tbuckley/cabot-search huggingface dataset:
Specific increase in T-cell potency via structure-based design of a T-cell receptor for adoptive immunotherapy.
Authors: Karolina Malecek, Arsen Grigoryan, Shi Zhong, Wei Jun Gu, Laura A. Johnson, Steven A. Rosenberg, Timothy Cardozo, Michelle Krogsgaard
Journal: Journal of Clinical Oncology (2014)

3063 Background: Adoptive immunotherapy with antigen-specific T lymphocytes is a powerful strategy for cancer treatment. However, most tumor antigens are non-reactive “self” proteins, which presents an immunotherapy design challenge. Studies have shown that tumor-specific T cell receptors (TCRs) can be transduced into normal peripheral blood lymphocytes, which persist after transfer in about 30% of patients and effectively destroy tumor cells. Still, recent clinical trial with affinity-enhanced TCRs has resulted in severe effects due to cross reactivity to an unrelated peptide. Thus, the challenge for targeted T cell therapy remains to increase T-cell potency in order to improve clinical responses and ensure on-target specificity by avoiding unwanted cross reactivity. Methods: We used structure based design to predict point mutations of a TCR (DMF5) that enhance its binding affinity for an agonist tumor differentiation antigen-major histocompatibility complex (pMHC), Mart-1(27L) HLA-A2, which elicits full T cell activation to trigger immune responses. Structural based approaches have been used to increase TCR affinity, however their potential cross-reactivity has not been reported. Here, we analyzed the effects of selected TCR point mutations alone and in combination on T cell activation potency. Further, we analyzed their specificity and cross-reactivity with related antigens presented by different melanoma cell lines and donor-derived antigen presenting cells. Results: Our structure-based approach allowed us to rationally design sequence substitutions that improve binding in contact areas between the TCR and pMHC without increasing cross-reactivity with a wide variety of self-antigens. We identified and evaluated point mutations in critical TCR positions resulting in more potent T cell activation but maintaining overall specificity. When double and triple combination mutations were introduced, they exhibited an additive enhancement that further improved T cell activation while retaining a high degree of specificity. Conclusions: Such affinity-optimized TCRs could potentially be used in adoptive immunotherapy to treat melanoma while avoiding adverse autoimmunity effects.
Inequities in Pap smear screening for cervical cancer between Brazilian urban and rural populations.
Authors: Jeovany Martínez-Mesa, Gustavo Werutsky, Carlos Alberto Sampaio-Filho, Aknar Calabrich, Carlos H. Barrios
Journal: Journal of Clinical Oncology (2013)

e12510 Background: Cervical cancer (CC) represents an important public health problem in Brazil being the second most common cancer in women. The expected incidence rate in 2012 was 17.5 per 100,000 women while the age-standardized mortality rate in 2010 was 4.04 per 100,000 women. Inequities in access to health preventive programs contribute to this figure. The goal of this analysis is to identify inequities in Pap smear screening in women from urban and rural populations from Brazil. Methods: Using the Health Supplement of the National Household Sample Survey 2008 (PNAD) with 102,108 Brazilian women aged 25-64 years Pap smear screening was analyzed dichotomously as women having ever or never been screened. Residence area was categorized as urban or rural. Age-adjusted prevalence of never-screened was analyzed using chi-squared test. Poisson regression modeling, crude and full adjusted for age, income, number of children, education, skin color, having visited a physician in the previous 12 months and healthcare insurance were performed for Brazil in general and for Brazilian major regions. Results: The prevalence of never-screened women for CC was 12.9% in Brazil, 11.5% in urban and 22.2% in rural areas. The poorest Brazilian major-regions showed the highest prevalence of never-screened women: North (17.4% in general, 14.7% in urban and 27.3% in rural areas) and Northeast (14.7% in general, 12.8% in urban and 23.7% in rural areas). After full-adjustment, the rural population showed a higher relative risk for never-screened as compared to those living in urban areas [PR=1.23 (95%CI 1.14; 1.31); p&lt;0,001]. The highest risk was also found in the North [PR=1.39 (1.13; 1.31); p=0.002]. However, South and Central-west regions showed no association between never-screened and area [PR=1.06 (0.88; 1.28); p=0.541; PR=1.18 (0.87; 1.58); p=0.270, respectively]. Conclusions: Our findings point out inequities in Pap smear screening between Brazilian urban and rural population. These inequities possibly contribute to the high incidence and mortality rate of CC in Brazil.
Trabectedin in pretreated pediatric patients with relapsed or progressive advanced sarcomas: Toxicity and efficacy.
Authors: Miguel Angel Palomo Colli, Aurora Medina Sanson, Pablo Lezama -Valle, Stanislaw Sadowinski Pine, Heynar Pérez Villanueva
Journal: Journal of Clinical Oncology (2012)

e20005 Background: Patients with advanced or metastatic soft tissue and bone sarcomas whose disease progresses after standard chemotherapy (CT) have few options and limited life expectancy. Trabectedin, an alkaloid derived from the sea squirt Ecteinascidia turbinate, has proven activity against some soft tissue (STS) and bone sarcomas. In pediatric patients there is limited information about its efficacy and toxicity profile. Purpose: To describe the toxicity and efficacy of trabectedin in a group of relapsed/refractory pediatric sarcomas. Methods: From January 2009 to December 2011, four relapsed/refractory pediatric sarcoma patients were treated with trabectedin in the Hospital Infantil de Mexico Federico Gomez. Trabectedin was administered as a 24-hour IV infusion every 21 days. Dose levels were 1.3-1.5 mg/m 2 . All received dexamethasone premedication. Grade 3-4 toxicity was evaluated according to the NCI criteria. Results: Diagnoses included a metastatic Ewing sarcoma, a triton tumor (TT), a metastatic alveolar soft tissue sarcoma and a phylodes sarcoma. All had previously failed to 2 or 3 CT regimens. In 3 patients radiotherapy had also been used and multiple surgical procedures were performed to treat recurrences, before trabectedin. A total of 13 courses of trabectedin were administered. Nausea/vomiting and fatigue were seen in 61.5% of the courses. Laboratory abnormalities included anemia (30.6%), neutropenia (15.3%), ALT (15.3%), AST (15.3%) and GGT (7.7%) elevations and lipasemia/amilasemia (7.7%). One patient presented significant transaminasemia, pancreatitis (probably steroid-related) and died after the first course due to IDC. The TT case, who had a massive unresectable lesion, exhibited a significant response, although her tumor progressed after 4 cycles and eventually died; none of the other patients responded to trabectedin. Conclusions: Trabectedin was generally well tolerated; however we faced a fatal event that might be not trabectedin related. The response observed in the TT case is an interesting finding considering the poor CT response of this aggressive tumor.
Prospective Multicenter Study for Evaluating Cognitive Disorders in Hematology-Oncology: A Pilot Study of 118 Patients
Authors: Jean François Rossi, Laurence Laurier, Jean-Louis Misset, Dominique Spaeth, F. Uwer, Pierre Soubeyran, Remy Largiller, Jean-Philippe Metges, Jean- Yves Blay, Michel Attal, Thierry Facon, Olivier Hermine, Roland Bugat, Jean-Philippe Spano, Laurent Cals, Hervé Cure, Dan Atlan, Mario Gjoklaj
Journal: Blood (2008)
Impact of adjuvant temozolomide and IDH mutation status among patients with anaplastic astrocytoma.
Authors: Sani Haider Kizilbash, Caterina Giannini, Jesse S Voss, Paul A. Decker, Robert B. Jenkins, Nadia N. Laack, Ian F Parney, Joon H. Uhm, Jan C. Buckner
Journal: Journal of Clinical Oncology (2013)

2025 Background: Although adjuvant radiation has demonstrated a clear survival benefit in anaplastic astrocytomas (AA), the role of concurrent temozolomide (TMZ) remains controversial. Methods: All adult patients diagnosed with AA from 2001 to 2011 and treated with standard doses of adjuvant radiation were identified retrospectively using the neuro-oncology database at the Mayo Clinic (Rochester, MN). Clinical data was extracted from the electronic medical record. IDH mutation status was also determined by obtaining either IDH1R132H immunostain on existing unstained slides or paraffin block sections, or by sequencing. Cumulative survival probabilities were estimated using the Kaplan-Meier method. Univariable and multivariable Cox proportional hazards regression models were fit to compare patients who did/did not receive TMZ. Results: 218 patients were identified that met inclusion criteria. 34 patients were excluded due to missing data on adjuvant chemotherapy. 146 patients had received adjuvant TMZ while 38 had not. Of these, IDH mutation status was determined on 124 patients who received TMZ and 33 of those who had not. The median duration of follow up was 36.4 months. On univariable analysis, adjuvant TMZ demonstrated a trend towards improved median survival from 35.2 to 53.1 months (p=0.06). As an independent variable, patients with IDH mutations had longer median survivals (111.7 months) when compared to IDH wild-type patients (23.3 months) (p&lt;0.001). On multivariable analysis, five-year-survival was significantly impacted by receipt of adjuvant TMZ (HR = 0.56, p=0.03) and IDH mutation status remained a significant prognostic factor (HR = 0.19, p &lt; 0.001) (see Table). Conclusions: IDH mutation strongly predicts a favorable outcome in patients with AA. Secondarily, concurrent TMZ is also associated with improved survival in patients with AA who are receiving adjuvant radiotherapy. [Table: see text]
Impact of sequencing weekly paclitaxel (T) and dose-dense doxorubicin/cyclophosphamide (DDAC) on tolerability and relative dose intensity (RDI) in breast cancer (BC) patients (pts) receiving neoadjuvant chemotherapy (NAC).
Authors: Nicholas Martin LeCroy, Irene Borrero, Dina Bernie Dumercy, Evelio Velis, Alejandra T. Perez, Michel Velez, Aruna Mani, Aurelio Bartolome Castrellon, Carla Hawkins Locke, Cynthia Frankel, Candice Sareli, Carmen Julia Calfa
Journal: Journal of Clinical Oncology (2015)

1048 Background: A preferred NAC regimen for HER2-negative BC is DDAC for 4 cycles followed by 12 weeks of T. RDI of 1 indicates that all intended doses are given at the scheduled interval. While large randomized studies are lacking, few studies indicated improved pCR and/or RDI when taxanes are given first. We hypothesize that tolerability and RDI are improved when T is given before DDAC. To our knowledge, this is the first study evaluating the impact of sequence on tolerability and RDI when using DDAC/weekly T. Methods: This IRB-approved, retrospective chart review included pts with stage II-III HER2-negative BC who received DDAC/weekly T NAC at our institution between August 2012 and May 2014. The sequence was based on physician preference. Conventional sequence group (CS) included pts who received weekly T after DDAC; reverse sequence group (RS) received T before DDAC. Our primary outcomes were rate of pCR and tolerability/RDI. Results: We identified 27 pts in CS and 29 pts in RS. No statistical differences between groups with respect to age, ethnicity or tumor characteristics (ER, PR, Ki67) were found. The RS had numerically more pts with stage III (p = 0.054). The table lists results relevant to the primary objectives. Conclusions: T before DDAC was associated with more pts tolerating the T maximum dose intensity (T-RDI = 1) without compromising DDAC-RDI or pCR. More pts experienced a T dose reduction (T-DR) in CS. The difference in tolerability of T cannot be explained by a specific toxicity but rather by a multitude of complications observed in CS. The most common reason for decreased T-RDI was peripheral neuropathy (PN) in both groups. Interestingly, significantly more pts in CS required pharmacologic intervention (Rx) for PN. Our study confirms the findings of others with respect to administering taxanes before antracyclines and provides specific evidence to support sequencing weekly T before DDAC. Outcome, # (%) CS (N = 27) RS (N = 29) p T-RDI = 1 11 (40.7) 20 (69) 0.034 DDAC-RDI = 1 22 (81.5) 21 (72.4) 0.422 T-DR 11 (40.7) 5 (17.2) 0.049 pCR 5 (18.5) 5 (17.2) 0.587 Rx for PN 16 (59.3) 9 (31) 0.034
A cross sectional retrospective study regarding patients and their physician willingness to wait for driver mutation report in NSCLC.
Authors: Vijay Maruti Patil, Vanita Noronha, Amit Joshi, Joydeep Ghosh, Atanu Bhattacharjee, Kumar Prabhash
Journal: Journal of Clinical Oncology (2015)

e17532 Background: Palliative chemotherapy or targeted therapy in accordance with mutation profile is the norm in NSCLC. However in certain situations patients or physicians are unwilling to wait for the mutation report .The objective of this audit was to determine the proportion of patients and their physicians refusing to wait for the mutation report prior to starting treatment and the reasons for the same. Methods: We maintain a database of newly registered NSCLC patients undergoing palliative intent treatment. In this database from september 2014, we routinely started documenting the patients and physicians willingness for waiting for treatment, till availability of mutation report and the reason for it.The relationship between patient willingness to wait and objective factors was explored. by Fisher's exact test . The factors considered were ECOG PS and presence of symptoms. The agreement between patients decision and physician decision was tested by contingency table. Results: Out of 168 patients,111 patients (66.1%) were willing to wait for biopsy report while 57 (33.9% 95% CI 27.2%-41.4%) were not. The reasons provided by patients for their unwillingness to wait were logistics,symptomatic status, poor general condition and unwilling for repeat biopsy in 14 (24.6%), 23 (40.1%), 19 (33.3%) and 01 (2.0%) patients respectively.The proportion of patient unwilling to wait were 33.0%, 23.5%,35.7%,61.1% and 50.0% in ECOG PS 0,1,2,3 and 4 status respectively(p = 0.0001).No other factor among the tested factors was associated with patients decision. Out of 168 patients,in 112 patients (66.6%) physicians were willing to wait for mutation report while in 56 patients (33.4% 95% CI 26.6%-40.7%) they were not. Among the tested factors physician unwillingness to wait for mutation report was affected by presence of poor ECOG PS (p = 0.000), presence of breathlessness(p = 0.000) and fatigue(p = 0.000).The estimated percentage corrected value of contingency between patients and physician decision was 78.74%. Conclusions: ⅓ of our patients are unwilling to wait and poor control of symptoms seem to be the predominant cause.There was a good level of agreement between patients and physicians decision.
A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: A trial of the ECOG-ACRIN Cancer Research Group (E2211).
Authors: Pamela L. Kunz, Paul J. Catalano, Halla Sayed Nimeiri, George A. Fisher, Teri A. Longacre, Iris Schrijver, Diane Lauren Reidy, Jonathan R. Strosberg, Peter J. O'Dwyer, Al Bowen Benson
Journal: Journal of Clinical Oncology (2015)

TPS4145 Background: Patients with advanced pancreatic neuroendocrine tumors (NETs) have few treatment options that yield objective radiographic tumor regression. Somatostatin analogues and biologics yield prolonged progression-free survival (PFS) but minimal overall response rates (RRs). Historical studies reporting the highest RRs and longest PFS intervals include regimens with cytotoxic chemotherapy, such as streptozocin. Recent retrospective and small, prospective studies, suggest that temozolomide is similarly active but less toxic than streptozocin-based therapy. The proposed study will provide prospective data on response rates and progression-free survival associated with temozolomide or temozolomide in combination with capecitabine, and will also assess the relative efficacy of these two regimens. Methods: E2211 is a two-arm, multi-center, randomized phase II trial comparing temozolomide (200 mg/m2 PO QD days 1-5) vs. capecitabine (750 mg/m2 PO BID days 1-14) and temozolomide (200 mg/m2 PO QD days 10-14) in patients with advanced pancreatic NETs. Eligibility criteria include: metastatic or unresectable, low or intermediate grade pancreatic NETs, progression within preceeding 12 months, and no prior temozolomide, DTIC, capecitabine, or 5-FU therapy. Primary endpoint is PFS; secondary endpoints are Overall Survival (OS), RR, safety, and MGMT status as evaluated by immunohistochemistry and promoter methylation status. This study will require a minimum of 138 patients (or a maximum of 145 patients to allow for 5% ineligibility) to be accrued at the rate of 6 patients per month. With 23 months of accrual time and 13 months of follow-up (3 years total study time), this trial will have at least 81% power to detect a difference in median PFS between the treatment arms of 9 versus 14 months (hazard ratio of 0.64) using a two-sided log-rank test at the overall 0.20 significance level. First patient entered onto the study in August 2013. As of January 2015 a total of 67 (46% of target) patients have been recruited. Clinical trial information: NCT01824875. Clinical trial information: NCT01824875.
Long-term follow-up of bone marrow micrometastases in colon cancer patients.
Authors: Carsten T. Viehl, Ulrich Guller, Michaela Ramser, Salome Dell-Kuster, Benjamin Weixler, Guido Sauter, Luigi Terracciano, Rachel Rosenthal, Daniel Oertli, Markus Zuber
Journal: Journal of Clinical Oncology (2015)

3529 Background: There is suggestive evidence from investigations with short follow-up that bone marrow (BM) micrometastases are a poor prognostic factor in colorectal cancer patients. The objective of the present prospective study was to evaluate the long-term prognosis of bone marrow micrometastases (BMM) in a large cohort of colon cancer patients. Methods: Overall, 144 stage I-III colon cancer patients underwent BM aspirations from both iliac crests prior to open oncologic colon resections. The BM aspirates were stained with the pancytokeratin antibody A45-B/B3, and analyzed for the presence of epithelial tumor cells by an automated cellular imaging system and by visual verification by a pathologist. Overall (OS) and disease-free survival (DFS) were analyzed by Cox proportional hazard regression analyses. Results: Median age was 74 years, 47% of patients were female. BMM were found in 55 patients (38%). Median follow-up was 74 months (87 months for patients who survived) with no loss to follow-up. Overall, 30 patients (21%) had a recurrence and 56 patients (39%) died. In univariate analyses, BMM-positive patients had a significantly worse OS (hazard ratio [HR] 0.61; 95% confidence interval [95%CI] 0.50,0.74; p < 0.001) and DFS (HR 0.61; 95%CI 0.57,0.65; p < 0.001) compared to BMM-negative patients. In multivariable analyses, the presence of BMM remained an independent prognostic factor for OS and DFS (table). Conclusions: The presence of BMM is a frequent phenomenon occurring in over one third of stage I-III colon cancer patients. The present prospective cohort study provides compelling evidence that BMM represent a significant, independent prognostic factor for DFS and OS in colon cancer patients even with long-term follow-up. The use of adjuvant chemotherapy in node negative patients with BMM may be justified. Clinical trial information: NCT00826579.Multivariable analysis. OS DFS HR (95%CI) p-value HR (95%CI) p-value BM negative vs positive 0.69 (0.59, 0.80) <0.001 0.69 (0.65, 0.72) <0.001 Age (per 10 years increase) 2.02 (1.73, 2.35) < 0.001 1.73 (1.58, 1.89) < 0.001 Male vs female 1.16 (0.79, 1.71) 0.440 1.33 (1.01, 1.75) 0.044 T stage (T1/2 vs T3/4) 1.34 (0.55, 3.28) 0.519 1.18 (0.57, 2.41) 0.658 Nodal status (N0 vs N+) 0.48 (0.39, 0.59) < 0.001 0.52 (0.42, 0.66) < 0.001
Contemporary incidence and epidemiologic trends of brain metastases at renal cell carcinoma diagnosis.
Authors: Maxine Sun, Guillermo de Velasco, Priscilla Kaliopi Brastianos, Raphael Brandao Moreira, Paul L. Nguyen, Quoc-Dien Trinh, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2017)

529 Background: The incidence of brain metastases (BM) in patients with renal cell carcinoma (RCC) is hypothesized to have increased in the last two decades.Our objective was to provide an overview of recent incidence trends in patients with primary renal cell carcinoma (RCC) and BM at diagnosis using a nationally representative cancer cohort originating from the US. Secondary objectives include developing a tool for prediction of BM at diagnosis and to assess their oncological outcomes, and externally validating it in second database. Methods: All patients with a primary diagnostic confirmation of RCC within the Surveillance, Epidemiology, and End Results (SEER, 2010–2013) database and the National Cancer Database (NCDB, 2010–2012) were abstracted. The incidence proportions (% IP) and 95% confidence intervals (CI) of BM were calculated. A 1000-bootstrap corrected multivariable logistic regression models was developed for prediction of BM at diagnosis using the SEER cohort. Backward variable selection was conducted to identify the most parsimonious model. Model performance was evaluated via measures of predictive accuracy in the NCDB cohort. Results: The overall % IP of BM at RCC diagnosis was 1.51% (95% CI: 1.39–1.64) in the SEER and 1.37% (95% CI: 1.29–1.45%) in the NCDB. The odds of harbouring BM at RCC diagnosis varied significantly according to sociodemographic and clinical characteristics. Following backward variable selection within the SEER database, only histology, tumor size, and cN stages were retained in the final model. Predictive accuracy was adequate in the external validation cohort (C-statistic: 0.778). Median time to any death was 6.37 months in patients with BM. After adjusting for confounders, patients with BM were more likely to succumb to any death than those without BM at diagnosis (hazard ratio: 1.87, 95% CI: 1.71–2.05, p&lt;0.001). Conclusions: The incidence of BM in patients with RCC is increasing. The oncological outcomes of such patients remain poor and their treatment management variable. A clinical risk model can predict the presence of BM at diagnosis and may justify baseline imaging in asymptomatic but high-risk patients.