tbuckley/cabot-search huggingface dataset:
Use of circulating endothelial cells to predict response to FOLFOX4 plus bevacizumab in metastatic colorectal cancer.
Authors: S. Matsusaka, N. Mizunuma, M. Suenaga, K. Chin, E. Shinozaki, T. Watanabe, Y. Kawazoe, Y. Kuboki, Y. Terui, K. Hatake
Journal: Journal of Clinical Oncology (2011)

427 Background: The purpose of this study was to identify CEC threshold proposal for determining response to FOLFOX4 plus bevacizumab in metastatic colorectal cancer (mCRC). Methods: All patients were enrolled using institutional review board-approved protocols at the Cancer Institute Hospital and provided informed consent. From July 2007 to June 2008, 33 patients treated with FOLFOX4 plus bevacizumab were enrolled in a prospective study. From January 2007 to June 2007, before bevacizumab was approved by the government in Japan, 31 patients treated with FOLFOX4 as a control were enrolled. The study population consisted of patients aged 18 years or older with histologically proven mCRC. Other inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate organ function. CECs of whole blood at the baseline, day 4, 2 weeks after initiation of chemotherapy were isolated and counted using immunomagnetics. Results: There was no correlation between CEC levels and the outcome in the FOLFOX4. In the FOLFOX4 plus bevacizumab, CEC levels at the baseline were significantly associated with the outcome. Patients with 65 or more CECs at the baseline had shorter median PFS (9.2 months), than the median PFS of fewer than 65 CECs at the baseline (18.9 months) in the FOLFOX4 plus bevacizumab (p = 0.003). Patients with 65 or more CECs at the baseline had shorter median OS (23.3 months), than the median OS of fewer than 65 CEC s at the baseline in the FOLFOX4 plus bevacizumab (p = 0.027). In the univariate analysis, lung metastasis, lymph node metastasis, and CEC levels at the baseline predicted PFS. In the univariate Cox regression analyses, peritoneal metastasis, CEC levels at the baseline were associated with OS. In order to evaluate the independent predictive effect of FOLFOX4 plus bevacizumab, multivariate Cox regression analysis was carried out. CEC levels at the baseline were the strongest predictor. Conclusions: A threshold of lower than 65 CEC/4mL at the baseline was a significant predictor of the outcome for colorectal cancer patients treated with FOLFOX4 plus bevacizumab. No significant financial relationships to disclose.
Frequency distribution of hepatitis C infection among patients with B-cell non-Hodgkin lymphoma in underserved minority population.
Authors: K. Adab, Y. Chongpison, A. V. Patel, M. Gaddh, T. Braik, A. Haidau, H. V. Poola, S. Nathan, M. C. Telfer, R. Catchatourian
Journal: Journal of Clinical Oncology (2011)

e18536 Background: The role of hepatitis C Virus (HCV) infection in the pathogenesis of non-Hodgkin lymphoma is not well clarified. Several studies show a variation (0% to 37%) in the prevalence of HCV infection in B-cell Non-Hodgkin Lymphoma (B-NHL) by geographical location. Mucosal-associated lymphoid tissue lymphoma (MALT) and diffuse large B-cell lymphoma (DLBCL) were reported to have the highest prevalence of HCV infection in subtype specific analysis of B-NHL in previous studies. Methods: We retrospectively studied 112 patients with histological diagnosis of B-NHL confirmed by flow cytometry and immunohistochemistry, consecutively seen from 2002 to 2007.Their clinical features and outcomes were evaluated. Results: Histopatholgy in patients with HCV was as follows: 12(67%) DLBCL, 3(16%) marginal zone lymphoma (MZL), 3(16%) Burkitt lymphoma (BL). 14(78%) patients had Stage III or IV disease, 11 (60%) had an IPI of ≥3, and 4(22%) had disease relapse. Regarding AA patients with HCV and B-NHL, the median age at diagnosis was 50 years, 6(60%) were males and 4 (40%) females. 8(80%) patients had DLBCL, 1(10%) had BL, and 1(10%) had MZL. 9 out of 10 had aggressive disease (DLBCL and BL). Conclusions: The prevalence of HCV infection in patients with B-NHL we presente is higher than previously reported in some U.S. studies. 83% of patients with B-NHL / HCV infection, and 90% of AA with B-NHL/HCV, had aggressive disease, which is significantly higher than previously reported. This linkage should be further studied, and its relationship to other healthcare disparities in underserved populations should be evaluated. Of 112 patients, 18 (16%) were HCV positive, 17 (15%) were HIV positive and 6(5%) were hepatitis B (HBV) positive. Among HCV positive patients, the median age at diagnosis was 48 years; 12 (67%) were males and 6 (33%) females. 10 (55%) were African American (AA), 4 (22%) Caucasian, 3 (16%) Hispanic and 1 (5%) was Asian. 1 (5%) patient had coinfection with HBV and 2 (11%) had coinfection with HIV. Race/ethnicity All patients HCV patients Caucasian 20 4 AA 50 10 Hispanic 35 3 Asian 5 1 Middle Eastern 2 0 Total 112 18 All types of B-NHL DLBCL MZL BL HCV patients 18 12 (67%) 3 (16%) 3 (16%)
Oxaliplatin, irinotecan, bevacizumab followed by docetaxel, bevacizumab in inoperable gastric cancer: Final efficacy results of a multicenter phase II trial (AGMT Gastric-3) of the arbeitsgemeinschaft Medikamentöse tumortherapie (AGMT).
Authors: Ewald Woell, Felix Keil, Josef Thaler, Birgit Gruenberger, Michael Hejna, Wolfgang Eisterer, Michael A. Fridrik, Franz Romeder, Richard Greil
Journal: Journal of Clinical Oncology (2013)

e15041 Background: We could show efficacy of oxaliplatin and irinotecan as well as oxaliplatin, irinotecan and cetuximab in previous trials.Time to progression however was short suggesting acquired chemotherapy resistance.To address this problem sequential chemotherapy combined with bevacizumab is investigated in the presented Gastric-3 trial. Methods: Oxaliplatin 85 mg/m 2 and irinotecan 125 mg/m 2 are administered biweekly (q2w) for the first three months followed by docetaxel 50mg/m2 q2w for subsequent three months. Chemotherapy is combined with bevacizumab 5 mg/kg q2w which is administered until progression. Primary endpoint is response rate. 40 patients (pts.) with histological proven unresectable and/or metastatic gastric adenocarcinoma treated in a first-line setting are evaluated. Median age: 62.5 years PS 0: 26 pts., PS 1: 12 pts., missing: 2 pts.,single metastatic site: 25 pts., multiple metastases: 13 pts., missing: 2. Results: Frequently reported adverse events (more than 20% of pts.) were predominantly grade 1 or 2 and included diarrhea (72.5%), nausea (65%), emesis (50%), abdominal pain (50%), fatigue (47.5%), polyneuropathy (40%), neutropenia (25%), hypokalemia (22.5%), hypertension (22.5%). Grade 3 and 4 toxicities included neutropenia (25%), diarrhea (12.5%), ileus/subileus (10%), hypokalemia (7.5%), leucopenia (7.5%), anemia (5%), meningiosis carcinomatosa (5%). Objective response rate after 3 cycles was available in 31 patients: CR 1/31 (3.2%), PR 48.4%, SD 35.5%, PD 12.9%. After 6 cycles there were 14 evaluable patients with CR 2/14 (14.3%), PR 42.9%, SD 35.7% and PD 7.1%. Median progression free survival was 32 weeks, median overall survival was53 weeks. Progression rate or death was 34/40 (85%), mortality 29/40 (72.5%). Maintenance therapy was given in 12/40 pts. (30%). Median time on maintenance therapy was 17 weeks, range (2 – 77). Conclusions: The combination of oxaliplatin and irinotecan with bevacizumab followed by docetaxel with bevacizumab is feasible and active in advanced gastric cancer. Clinical trial information: 2008-006128-79.
Phase I study of veliparib with gemcitabine and radiation therapy in patients with borderline resectable and locally advanced unresectable pancreatic cancer.
Authors: Richard Tuli, Nicholas N. Nissen, Alagappan Annamalai, David M. J. Hoffman, Miranda Bryant, Mourad Tighiouart, Andre Rogatko, Sepehr Rokhsar, Kevin S. Scher, Laith Jamil, Simon Lo, Andrew Eugene Hendifar
Journal: Journal of Clinical Oncology (2016)

TPS487 Background: Targeted inhibition of PARP1/2 is one way to further exploit the well-known synergy between gemcitabine (G) and radiotherapy (RT) in locally advanced pancreatic cancer (LAPC). PARP1/2 inhibitors, such as veliparib (V), have shown excellent anti-tumor activity when used with other cytotoxic therapies. This synergy may be further exploited in pancreatic cancer by targeting tumors with pre-existing defects in double- strand DNA repair. Extrapolating from our own laboratory findings (Tuli et al, Transl Oncol, 2014) and based on our hypothesis that PARP1/2 inhibition with G and RT will result in enhanced tumor control, we are conducting an IRB- approved phase I study in patients with borderline resectable and LAPC. Methods: The primary objective of this study is to determine the maximum tolerated dose (MTD) of V, which is defined as the dose level resulting in a probability (θ = 0.4) that a dose limiting toxicity (DLT) will occur within six weeks. Treatment cycle is 3 weeks followed by weekly evaluation for an additional 3 weeks. G (1000 mg/m2) is administered on days 1, 8, 15. RT (36 Gy) is given in 15 fractions (2.4 Gy/day). V is administered BID in 20 mg increments beginning at a dose of 20 mg. Inclusion criteria: histolopathological diagnosis of borderline resectable or LAPC, age &gt; 18 years, KPS &gt; 70%, life expectancy &gt; 6 months, normal organ and marrow function, and negative pregnancy test. Dose escalation follows a Bayesian escalation without control (EWOC) design, where time to DLT is modeled using a proportional hazards model with constant baseline hazard rate. Secondary objectives: 1) measure clinical activity using RECIST 1.1 for PFS, OS; 2) evaluate pre-treatment tumor biopsy specimen and longitudinal blood samples for baseline levels of DNA repair proteins (ERCC1, XRCC1, PAR, etc.) as potential prognostic, predictive and correlative biomarkers; and 3) assess BRCA1/2, PALB2, PTEN germline and somatic mutations using validated gene sequencing, immunohistochemical and quantitative PCR methods. Since December 2013, 26 patients have consented with 22 enrolled. Clinical trial information: NCT01908478.
Effect of neoadjuvant chemotherapy in advanced breast cancer at cellular level to identify the chemosensitivity by measuring the levels of activated Caspase-3, which is an index of activated apoptotic activity.
Authors: S. K. Branham, M. K. Voonna, R. S. Gopal, H. Kalagara
Journal: Journal of Clinical Oncology (2011)

e13535 Background: Agents that induce apoptosis in breast cancer cells have great potential to facilitate chemotherapeutic intervention and improve patient outcomes. Apoptotic execution requires activation of members of the caspase family of aspartate-specific proteases. Caspase-3 is the key in this signaling cascade. In this study its activity is detected in apoptosis by inducing chemotherapeutic agents. Methods: 80 patients within the age 18-75 years were enrolled with prior approvals from Ethics Committee and Informed Consent from patients. Neoadjuvant chemotherapy with FAC regimen is administered. Biopsy was performed in patients’ prior chemotherapy, before II cycle and at surgery/before fourth cycle. Caspase-3 activity is measured by Caspase-3/CPP32 Fluorometric Assay Kit, Pathological response by Criteria of Japanese Breast Cancer Society and Clinical Response by RECIST. Results: Confidence intervals are 95%. P-value is 0.05. Pathological grade 0 and clinical progressive disease with < 1 fold increase in Caspase-3, pathological grade 2 and 3 with ≥ 3 folds increase in Caspase-3, has the highest probability to predict chemosensitivity before II cycle. Probability of occurrence of the same response at surgery/before fourth cycle for pathological grade 0 is 66.67%, grade 2 is 70% and grade 3 is 80%. Testing significant difference in clinical response is dependent on stable disease, partial and complete response categories of RECIST. Pearson Correlation Coefficients for Caspase-3 fold increase with pathological response before II cycle of chemotherapy is 0.97 and at surgery/before fourth cycle is 0.88. With clinical response, it is 0.57 before II cycle and 0.78 at surgery/before fourth cycle. Conclusions: Patients in the group grade 0 pathologically and progressive disease clinically with < 1 fold increase in Caspase-3 are suggested for a change in chemotherapy before II cycle. The correlation between Caspase-3 fold increase and pathological response is strong and predicted more effectively than clinical response. Recommends Caspase-3 as a surrogate marker for chemosensitivity.
Myeloid-derived suppressor cells as a potential treatment target for pancreas adenocarcinoma.
Authors: M. R. Porembka, J. B. Mitchem, P. S. Goedegebuure, D. Linehan
Journal: Journal of Clinical Oncology (2011)

194 Background: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immunosuppressive cells that are upregulated in cancer. Little is known about the prevalence and importance of MDSC in pancreas adenocarcinoma (PA). Here, we quantify MDSC prevalence in patients with PA and assess the efficacy of MDSC depletion in a murine model of PA. Methods: Peripheral blood and tumor samples were collected from patients with PA, analyzed for MDSC (CD15 + 11b + ) by flow cytometry (FC) and compared to cancer-free controls (CFC). The suppressive capacity of MDSC and the effectiveness of MDSC depletion were assessed in C57BL/6 mice inoculated with Pan02, a murine PA, and treated with placebo or zoledronic acid (ZA), a potent aminobisphosphonate previously shown to target MDSC. Endpoints included tumor size, survival, and MDSC prevalence. Tumor cell infiltrate was analyzed by FC for MDSC (Gr1 + CD11b + ) and effector T cells; tumor cytokine levels were measured by Luminex assay. Results: Patients with PA demonstrated increased circulating MDSC compared to CFC, which correlated with disease stage (metastatic PA: 68%±3.6% of CD45 + cells, resectable PA: 57%±3.5%, CFC: 37%±3.6%; p&lt;0.0001). Normal pancreas tissue showed no MDSC infiltrate while PA avidly recruited CD11b + 15 + cells to the primary tumor. Murine tumors similarly recruited MDSC that actively suppressed CD8 + T cells in vitro measured by CFSE dilution and accelerated tumor growth in vivo by adoptive transfer with Pan02 cells (p&lt;0.001). Treatment with ZA impaired MDSC accumulation in the tumor (Placebo: 78%, ZA: 51%, p&lt;0.05) resulting in delayed tumor growth rate (p&lt;0.0001) and prolonged median survival (Placebo: 59 days, ZA: 73 days, p&lt;0.05). MDSC blockade increased recruitment of T cells to the tumor (CD4: 4.4%±1.1% vs 12.2%±2.0%, p&lt;0.05; CD8: 3.9%±1.3% vs 10.6%±2.2%, p&lt;0.05) and a more robust type 1 response with increased levels of IFN-g (p&lt;0.05) and decreased levels of IL-10 (p&lt;0.05). Conclusions: MDSC are an important mediator of tumor-induced immunosuppression in PA. Treatment with ZA effectively blocks MDSC accumulation improving anti-tumor response in animal studies. Efforts to block MDSC may represent a novel treatment strategy for PA. [Table: see text]
Genomic and imaging biomarkers associated with cabozantinib therapy in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Ulka N. Vaishampayan, Izabela Podgorski, Lance K. Heilbrun, Daryn W. Smith, Jawana Lawhorn-Crews, Kimberlee Dobson, Joseph A. Fontana, Elisabeth I. Heath, Anthony Frank Shields
Journal: Journal of Clinical Oncology (2016)

212 Background: Cabozantinib (C) is a c-met and vascular endothelial growth factor receptor inhibitor that demonstrated remarkable responses on bone scan, but failed to demonstrate overall survival benefit. We studied the dynamics of biomarker changes with imaging and biopsies pre- and post-therapy with C to explore predictors of efficacy. Methods: Eligibility included mCRPC patients (pts) with normal organ function and performance status 0-2. C 60 mg orally was administered daily. Pretherapy and 2 weeks post, 99m Tc-labeled bone scans (BS), positron emission tomography with 18 F-sodium fluoride (NaF-PET) and 18 F-(1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl) thymine (FMAU-PET) scans were conducted. The maximum tumor standardized uptake values (SUVmax) were measured for the 5 most active lesions in at least 3 skeletal areas with each tracer. Tumor biopsies were conducted, and bone markers were measured. Results: 20 evaluable pts, 5 African American and 15 Caucasian were enrolled. Median age was 69 years, 11 had received prior chemotherapy. 16 had received prior abiraterone/enzalutamide or both.5 pts had visceral disease. 11 and 6 pts required dose reduction to the 40 mg and 20 mg daily dose respectively.8 patients had a PSA decline, of which 2 had a decline &gt; 50%. Median PFS and OS for all 20 pts were 4.1 and 11.2 months, respectively and 3 pts were on therapy for 8, 10 and 13 months. Circulating tumor cell count changes did not correlate with PFS or OS. The NaF-PET demonstrated a median change in SUVmax of -56% (range -85 to -5%, n = 11) and -41% (range -60 to -25%, n = 9) for the pts who were clinically stable and remained on therapy for ≥ 4 or &lt; 4 cycles, respectively. The FMAU-PET demonstrated a median change in SUVmax of -44% (-60 to -14%) and -42% (-63 to -23%) for these groups. A 50% decrease in serum BSAP was associated with a hazard ratio (HR) for progression of 0.91 (90% confidence interval [CI]: 0.71 – 1.16). For serum NTx and urine NTx, the analogous HR’s were 0.79 (90% CI: 0.61 – 1.01) and 1.07 (90% CI: 0.66 – 1.73), respectively. Conclusions: Early changes in imaging and bone markers were not predictive of clinical benefit with C. Tissue C-met testing is in process and will be correlated with PFS and OS.
Long-term risk of myelodysplasia in melphalan-treated patients with immunoglobulin light chain amyloidosis
Authors: M. A. Gertz, M. Q. Lacy, J. Lust, P. R. Greipp, T. E. Witzig, R. A. Kyle
Journal: Journal of Clinical Oncology (2008)

8559 Background: With the increasing use of melphalan for plasma cell disorders, the previously known risks of treatment-induced myelodysplasia may become an increasingly important issue as long-term survival increases with the advent of novel agents. Methods: The diagnosis of myelodysplasia required bone marrow morphology consistent with dysplasia as previously defined. All patients have been previously reported in this study, this earlier report dealt only with response and survival as an endpoint. All patients were prospectively entered into a database and have been followed long-term since the time of initial study activation in August of 1991. No patients are excluded and none have been lost to follow-up. All were treated uniformly and prospectively as part of a protocol. Results: Long-term follow-up of 101 immunoglobulin light chain amyloidosis patients for a minimum of 12 years resulted in the recognition of ten patients having myelodysplasia or acute leukemia directly causing death in eight and transfusion dependency in the two survivors. Two of the patients did not develop myelodysplasia until 144 months after first exposure to alkylating agents. Although the overall risk was 10%, the actuarial risk at ten years was 18%. As the survival of patients with plasma cell disorders improves, myelodysplasia may be an increasingly common cause of morbidity and mortality in this patient group. Conclusions: In the current cohort with a minimum 12-year follow-up of survivors and none lost to follow-up, a more accurate appraisal of the risk of alkylating agents can be made. Clearly, this will not alter the management of patients with myeloma and amyloidosis but should remind clinicians to engage in the discussion of the late risks of treatment with patients so they can make a fully informed decision. Transplant remains an effective regimen with a 1% to 2% treatment-related mortality and a risk of clinical myelodysplasia of 2%. Prolonged alkylating agent exposure may result in an overall risk of 10% myelodysplasia with an actuarial risk of 18%. These late risks cannot be accurately estimated with current reports with median follow-ups in the five-year range and may precede a future ground swell in the redevelopment of this previously recognized complication. No significant financial relationships to disclose.
Comorbidity and treatment regret in men with recurrent prostate cancer.
Authors: P. L. Nguyen, M. Chen, R. C. Chen, K. E. Hoffman, J. C. Hu, C. L. Bennett, M. W. Kattan, A. O. Sartor, K. Stein, A. V. D'Amico
Journal: Journal of Clinical Oncology (2011)

187 Background: To determine whether concurrent comorbidity is associated with treatment regret among men with PSA recurrence following primary therapy for prostate cancer. Methods: Among 795 men in the Comprehensive, Observational, Multicenter, Prostate Adenocarcinoma Registry (COMPARE) study who experienced PSA failure and were assessed a median of 5.5 (interquartile range 2.8-9.1) years after prostatectomy (n=410), external beam radiation (n=237), brachytherapy (n=124), or primary androgen deprivation (n=24), multivariable logistic regression was used to determine whether comorbidity level, sociodemographic factors, and other treatment factors were associated with treatment regret, as defined by a validated two-question screen. Significant comorbidity was defined as myocardial infarction, congestive heart failure, angina, diabetes, stroke, circulation problems, inflammatory bowel disease, or amputation. Results: Of 795 men, 14.8% reportedregret. Men with significant comorbidity were more likely to experience post-therapy bowel toxicity (p=0.029) and urinary problems (p=0.051). On multivariable analysis, significant comorbidity [adjusted odds ratio (AOR)=1.57 (95% CI:1.04-2.37); p = 0.033] and younger age [AOR: 0.965 (0.937-0.994) per year increase in age; p = 0.019] were associated with increased regret even after adjusting for post-therapy bowel and urinary complications. Conclusions: In a population of men with PSA recurrence, those with significant comorbidity were particularly prone to treatment regret, which highlights the growing importance of considering comorbidity when counseling patients about prostate cancer treatment options. To properly set expectations, such men should be informed about their potential for increased post-treatment toxicity, which may reduce their risk of regret if toxicity occurs, and serious consideration should be given to active surveillance. [Table: see text]