tbuckley/cabot-search huggingface dataset:
Variable penetrance of CDH1 mutation diffuse gastric cancer: A genomic analysis.
Authors: David Paul Kelsen, Kasmintan A. Schrader, Raya Khanin, Laura H. Tang, Erin E. Salo-Mullen, Kenneth Offit, Vijai Joseph, Agnes Viale, Markenya Mirander, Daniel G. Coit, Vivian E. Strong, Yelena Yuriy Janjigian, David H. Ilson, Manish A. Shah
Journal: Journal of Clinical Oncology (2013)

4082 Background: CDH1 encodes E-cadherin; mutations (CDH1mut) increase the risk of diffuse gastric (DGC) and lobular breast cancers. Life-time risk of DGC is estimated at 80%. Current recommendations are prophylactic gastrectomy (PG) in CDH1mut carriers after age 20. Foci of DGC are found in some PG; others have none at PG, and some CDH1mut without PG never develop cancer. Identifying risk modifying alleles or other genomic events which increase the risk of DGC may improve understanding of DGC and may provide a biomarker for when to perform PG. Methods: For a Gastric Cancer Registry, we collected family pedigrees, germline DNA and FFPE tumor from CDH1mut DGC patients (pts) and their families. From 24 families, with 52 CDH1mut individuals, we identified 4 families in which a young CDH1mut pt developed advanced DGC while their CDH1mut parent and siblings had no clinical evidence of DGC. Several relatives had undergone PG with no DGC found. We hypothesize that there are risk modifying alleles and/or a “second hit” that causes variable penetrance and early onset of DGC in the young CDH1mut pts. Whole genome sequencing was performed on germ line DNA (Complete Genomics, Inc. Mountain View, CA); and whole exome sequencing on tumor specimens (MSKCC). Results: To date, 4 DGC pts and 8 relatives from 4 families have been studied. All 4 affected pts were women (ages 17, 25, 27, 42); their unaffected CDH1mut parents were 41, 51, 54, and 70 years old. The families are of Kenyan, Scandinavian, Italian, Eastern European, and Scottish origin. CDH1 mutations for the pts and their families were confirmed on WGS, and were as follows: 1451C&gt;A(pro484his);c. 1792C&gt;T (arg598ter);c. 1893dupA in exon 12;c. 1565+1G&gt;A (IVS10+1G&gt;A). Analysis of germline DNA for modifying alleles is being performed (Ingenuity Systems, Redwood, Ca.); whole exome sequencing of tumor to identify a possible "second hit" is underway. These data will be presented. Conclusions: Since at least some older pts with proven CDH-1mut do not develop DGC while their children do, CGH-1mut alone may not be sufficient to cause early onset DGC. We hope to identify the additional genomic events associated with early onset advanced DGC. Supported in part by grants from the Gerstner and DeGregorio Foundations.
Phase I study cohort evaluating an optimized administration schedule of SAR3419, an anti-CD19 DM4-loaded antibody drug conjugate (ADC), in patients (pts) with CD19 positive relapsed/refractory b-cell non-Hodgkin’s lymphoma (NCT00796731).
Authors: Bertrand Coiffier, Franck Morschhauser, Jehan Dupuis, Corinne Haioun, Fabrice Laine, Roch Houot, Herve Tilly, Oana Brehar, John M. Lambert, Nathalie Fagniez, Sandrine Payrard, Vincent Ribrag
Journal: Journal of Clinical Oncology (2012)

8057 Background: The recommended dose (RD) of SAR3419 administered intravenously every 3 weeks (q3w) for 6 cycles is 160 mg/m2 and is 55 mg/m2 when administered weekly (q1w) for 8-12 doses. Reversible corneal deposits were dose limiting (DLT) in the q3w schedule. The q1w schedule was well tolerated and active. However, based on the occurrence of late/cumulative adverse events (AE) at the RD supported by pharmacokinetic (PK) analyses showing ADC plasma accumulation after 4 weekly doses, an optimized schedule consisting of 4 weekly doses followed by 4 bi-weekly doses at the RD was tested. Methods: The q1w study was extended to treat 25 pts with the optimized schedule for 8 to 12 doses. Results: Twenty-one pts were evaluable. Main histologies were diffuse large B-cell (DLBCL) (9; 43%) and follicular (6; 29%). Median number of prior regimens was 2 [1-8], 6 pts received prior autologous transplantation and 95% of pts were Ann Arbor stage III-IV at study entry. Median number of doses received was 8 as planned with a median relative dose intensity of 1.0 [0.8-1.0]. Most frequent AEs were asthenia (1 pt with grade 3) and gastrointestinal disorders in 7 pts each. No AE fulfilled the defined DLT criteria. Reversible grade 1 blurred vision/corneal event occurred in 1 pt. Grade 3-4 haematological toxicities were minor consisting of non complicated neutropenia in 4 pts, thrombocytopenia in 2 pts and anemia in 1 pt with no transfusion support. Six (29%) pts, among them 3 with DLBCL, achieved an objective response including 3 CRu (1 in a pt refractory to last regimen). In addition, 9 (43%) pts had stable disease. Response duration was [8-35+] weeks, 5 pts still responding at the cut-off date. Conclusions: The optimized administration schedule shows an improved safety profile compared to prior tested schedules. The clinical efficacy is preserved essentially in aggressive lymphoma. The optimized schedule is being assessed in 2 phase II studies evaluating SAR3419 either as a single agent or in combination with rituximab in pts with DLBCL histology.
Breast cancer risk reduction among patients with DCIS.
Authors: Melanie R. Palomares, Michelle Banzet, Kelley Lu, Jacob Justus, Rebecca A Ottesen, Joyce C. Niland
Journal: Journal of Clinical Oncology (2012)

1562 Background: The incidence of ductal carcinoma in situ (DCIS) has dramatically increased with widespread mammographic screening. Although risk of recurrence of DCIS is low, it is associated with a higher risk for subsequent contralateral breast cancer (CBC), for which preventive measures are available. We evaluated the uptake of surgical and pharmacologic interventions to reduce CBC risk at our institution and investigated factors that may influence treatment choices for DCIS. Methods: City of Hope (COH) DCIS patients were identified using two sources, the Circulating Breast Tumor Marker (BrTM) Registry and the National Comprehensive Cancer Network (NCCN) database. Datasets were linked together, and treatment variables were cross-tabulated with patient and tumor characteristics. Results: Of 782 patients with breast malignancy diagnosed since 1997, 370 were excluded due to concurrent or prior invasive disease, 8 due to suspected misclassification based on therapies received, and 4 due to treatment on protocol. Of the remaining pure DCIS patients, treatment choices were recorded for 289. Of those, 40 (14%) chose bilateral risk reduction mastectomy (BRRM), 82 (28%) unilateral mastectomy, 165 (57%) lumpectomy, and 2 had no surgery. Hormonal therapy (HT) was recorded for 215 individuals who did not pursue BRRM: 124 (57%) took tamoxifen, 3 of whom switched to raloxifene, 5 (2%) started with raloxifene, and 7 (3%) took an unspecified hormonal agent, for a total HT uptake of 55%. This included 8 of 29 women with ER-negative DCIS who chose HT for CBC risk reduction. Younger age at diagnosis was associated with BRRM (24% of women diagnosed before age 50, 10% of those diagnosed 50-64, and 5% of women 65+ had BRRM, p&lt;0.001) and HT (59% of women &lt;65 chose HT compared to 40% of women 65+, p=0.009). Within ethnic minorities, more Asian women chose BRRM (22% vs 7% of other minorities, p=0.08). Interestingly, fewer high grade DCIS women opted for HT (39% vs 55% for low to intermediate grade, p=0.06). Conclusions: Young women tend to pursue surgical prophylaxis. Among women who keep their breasts, HT uptake was high across all age and ethnic groups, except for those older than 65 at diagnosis. It is unclear if this is due to patient choice or reflects age bias in physician recommendation.
Relationship of FAP-alpha, ADAM12, WISP1, and SOX11 expression to tumor activity in aggressive fibromatosis: Demonstration of heterogeneity within and between cases.
Authors: Benjamin Misemer, Amy Skubitz, Carlos Manivel, Stephen Schmechel, Edward Cheng, Jonathan Henriksen, Joseph Koopmeiners, Keith M. Skubitz
Journal: Journal of Clinical Oncology (2013)

10560 Background: Aggressive fibromatosis (AF) represents a group of tumors with an unpredictable clinical course and is characterized by a monoclonal proliferation of myofibroblasts. The optimal treatment for AF is unclear. In earlier gene expression studies we identified four genes, ADAM12, WISP1, SOX11, and FAP-alpha, that were uniquely overexpressed in AF compared with 16 different normal tissues. This study was designed to examine the expression of these four proteins in AF. Methods: Immunohistochemistry (IHC) was performed in 29 cases of AF, and analyzed by a pathologist with expertise in the field. Automated imaging analysis was performed to independently quantify IHC staining, nuclear size, and nuclear chromatin density. Nuclear size was determined on control slides. Slides were scanned using ScanScope XT (Aperio) and images were divided into tiled regions of interest (ROIs) for measurements. A nuclear chromatin density ratio (CDR), defined as the measure of nuclear area with light staining divided by nuclear area with dark staining, was quantified as a surrogate for nuclear activity. To compare the image analysis with pathologic examination, an operational definition of “morphologic tumor activity” (MTA) was determined by a pathologist using a scale of 1 (inactive), 2 (probably inactive), 3 (probably active), and 4 (active) on a random set of 322 ROIs. The MTA score was then correlated with the CDR. We also assessed the relationship of CDR to IHC staining intensity for each of the four proteins in ~26,000 ROIs derived from all 29 AF samples. Results: Different areas of AF cases had different degrees of MTA. The expression of the four proteins generally correlated with the areas of tumor that were pathologically more “active.” Staining was more intense in areas with larger more open nuclei suggesting “more active” regions. There was a significant correlation between MTA and log [CDR] (0.46, p&lt;0.001). Conclusions: The results confirm, on the protein expression level, our earlier gene expression results, and demonstrate the regional variation of tumor activity within and among AF cases.
Recurrent ovarian cancer and management of elderly patients: Results of a prospective trial of treosulfan focusing on patient's preference and clinical outcome (NOGGO-Preference-Study).
Authors: Radoslav Chekerov, Ioana Braicu, Philipp Harter, Stefan Fuxius, Sven Mahner, Lars Christian Hanker, Lothar Müller, Peter Klare, Georg Heinrich, Harald Leo Sommer, Christina Fotopoulou, Jalid Sehouli
Journal: Journal of Clinical Oncology (2012)

e15520 Background: There is an increasing interest in the management of elderly patients in oncology. Treosulfan is effective as oral (p.o.) and intravenous (i.v.) formultion for recurrent ovarian carcinoma. Primary aim of this study was to explore the individual preference and compliance of elderly patients (≥ 65 years) for p.o. or i.v.-treosulfan. Secondary aims were to evaluate the ADL-score, toxicity, response and survival. We present the final analysis of patient’s characteristics and treatment choice, compliance of the treatment and toxicities for 123 included patients. Methods: Patients with platinum sensitive and resistant ovarian cancer had free choice of treosulfan i.v. (7000 mg/m² d1, q28d) or p.o. (600 mg/m² d1-28, q56d) for a maximum of 12 cycles (i.v.) or 12 months (p.o.). Indecisive patients were randomized. Toxicity was evaluated according to the NCI-CTC version 2.0. Results: 123 recruited patients received therapy and were able for analysis (median age 72 years, range 65-87). 102 patients chose i.v. and 17 p.o., 3 were randomized to i.v and 1 to p.o. Median ECOG was 1 (n=0-2), and median number of prior chemotherapy-regimens was 3 (n=1-6). Most common hematological toxicities (grade 3/4) were thrombopenia (18.7%), leukopenia (15.4%) and anemia (3.6%). Most frequent non-hematological toxicities (grade 3/4) were abdominal pain (7.3%), fatigue (5.7%) and constipation (4.9%). The median progressive-free survival was 116 days, and the median overall-survival was 239 days. There was no difference in survival and activities of daily life (ADL) score between i.v. and p.o. treosulfan. Conclusions: Although heavily pre-treated most elderly patients with recurrent ovarian cancer (85%) preferred the i.v.-treosulfan administration following their individual preference. Treosulfan therapy was generally well tolerated. There were no differences in the patient’s characteristics, survival and ADL-scores in both groups.
Pattern of progression during castration with GnRH agonists (A) and rescue with GnRH antagonist degarelix (D) in patients (PTS) with metastatic prostate cancer (MPC).
Authors: Nicolo Borsellino, Mario Lo Mauro, Rosalia Nicastro, Simona Macaluso, Maria Elia Vitale, Danilo Di Trapani, Alberto Lagana', Vittorio Gebbia
Journal: Journal of Clinical Oncology (2014)

e16072 Background: For years, the treatment of MPC has been testosterone (T) suppression with A. Compared with A in 1st line, D resulted in faster PSA and T suppression, no surge or microsurges, improvement in PSA PFS. Castration resistance (CR) is defined as a progressive disease with T at castrate level, so far considered<50 ng/dL. Although modern methods have shown the median T level in surgical castrated men is 15 ng/dL, and<20 ng/dL has been recently proposed as new cut-off of efficient castration, pts with rising PSA during A, and T>20 and<50 ng/dL are considered castrate resistant, but they may still be responsive to a more efficient T ablation. Aim of this study was to evaluate PSA and T after switching from A to D pts with rising PSA and T<50 ng/dL.Methods: CR definition: 3 consecutive rises in PSA during A, despite a T<50 ng/ml. After evidence of castration resistance, we switched pts to D at dose of 240 mg, then 80 mg every month. PSA and T were measured baseline and after 3 months. PSA response: decrease >10%; PSA stabilization: rise/decrease<10%, PSA progression: rise >10%. Results: From Oct 2012, we enrolled 20 consecutive pts with MPC in progression during A and T<50 ng/dL; median age 77.5 years (65-86), median PS 1 (0-2), sites of M: bone 17, nodes 5, lung 3, local 4. Baseline T was<20 ng/dL in 7 pts (35%) and >20 and <50 ng/dL in the remaining 13 pts (65%). After 3 mos of D, T was <20 ng/dL in 17 pts (85%). In the 7 pts with baseline T< 20 ng/dL we observed 7 (100%) progression, whereas in the 13 pts with baseline T>20 and<50 ng/dL we observed 8 response, 2 stabilization and 3 progression. Overall, 10 (50%) out of 20 pts considered castrate resistant to A had a PSA control after switching to D. Conclusions: Our data confirm the most efficient T ablation and PSA control with D compared to A, also in a hard setting of pts, and suggest that D may be a better partner for continuing on castration in II line, whatever the chosen treatment (chemo- or endocrine therapy). Although T<50 ng/dL is still considered the threshold of efficient castration, pts with rising PSA during A and T between 20 and 50 ng/dL should be considered with caution because of a possible retention of sensitivity to a deeper T ablation.
Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease
Authors: Myrna R. Nahas, Robert J. Soiffer, Haesook T. Kim, Edwin P. Alyea, Jon Arnason, Robin Joyce, Joseph H. Antin, Vincent T. Ho, Dina Stroopinsky, Shuli Li, James D. Levine, Malgorzata McMasters, Salvia Jain, Ayad Hamdan, Dimitrios Tzachanis, Mary Paty Bryant, Emma K. Logan, Josie Bazemore, Jeremy Stewart, Amy Joyce, Susan Stephenson, Abigail Washington, Leandra Cole, Athalia Pyzer, Rebecca Karp Leaf, David E. Avigan, Jacalyn Rosenblatt
Journal: Blood (2018)
Growth Differentiation Factor-15 (GDF-15) Is a New Biomarker with Independent Prognostic Significance for Survival and Renal Outcomes in Different Cohorts of Patients with Light Chain (AL) Amyloidosis
Authors: Efstathios Kastritis, Giampaolo Merlini, Ioannis Papassotiriou, Paolo Milani, Evangelos Terpos, Marco Basset, Athanasios Akalestos, Francesca Russo, Erasmia Psimenou, Filia Apostoloakou, Maria Roussou, Maria Gavriatopoulou, Despina Fotiou, Dimitrios Ziogas, Constantinos Pamboucas, Elektra Papadopoulou, Meletios A Dimopoulos, Giovanni Palladini
Journal: Blood (2016)
Efficacy of the hypomethylating agents as frontline, salvage, or maintenance therapy among older adults with acute myeloid leukemia (AML).
Authors: Bernard Tawfik, Sarunas Sliesoraitis, Heidi D. Klepin, Julia Lawrence, Scott Isom, Leslie R. Ellis, Susan Lyerly, Megan Manuel, Sarah Dralle, Dmitriy P. Berenzon, Bayard L. Powell, Timothy S. Pardee
Journal: Journal of Clinical Oncology (2013)

e18002 Background: The hypomethylating agents, azacitidine and decitabine, have emerged as an alternative to initial and salvage therapy in patients with AML. Little is known about how AML responds to hypomethylating agents after standard therapy and the use of these agents in the treatment of AML is currently evolving. Methods: We retrospectively examined 76 consecutive AML patients ≥60 years old treated with hypomethylating agents at Wake Forest from 2002-2009 as either 1 st -line therapy (n=35), salvage (n=28) or consolidation (n=13). We collected data on age, gender, race, Charleston Comorbidity index (CCI), cytogenetics, type of treatment, Complete Remission (CR), Complete Remission with incomplete count recovery (CRi), and survival. Statistical analysis was performed using Kaplan-Meier estimates and cox proportional hazards models. Results: In the front line setting 11.4% of patients received azacitidine (AZA), 34.3% received 5 days of decitabine (5DD) and 54.3% received 10 days (10DD). In the salvage cohort 3.6% received AZA, 42.8% received 5DD and 53.6% received 10DD. In the consolidation cohort 18.2% received AZA and 81.8% received 5DD. Response rates (CR+CRi) were reduced in the salvage cohort compared to frontline (3.6% versus 25.7%, p=0.033). Despite the reduced response rate, overall survival in the two cohorts was similar when survival was calculated from time of hypomethylating agent (8.2 [CI 4.8-10.3] vs. 3.1 [CI 1.9-12.0] months, p = 0.2967). In the salvage cohort overall survival from the time of relapse was similar to the overall survival of those treated in 1st consolidation (18.3 [CI 15.1 -23.5] vs. 13.7 [CI 8.0 – 21.6] months, p= 0.3346). This suggests that hypomethylating agents given in first remission did not improve survival over patients who received them only after relapse. Comorbidity burden (by the CCI) showed a non-significant trend with prognosis (p= 0.0667). Conclusions: These data suggest prior cytotoxic therapy decreases marrow response rates to hypomethylating agents but not survival. Furthermore, use of hypomethylating agents for consolidation did not result in an increase in median overall survival when compared to their use in salvage.
Metformin with a carbohydrate-restricted diet in combination with platinum-based chemotherapy in advanced-stage lung adenocarcinoma.
Authors: Benjamin Philip Levy, Daniel Jacob Becker, Bilal Piperdi, Abraham Chachoua, Jorge E. Gomez, Lynn Goldstein, Mimi Kim, Michael L. Grossbard, Roman Perez-Soler
Journal: Journal of Clinical Oncology (2014)

TPS8132 Background: Metformin (MTF), an oral biguanide, has recently demonstrated preventative and therapeutic effects in both preclinical and observational clinical studies in non-small cell lung cancer (NSCLC), with minimal toxicity. MTF’s antineoplastic effects are mediated by inhibition of the “energy sensing” AMP kinase pathway (AKP) and reversal of hyperinsulinemia. Preclinical data suggest that carbohydrate restriction (CR) also inhibits cancer growth by down-regulation of the AKP as this strategy is currently being investigated in multiple tumor types (NCT01716468). In vivo studies suggest alterations in LKB1, an upstream kinase of the AKP, may predict sensitivity to MTF and is altered in up to 30% of lung adenocarcinoma. We seek to exploit the potential synergy of MTF and a CR diet on this novel pathway as a unique approach to the treatment of NSCLC. Methods: Two out of a planned 60 patients have been enrolled in this open label, single arm phase II trial. Advanced stage adenocarcinoma patients with measurable disease, ECOG < 2, and preserved organ function are included. Exclusion criteria included weight less than 80% of ideal body weight (IBW), previous use of metformin, or history of lactic acidosis. Patients are treated with carboplatin (Cb) AUC 5, pemetrexed (P) 500mg/m2 IV every three weeks followed by maintenance P until disease progression or unacceptable toxicity. MTF is initiated at 500mg bid on day 1 of chemotherapy and dose escalated in 500mg increments every 7 days to a final dose of 1,000 mg bid. Patients receive an early referral to a registered dietitian to assess daily caloric needs based on height and weight, and subsequent counseling on a CR diet (<30% of the patient’s caloric needs from carbohydrates). Patients are removed from the diet portion of the study if they lose more than 10% of their IBW. The primary endpoint of the study is PFS, and the study will be considered positive if PFS is 6.6 months, based on comparison to 4.4 months in historic controls. Secondary objectives include correlation of archival tissue LKB1 mutations assessed by next generation sequencing (Ion Torrent, Integrative Oncology) and changes in serum insulin levels with clinical outcomes (ORR and PFS). Clinical trial information: NCT02019979.
Fludarabine, cyclophosphamide, and multiple-dose rituximab as frontline therapy for chronic lymphocytic leukemia.
Authors: Nicholas James Short, Michael J. Keating, William G. Wierda, Stefan Faderl, Alessandra Ferrajoli, Zeev Estrov, Susan C. Smith, Susan Mary O'Brien
Journal: Journal of Clinical Oncology (2015)

7042 Background: FCR results in durable responses in patients with previously untreated CLL. Previous reports suggest that dose-intensified rituximab increases response rates compared to standard-dose rituximab in patients with relapsed CLL. The effect of rituximab intensification of FCR in patients with previously untreated CLL is unknown. Methods: We evaluated the safety and efficacy of a modified FCR regimen with multiple-dose rituximab (FCR3) in 65 patients with previously untreated CLL. The FCR3 regimen consisted of six 28-day cycles of IV fludarabine (25 mg/m2/d) and cyclophosphamide (250 mg/m2/d) over 3 days. For cycle 1, rituximab was given at 375 mg/m2 on day 1 and at 500 mg/m2 on days 2-3. For cycles 2-6, rituximab was given at 500 mg/m2 on days 1-3. Results were compared to a historical cohort treated with FCR. Results: The overall response rate to FCR3 was 97%. Forty-eight patients (75%) achieved CR, 10 (16%) achieved nPR, 4 (6%) achieved PR, and 2 (3%) did not respond to FCR3. Response rates were not significantly different from the historical FCR cohort. The median time to progression (TTP) for patients achieving CR, nPR and PR was 86 months, 49 months and not evaluable, respectively (P = 0.14 for CR vs. nPR). MRD negativity by flow cytometry was achieved in 62% of patients. Median TTP was 81 months, which was similar to the median TTP of 84 months with FCR (P = 0.63). Median OS was not reached, with 58% of patients still alive at a median survivor follow-up of 9.7 years (P = 0.58 compared to FCR). Thirty-one (65%) of those patients who achieved CR, 6 patients (60%) who achieved nPR and 1 patient (25%) who achieved PR are still alive. Grade 3-4 neutropenia, grade 3-4 thrombocytopenia and major infection were observed with 45%, 5% and 1.9% of FCR3 courses (not significant compared to FCR). Therapy-related MDS or AML developed in 7 patients (11%) (P < 0.01 compared to FCR) at a median of 32 months and accounted for 26% of all deaths. Conclusions: In patients with previously untreated CLL, FCR3 resulted in similar response rates, TTP and OS compared to a historical cohort of patients treated with FCR. FCR3 was associated with a significantly increased incidence of therapy-related MDS/AML, which warrants further evaluation. Clinical trial information: NCT00794820.