these inhibitors do not induce apoptosis in several human normal cell lines. This selective activity makes proteasome inhibition a promising target for new generation of anticancer drugs. Clinical validation of the proteasome, as a therapeutic target in oncology, has been provided by the dipeptide boronic acid derivative; bortezomib. Bortezomib has proven to be effective as a single agent in multiple myeloma and some forms of non-Hodgkin's lymphoma. Syringic acid (4-hydroxy-3,5-dimethoxybenzoic acid, 1), a known phenolic acid, was isolated from the methanol extract of Tamarix aucheriana and was shown to possess proteasome inhibitory activity. Methods: Using Surflex-Dock program interfaced with SYBYL, the docking affinities of syringic acid and its proposed derivatives to 20S proteasome were studied. Several derivatives were virtually proposed, however, five derivatives: benzyl 4-hydroxy-3,5-dimethoxybenzoate (2), benzyl 4-(benzyloxy)-3,5-dimethoxybenzoate (3), 3[prime]-methoxybenzyl 3,5-dimethoxy-4-(3[prime]-methoxybenzyloxy)benzoate (4), 3[prime]-methoxybenzyl 4-hydroxy-3,5-dimethoxybenzoate (5) and 3[prime],5[prime]-dimethoxybenzyl 4-hydroxy-3,5-dimethoxybenzoate (6), were selected based on high docking scores, synthesized, and tested for their anti-mitogenic activity against human colorectal, breast and malignant melanoma cells as well as normal human fibroblast cells. Results: Derivatives 2, 5, and 6 showed selective dose-dependent anti-mitogenic effect against human malignant melanoma cell lines HTB66 and HTB68 with minimal cytotoxicity on colorectal and breast cancer cells as well as normal human fibroblast cells. Derivatives 2, 5 and 6 significantly (p <= 0.0001) inhibited the various proteasomal chymotrypsin, PGPH, and trypsin like activities. They growth arrested the growth of HTB66 cells at G1 and G2-phases. They also arrested the growth of HTB68 cells at S- and G2-phase, respectively. Moreover, derivatives 2, 5, and 6 markedly induced apoptosis (>= 90%) in both HTB66 and HTB68. Conclusions: Computer-derived syringic acid derivatives possess selective anti-mitogenic activity on human malignant melanoma cells that may be attributed to perturbation of cell cycle, induction of apoptosis and inhibition of various 26S proteasomal activities.

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Partial response after transcatheter arterial infusion chemotherapy in a patient with systemic chemotherapy-resistant unresectable colon cancer and hepatic metastasis: (case report)

We report here a case of partial response to hepatic arterial infusion chemotherapy in a patient who developed serious hepatic failure due to unresectable colorectal cancer and hepatic metastasis and showed resistance to systemic chemotherapy with molecular targeted drugs, mFOLFOX6, and FOLFIRI. The patient was a 60-year-old woman who underwent sigmoidectomy for sigmoid colon cancer, lateral posterior hepatic segmentectomy for metastatic liver cancer, and postoperative radiation therapy for metastatic lung cancer. As first-line systemic chemotherapy, mFOLFOX6 (oxaliplatin, 5-fluorouracil, and leucovorin), bevacizumab + FOLFIRI (irinotecan, 5-fluorouracil, leucovorin), and anti-epidermal growth factor receptor antibody + irinotecan were administered, in that order. However, recurrent hepatic metastasis was exacerbated, which induced serious hepatic failure manifested by general malaise, jaundice, abnormal hepatic function, difficulty in walking due to bilateral lower extremity edema, and decreased appetite. The patient was admitted in a serious condition. After hospitalization, the patient received hepatic arterial infusion chemotherapy with 5-fluorouracil and l-leucovorin. After two complete courses, the symptoms improved. The patient's performance status also improved, and she was discharged from the hospital. Four months after discharge, the patient had continued outpatient chemotherapy and maintained excellent performance status. Although HAIC is not presently considered an alternative to systemic chemotherapy, it is sometimes effective in patients who show resistance to molecular targeted drug therapy, FOLFOX, and FOLFIRI, and in whom hepatic metastasis is a key factor in determining prognosis and serious hepatic failure. Further studies should be performed in the future to verify these findings.

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Histopathological and clinical characteristics of duodenal gastrointestinal stromal tumors as predictors of malignancy

Background: Although gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, they are very rare. This study evaluated clinical and histopathological characteristics of duodenal GISTs to identify factors useful in predicting prognosis for patients with these tumors. Methods: A retrospective study was performed on 20 patients who had undergone surgery between 1987 and 2009 for duodenal GISTs. Clinical, histopathological, and immunohistochemical data were evaluated. Survival analyses were conducted using Kaplan-Meier estimates. Results: In 12 patients (60%), duodenal GISTs were diagnosed incidentally. Eight cases (40%) were classified as high risk grade GISTs. Skeinoid fibers (SkF), which are eosinophilic globular hyaline deposits in the extracellular interstitium of the tumor, were found in 12 patients. Skeinoid fibers were not recognized in 8 cases, and these included 3 cases (37.5%) where tumors recurred after surgery and the patient died. Tumors without SkF were larger (81 +/- 92 vs. 23 +/- 8 mm, P < 0.001) and had a higher mitotic count (224.0 +/- 336.6 vs. 0.0 +/- 0.0 /50 high-power field, P < 0.001) than those with SkF. Survival time was shorter in patients with tumors lacking SkF (52.9 +/- 50.7 vs. 108.9 +/- 86.5 months, P = 0.019). Conclusions: We have identified clinical and histopathological characteristics that were useful in predicting the prognosis of patients with duodenal GISTs. In this study, 60% of the tumors were found incidentally, SkF were not recognized in tumors from 40% of patients, and all cases of post-operative tumor recurrence and death occurred in this subgroup of patients.

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Family history of malignant neoplasm and its relation with clinicopathologic features of gastric cancer patients

Background: Few studies to date have evaluated gastric cancer(GC)-related malignant neoplasm family history (MN-FH), and their findings have been largely inconsistent. The aim of this study is to evaluate the prevalence of MN-FH and its relation to the clinicopathologic features of GC. Methods: A total of 104 hospitalized patients with primary gastric adenocarcinoma was prospectively analyzed from 2008 to 2009. Positive MN-FH was defined as MN-affected first- and second-degree relatives of the current GC cases. The relation between prevalence of positive MN-FH and clinicopathologic features in the current GC patients was assessed by using the Chi-square test with Cramer's V coefficient. Results: Thirty-seven (35.6%) of the GC patients had positive MN-FH, with 42 associated tumors in first- and second-degree relatives. Twenty-six (61.9%) of the associated tumors were located in the digestive system, including the esophagus (26.2%), stomach (23.8%), liver (9.5%) and colon (2.4%). Lung cancers were the most prevalent non-digestive system-associated tumors (9.5%). Correlation analysis revealed no significant relations with prevalence of MN-FH and any of the clinicopathologic features (all, P>0.05), including sex (V = 0.044), age (V = 0.060) and histological subtypes (V = 0.109). Conclusions: More than one-third of the GC patients in our hospital had positive MN-FH. The most frequent forms of MN-FH were esophageal cancer and GC. The prevalence of positive MN-FH was not correlated to any of the clinicopathologic features, including sex, age and histological subtypes in the study population of GC patients.

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Correlation between B7-H3 expression and matrix metalloproteinases 2 expression in pancreatic cancer

Background: B7-H3 and matrix metalloproteinases 2 (MMP-2) are reported highly expressed in malignant tumor, we investigate the relationship between B7-H3 expression and MMP-2 on malignant behavior and prognosis predictable value in pancreatic cancer. Methods: We tested the expressions of B7-H3 and MMP-2 protein in 45 pancreatic surgical resected cancer samples; meanwhile, the clinicopathological data of enrolled patients were obtained for correlation analysis to obtain their relationship with pancreatic cancer progress. Results: The expression of B7-H3 was up-regulated with infiltrating depth, lymph node metastasis and TNM stage (P < 0.01). Positive expression rate of MMP-2 in pancreatic cancer tissues was 44.35%, whereas negative in normal pancreatic tissues. Multivariate analysis of Logistic regression showed B7-H3 and MMP-2 expressions were hazardous makers correlated with infiltrating depth (P < 0.05). Conclusion: Our study showed combined detections of B7-H3 and MMP2 protein expression could identify patients at high risk in disease recurrence and prognosis more efficiently.

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