Yulia Kundel

MicroRNAs as a potential prognostic factor in gastric cancer

AIM To compare the microRNA (miR) profiles in the primary tumor of patients with recurrent and non-recurrent gastric cancer. METHODS The study group included 45 patients who underwent curative gastrectomies from 1995 to 2005 without adjuvant or neoadjuvant therapy and for whom adequate tumor content was available. Total RNA was extracted from formalin-fixed paraffin-embedded tumor samples, preserving the small RNA fraction. Initial profiling using miR microarrays was performed to identify potential biomarkers of recurrence after resection. The expression of the differential miRs was later verified by quantitative real-time polymerase chain reaction (qRT-PCR). Findings were compared between patients who had a recurrence within 36 mo of surgery (bad-prognosis group, n = 14, 31%) and those who did not (good-prognosis group, n = 31, 69%). RESULTS Three miRs, miR-451, miR-199a-3p and miR-195 were found to be differentially expressed in tumors from patients with good prognosis vs patients with bad prognosis (P < 0.0002, 0.0027 and 0.0046 respectively). High expression of each miR was associated with poorer prognosis for both recurrence and survival. Using miR-451, the positive predictive value for non-recurrence was 100% (13/13). The expression of the differential miRs was verified by qRT-PCR, showing high correlation to the microarray data and similar separation into prognosis groups. CONCLUSION This study identified three miRs, miR-451, miR-199a-3p and miR-195 to be predictive of recurrence of gastric cancer. Of these, miR-451 had the strongest prognostic impact.

Is local excision after complete pathological response to neoadjuvant chemoradiation for rectal cancer an acceptable treatment option

PURPOSE: The role of local excision in patients with good histological response to neoadjuvant chemoradiation for locally advanced rectal cancer is unclear, mainly because of possible regional nodal involvement. This study aims to evaluate the correlation between pathological T and N stages following neoadjuvant chemoradiation for locally advanced rectal cancer and the outcome of patients with mural pathological complete response undergoing local excision. METHODS: This investigation was conducted as a retrospective analysis. Between January 1997 and December 2007, 320 patients with T3 to 4Nx, TxN+ or distal (≤6 cm from the anus) T2N0 rectal cancer underwent neoadjuvant concurrent chemoradiation followed by surgery. Radiotherapy was standard and chemotherapy consisted of common fluoropyrimidine-based regimens. RESULTS: After chemoradiation, 93% patients had radical surgery, 6% had local excision, and 3% did not have surgery. In the 291 patients undergoing radical surgery, the pathological T stage correlated with the N stage (P = .036). We compared the outcome of patients with mural complete pathological response (n = 37) who underwent radical surgery (group I) and those (n = 14) who had local excision only (group II). With a median follow-up of 48 months, 4 patients in group I had a recurrence and none in group II had a recurrence; one patient died in group I and none died in group II. Disease-free survival, pelvic recurrence-free survival, and overall survival rates were similar in both groups. CONCLUSION: In this retrospective study, nodal metastases were rare in patients with mural complete pathological response following neoadjuvant chemoradiation (3%), and local excision did not compromise their outcome. Therefore, local excision may be an acceptable option in these patients.

Early prediction of histopathological response of rectal tumors after one week of preoperative radiochemotherapy using 18 F-FDG PET-CT imaging. A prospective clinical study

BackgroundPreoperative radiochemotherapy (RCT) is standard in locally advanced rectal cancer (LARC). Initial data suggest that the tumor’s metabolic response, i.e. reduction of its 18 F-FDG uptake compared with the baseline, observed after two weeks of RCT, may correlate with histopathological response. This prospective study evaluated the ability of a very early metabolic response, seen after only one week of RCT, to predict the histopathological response to treatment.MethodsTwenty patients with LARC who received standard RCT regimen followed by radical surgery participated in this study. Maximum standardized uptake value (SUV-MAX), measured by PET-CT imaging at baseline and on day 8 of RCT, and the changes in FDG uptake (ΔSUV-MAX), were compared with the histopathological response at surgery. Response was classified by tumor regression grade (TRG) and by achievement of pathological complete response (pCR).ResultsAbsolute SUV-MAX values at both time points did not correlate with histopathological response. However, patients with pCR had a larger drop in SUV-MAX after one week of RCT (median: -35.31% vs −18.42%, p = 0.046). In contrast, TRG did not correlate with ΔSUV-MAX. The changes in FGD-uptake predicted accurately the achievement of pCR: only patients with a decrease of more than 32% in SUV-MAX had pCR while none of those whose tumors did not show any decrease in SUV-MAX had pCR.ConclusionsA decrease in ΔSUV-MAX after only one week of RCT for LARC may be able to predict the achievement of pCR in the post-RCT surgical specimen. Validation in a larger independent cohort is planned.

Radiation rescue for biochemical failure after surgery for prostate cancer: predictive parameters and an assessment of contemporary predictive models.

Objectives:To determine pretreatment prognostic variables that predict outcome of radiotherapy for biochemical failure after prostate cancer surgery and evaluate contemporary clinical decision tools for patient selection. Methods:Fifty patients were identified with failure after rescue radiation was defined as a confirmed rise in PSA, distant metastases, prostate cancer death, or initiation of hormonal therapy. Univariate analysis and multivariate Cox models were constructed. Outcome was compared with decision tree and recursive partitioning predictive models. Results:The median preradiation PSA (pre-RT PSA) was 1.2 ng/mL and the median dose of radiation was 66.6 Gy; median follow-up was 39.6 months. Overall, the estimated 3-year failure free survival was 54%, 95%CI [43,74]. Seminal vesicle involvement (SVI) (P = 0.003) and preradiation PSA Doubling Time (PSADT) <10 months (P = 0.01) were both significant predictors for treatment failure whereas pre-RT PSA was of borderline significance (P = 0.07). On multivariate analysis a pre-RT PSA of >1 and SVI were associated with hazard ratios of 6.2 and 7.3 (P = 0.01 and P = 0.004), respectively. An additional Cox model constructed for 31 patients for whom pre-RT PSADT could be calculated showed PSADT and SVI to be independent prognostic parameters. Two predictive models, a decision tree analysis, and a recursive partitioning model were moderately accurate in predicting outcome in this series, however, high-risk patients experienced less treatment failures than predicted. Conclusions:Pre-RT PSA <1 ng/mL, longer PSADT (>10 months) and no SVI are associated with improved outcome after rescue radiation. Contemporary clinical prediction tools are imperfect predictors of outcome for rescue radiation therapy.

Gastric cancer: Biology and clinical manifestations in Israel

Gastric cancer (GC) in Israel remains incompletely characterized. The aim of this study was to define the clinical and pathological characteristics of GC in Israel and to compare them to the general Western population.

Phase II Study of Concurrent Capecitabine and External Beam Radiotherapy for Pain Control of Bone Metastases of Breast Cancer Origin

Background Pain from bone metastases of breast cancer origin is treated with localized radiation. Modulating doses and schedules has shown little efficacy in improving results. Given the synergistic therapeutic effect reported for combined systemic chemotherapy with local radiation in anal, rectal, and head and neck malignancies, we sought to evaluate the tolerability and efficacy of combined capecitabine and radiation for palliation of pain due to bone metastases from breast cancer. Methodology/Principal Findings Twenty-nine women with painful bone metastases from breast cancer were treated with external beam radiation in 10 fractions of 3 Gy, 5 fractions a week for 2 consecutive weeks. Oral capecitabine 700 mg/m2 twice daily was administered throughout radiation therapy. Rates of complete response, defined as a score of 0 on a 10-point pain scale and no increase in analgesic consumption, were 14% at 1 week, 38% at 2 weeks, 52% at 4 weeks, 52% at 8 weeks, and 48% at 12 weeks. Corresponding rates of partial response, defined as a reduction of at least 2 points in pain score without an increase in analgesics consumption, were 31%, 38%, 28%, 34% and 38%. The overall response rate (complete and partial) at 12 weeks was 86%. Side effects were of mild intensity (grade I or II) and included nausea (38% of patients), weakness (24%), diarrhea (24%), mucositis (10%), and hand and foot syndrome (7%). Conclusions/Significance External beam radiation with concurrent capecitabine is safe and tolerable for the treatment of pain from bone metastases of breast cancer origin. The overall and complete response rates in our study are unusually high compared to those reported for radiation alone. Further evaluation of this approach, in a randomized study, is warranted. Trial Registration ClinicalTrials.gov NCT01784393NCT01784393

Octogenarian patients with colorectal cancer: Characterizing an emerging clinical entity

AIM To characterize colorectal cancer (CRC) in octogenarians as compared with younger patients. METHODS A single-center, retrospective cohort study which included patients diagnosed with CRC at the age of 80 years or older between 2008-2013. A control group included consecutive patients younger than 80 years diagnosed with CRC during the same period. Clinicopathological characteristics, treatment and outcome were compared between the groups. Fisher’s exact test was used for dichotomous variables and χ2 was used for variables with more than two categories. Overall survival was assessed by Kaplan-Meier survival analysis, with the log-rank test. Cancer specific survival (CSS) and disease-free survival were assessed by the Cox proportional hazards model, with the Fine and Gray correction for non-cancer death as a competing risk. RESULTS The study included 350 patients, 175 patients in each group. Median follow-up was 40.2 mo (range 1.8-97.5). Several significant differences were noted. Octogenarians had a higher proportion of Ashkenazi ethnicity (64.8% vs 47.9%, P < 0.001), a higher rate of personal history of other malignancies (22.4% vs 13.7%, P = 0.035) and lower rates of family history of any cancer (36.6% vs 64.6%, P < 0.001) and family history of CRC (14.4% vs 27.3%, P = 0.006). CRC diagnosis by screening was less frequent in octogenarians (5.7% vs 20%, P < 0.001) and presentation with performance status (PS) of 0-1 was less common in octogenarians (71% vs 93.9%, P < 0.001). Octogenarians were more likely to have tumors located in the right colon (45.7% vs 34.3%, P = 0.029) and had a lower prevalence of well differentiated histology (10.4% vs 19.3%, P = 0.025). They received less treatment and treatment was less aggressive, both in patients with metastatic and non-metastatic disease, regardless of PS. Their 5-year CSS was worse (63.4% vs 77.6%, P = 0.009), both for metastatic (21% vs 43%, P = 0.03) and for non-metastatic disease (76% vs 88%, P = 0.028). CONCLUSION Octogenarians presented with several distinct characteristics and had worse outcome. Further research is warranted to better define this growing population.

A Phase Ib/II Study Evaluating the Combination of Weekly Docetaxel and Cisplatin Together with Capecitabine and Bevacizumab in Patients with Advanced Esophago-Gastric Cancer

Introduction Current treatment options for advanced esophagogastric cancer (AEGC) are still unsatisfactory. The aim of this prospective phase Ib/II study was to evaluate the safety and efficacy of a novel regimen, AVDCX, consisting of weekly docetaxel and cisplatin together with capecitabine and bevacizumab, in AEGC. Methods Patients with AEGC received treatment with different dose levels of AVDCX (cisplatin and docetaxel 25–35 mg/m2, days 1,8, capecitabine 1,600 mg/m2 days 1–14, bevacizumab 7.5 mg/kg, day 1, Q:21 days). The studys primary objectives were to establish the recommended phase II doses of docetaxel and cisplatin in AVDCX (phase Ib part) and to determine the tumor response rate (phase II part). Results The study was closed early, after the accrual of 22 patients, due to accumulating toxicity-related deaths. The median age was 59 years and 77% of patients had gastric or gastroesophageal adenocarcinomas. Grade ≥3 adverse events were documented in 18 patients (82%), usually neutropenia (36%), fatigue (54%) or diarrhea (23%). There were three fatal toxicities (14%): mesenteric thromboembolism, gastric perforation and pancytopenic sepsis. The recommended phase II doses of cisplatin and docetaxel were determined to be 25 mg/m2 and 30 mg/m2, respectively. Twenty-one patients were evaluable for response: 12 (54%) had partial response (PR), 4 (18%) had stable disease (SD) and none had complete response (CR). Hence, the objective response rate (CR+PR) was 54% and the disease control rate (CR+PR+SD) was 72%. For the 17 patients treated at the MTD, the objective response rate was 41% and the disease control rate was 88%. The median overall survival (OS) for these patients was 13.9 months (range, 1.5–52.2 months) and the median progression-free survival was 7.6 months (range, 1.3–26.6 months). The 2-year OS rate reached 23.7%. Conclusions AVDCX was associated with a high rate of regimen related fatal adverse events and is not appropriate for further development in AEGC patients. Trial Registration ClinicalTrials.gov NCT00845884,

Molecular Predictors of Response to Neoadjuvant Chemoradiation for Rectal Cancer.

Objectives: To determine whether the expression of specific molecular markers in the rectal cancer biopsies prior to treatment, can correlate with complete tumor response to chemoradiotherapy (CRT) as determined by the pathology of the surgical specimen. Methods: We retrospectively examined pretreatment rectal biopsies of patients aged 18 years or older with locally advanced rectal cancer who had been treated with neoadjuvant CRT and surgical resection in our tertiary-care, university-affiliated medical center, between January 2001 and December 2011. Samples were analyzed for expression of B-cell lymphoma 2, P53, Ki67, epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor, and the tumor regression grade after CRT and radical surgery. Results: Forty-seven patients were included in the final analysis. Main outcome measures were the correlation between the expression of the molecular markers tested in the pretreatment biopsy, and complete tumor response. Complete pathologic response after CRT was attained in 27% of the patients. Percentage of cells expressing EGFR in the pretreated biopsies of patients having complete pathologic response after CRT and surgery was 33.08±7.87% compared to 19±15.36% (P=0.38), 6.66±2.83% (P<0.003), and 12.5±4.93% (P=0.033) in patients with partial response and tumor regression grades of 2, 3, and 4, respectively. The other molecular markers tested in the pretreatment biopsy did not corresponded with complete pathologic response. Conclusions: EGFR expression pattern in the pretreatment biopsies of rectal tumors can assist in identifying patients who will benefit from neoadjuvant CRT.

Early PET-CT in patients with pathological stage III colon cancer may improve their outcome: Results from a large retrospective study

Current staging of pathological stage III colon cancer (CC) is suboptimal; many patients recur despite unremarkable preoperative staging. We previously reported that early postoperative PET‐CT can alter the stage and management of up to 15% of patients with high‐risk stage III CC. This study aimed to determine the role of the test in the general stage III CC population.