tbuckley/cabot-search huggingface dataset:
A novel anti-GD2 monoclonal antibody (mAb), hu14.18K322A, in children with refractory or recurrent neuroblastoma: Early-phase evaluation.
Authors: F. Navid, R. C. Barfield, R. Handgretinger, P. M. Sondel, B. L. Shulkin, R. Kaufman, C. Billups, J. Wu, W. L. Furman, L. M. McGregor, M. Otto, S. Gillies, V. M. Santana
Journal: Journal of Clinical Oncology (2011)

9523 Background: Immunotherapy, including combination anti-GD2 mAb ch14.18 and cytokines, improves the outcome of patients with advanced neuroblastoma. Dose escalation of antibodies targeting GD2 antigen on neuroblastoma cells has been limited by toxicities which may be partially mediated by complement activation. Hu14.18K332A is a humanized anti-GD2 mAb with a single point mutation (K322A) reducing complement-dependent lysis. We report the preliminary results of a phase I trial to determine the maximum tolerated dose (MTD) and toxicity profile of hu14.18K322A. Methods: Cohorts of 3-6 eligible patients with refractory or recurrent neuroblastoma received a 4-hour daily IV infusion of escalating doses of hu14.18K322A (2, 4, 6, 10, 20, 40, 50, and 60 mg/m2/dose) for 4 consecutive days every 28 days (1 course). Patients were allowed to receive up to 4 courses in the absence of progressive disease or unacceptable toxicity. Results: A total of 32 patients (22 males, median age 6.5 years) received a total of 71 courses. Patients received a median of 2 courses. Dose-limiting grade 3 toxicities occurred in 2 of 29 evaluable patients and were characterized by cough and asthenia. The most common grade 3 or 4 toxicities were pain (65% of patients), fever (19%) and hyponatremia (13%). Pain was well managed and predominately occurred on the first day of course 1. Grade 1 or 2 ocular abnormalities were noted in 13 patients and appear to be dose related. No objective responses by RECIST have been observed; however, 9 patients completed the maximum of 4 courses allowed by protocol. Conclusions: Hu14.18K322A is well tolerated at the doses tested which exceed the dosages of similar GD2 mAbs used in other trials. MTD has not been defined and the study continues to accrue patients at higher doses.
Gender specific profiling in <i>SCN1A</i> polymorphisms and time to recurrence in patients with stage II/III colorectal cancer.
Authors: Leonor Benhaim, Armin Gerger, Pierre Oliver Bohanes, David Paez, Takeru Wakatsuki, Dongyun Yang, Melissa Janae Labonte, Wu Zhang, Yan Ning, Fotios Loupakis, Rita El-Khoueiry, Pierre Laurent-Puig, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2013)

393 Background: Voltage-gated Na + channels (VGSCs) are involved in cells signalling and strongly contribute in the process of tumour progression. Two single nucleotide polymorphisms (SNPs) in the SCN1A gene encoding the α-subunit of VGSC recently showed an interesting gender-related association with survival in patients with metastatic colorectal cancer (CRC). The current study was designed to confirm the association between SCN1A and time to recurrence (TTR) in patients with stage II and III CRC and determine the influence of the gender on this association. Methods: The study enrolled patients with histologically confirmed CRC high risk stage II and stage III treated from 1987 to 2007 with adjuvant 5-FU-based chemotherapy at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC) or in the Los Angeles County/USC Medical Center (LAC/USCMC). Peripheral blood samples were collected for each patient at the date of diagnosis. Genotypes were determined after DNA extraction and PCR amplification by direct sequencing. Results: A total of 127 males and 107 females were enrolled in this study. Baseline demographic and clinical characteristics according to the gender were similar. In univariate analysis female patients carrying the SCN1A rs3812718 TT genotype showed a significant shortened time to recurrence rate when compared to females with the alternate CT or CC genotype (HR: 2.26 [95%CI: 0.89, 5.70], p=0.039). This association remained significant in multivariate analysis. By contrast, in the male population, the shortened time to recurrence rate was oppositely associated with the CC genotype (HR: 0.49 [95%CI: 0.18, 1.38], p=0.048). For the SCN1A rs229877, in both female and male populations the CT genotype was associated with a trend for a shorter TTR. Conclusions: Our findings confirm that genomic SCN1A rs3812718 polymorphism is associated with TTR in patients with stage II and III CRC, supporting the hypothesis that this association is gender dependent. We furthermore verified the trend of a shorter recurrence rate for patients harboring the CT genotype in SCN1A rs229877 regardless of their gender.
Acral melanoma among the minority population in Hawaii and the Pacific basin: Analysis of downstream effectors within the PI3K pathway.
Authors: Shane Young Morita, Christopher A. Lum, James W. Davis
Journal: Journal of Clinical Oncology (2012)

e19051 Background: Acral melanoma (AM) has been described as a distinct entity in the molecular classification of melanoma. The minority population tends to be more commonly afflicted by AM. Recent studies have profiled the importance of the PI3K (phosphatidylinositol 3-kinase) cascade in melanoma biology and therapy. Both mTOR (mammalian target of rapamycin) and S6K (S6 kinase) are involved in translational control and protein synthesis. However, characterization of this pathway focusing on these pivotal components in a multi-ethnic AM population has not been reported. We elected to determine the frequency of PI3K involvement of the critical downstream effectors, mTOR and S6K. Methods: IRB approval was obtained. From 1992 to 2011, 24 non-Caucasian patients histologically confirmed to have AM were evaluated at a tertiary institution. Data including age, gender, tumor location, Breslow thickness, Clark level, ulceration and mitoses per mm squared were compiled. Immunohistochemical expression for both phosphorylated mTOR and S6K was performed on archived biospecimens (primary lesions). Both mTOR and S6K expression were graded on a scale from 0 (absent) to 2 (high). Results: Our findings demonstrated that mTOR 12/24 (50%) and S6K 20/24 (84%) were highly expressed. Demographics of the non-Caucasian cohort (17 Filipino and 7 Pacific Islanders) included mean age of 67.2 years old (range 44-89) and male gender 12/24 (50%). Tumor location principally involved the foot 20/24 (83%); mean Breslow thickness was 5.0 mm (range 1.6-11.0), Clark IV or higher 18/24 (75%), ulceration 18/24 (75%) and mean mitoses per mm squared was 8.9 (range 1-30). Conclusions: A high proportion of minority patients with AM displayed evidence of an activated PI3K pathway. Over half of our cohort had thick primary lesions with a high propensity for ulceration. This is the first study to our knowledge that has examined the downstream effectors, mTOR and S6K within the PI3K pathway in a minority population of AM patients. This is compelling data that may be applied to the metastatic phenotype in future trials and help stratify which patients will benefit from rapalogs.
Anthracycline adherence in older patients with breast cancer.
Authors: C. H. Barcenas, N. Zhang, H. Zhao, Z. Duan, G. N. Hortobagyi, S. H. Giordano
Journal: Journal of Clinical Oncology (2011)

6033 Background: Rates of anthracycline adherence in patients with breast cancer (BC) are unknown, but non-completion of chemotherapy has been associated with worse outcomes. Methods: Using the SEER-Medicare linked database, we obtained demographics, tumor characteristics, treatment and hospitalization data on stage I-III BC patients diagnosed between 1996 and 2005, age 66 or older, treated with surgery, and who had claims for anthracyclines starting within 4 months of diagnosis. Comorbidities were calculated using the Charlson index. We compared demographics (age, race, marital status, education, poverty level, geographic region), tumor data (year of diagnosis, lymph nodes, size, grade, hormone receptors), comorbid index, treatments and hospitalizations, between patients who had <4 cycles considered non-adherence (NA) cases, and those who had 4 or more cycles, by conducting both univariable and multivariable logistic regressions. Results: Of 71,150 BC patients, 7399 had claims for anthracycline, of whom 1,222 (16.5%) were NA cases. 243 (3.3%) patients only had 1 claim, 298 (4.0%) had 2 claims and 681 (9.2%) had 3 claims. Univariable analysis showed the following factors associated with NA cases: older age, black race, not married, high comorbid index, high number of hospitalizations and days, and some geographic regions. After adjusting for all other variables in the multivariable regression model, the factors that had a statistically significant association with NA were: older age (76-80 yrs), black race, not married, and two or more hospitalizations (OR=2.81, 95% CI, 2.26 – 3.50). Conclusions: In this SEER-Medicare population based study of stage I-III BC patients of age 66 years or above, older age, race, and the number of hospitalizations was associated with NA to anthracycline. Further research is needed to determine reasons for non-completion of therapy.
Improved prognostic classification of patients receiving salvage systemic therapy for advanced urothelial carcinoma.
Authors: Guru Sonpavde, Gregory Russell Pond, Jonathan E. Rosenberg, Dean F. Bajorin, Ashley Marie Regazzi, Toni K. Choueiri, Stephanie A. Mullane, Guenter Niegisch, Peter Albers, Andrea Necchi, Giuseppe di Lorenzo, Ronan Fougeray, Matt D. Galsky, Srikala S. Sridhar, Yoo-Joung Ko, Matthew I. Milowsky, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2015)

311 Background: Previously identified prognostic factors in patients (pts) receiving salvage systemic therapy for advanced urothelial carcinoma (UC) include performance status (PS), liver metastasis (LM), hemoglobin (Hb) and time from prior chemotherapy (TFPC). Given the prognostic impact of peripheral blood neutrophils (N), lymphocytes (L), thrombocytes (T) and albumin (Alb) in other malignancies, we investigated their impact in the salvage setting of advanced UC. Methods: Phase II trials of salvage systemic therapy were utilized. Data on N, L, T and Alb were required in addition to TFPC, Hb, PS and LM status. N, L, T and Alb were categorized as normal, &lt;lower limit of normal (LLN) and &gt;upper limit of normal (ULN). Cox proportional hazards regression was used to evaluate their association with overall survival (OS). An optimal regression model was constructed using forward stepwise selection and risk groups defined using number of identified adverse risk factors. Trial was a stratification factor. Results: Data was obtained from 10 trials accruing 708 pts. Of these, 682 pts had available TFPC, Hb, PS and LM status, while 631, 554, 649 and 491 had N, L, T and Alb available. Median OS was 6.8 (95% CI: 6.0-7.0) months. Neutrophilia (N&gt;ULN), thrombocytosis (T&gt;ULN) and hypoalbuminemia (Alb &lt;LLN) were significant poor prognostic factors for OS on univariate analyses. After adjustment for TFPC &lt;3 months, Hb &lt;10 g/dl, PS &gt;0 and LM status, only thrombocytosis and hypoalbuminemia remained significant (Table). Risk groups were constructed. Median OS was 8.8, 6.3, 5.0 and 3.8 months for n=290, 220, 123 and 49 patients with 0-1, 2, 3 and ≥4 factors. This 6-factor prognostic model was internally validated with an improvement in the c-index from 0.564 to 0.590. Conclusions: The addition of hypoalbuminemia and thrombocytosis to TFPC, Hb, PS and LM status enhanced the prognostic risk groupings in pts receiving salvage systemic therapy for advanced UC. [Table: see text]
A phase II study of laparoscopic hyperthermic intraperitoneal chemoperfusion (HIPEC) for gastric carcinomatosis or positive cytology.
Authors: Brian D. Badgwell, Mariela A. Blum, Prajnan Das, Elena Elimova, Paul F. Mansfield, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2016)

TPS186 Background: Over the last 2 decades, intraperitoneal chemotherapy has been found to have activity for select subgroups of patients with carcinomatosis from colon, ovarian, appendiceal, and recently, gastric origins. However, there is little data to support an aggressive surgical approach of cytoreduction (debulking) and HIPEC for patients with gastric cancer and positive cytology or carcinomatosis. The morbidity and mortality rates of cytoreduction and HIPEC, in combination with gastrectomy, are significant and the survival rates of this approach may not extend beyond that of treatment with systemic chemotherapy. The purpose of this clinical trial, therefore, is to perform HIPEC in a neoadjuvant fashion via a minimally invasive approach without cytoreduction for patients with gastric cancer and positive cytology or low volume carcinomatosis. Patients found to have resolution of all extra-gastric disease will then be candidates for gastrectomy. Methods: Patients with gastric and gastroesophageal adenocarcinoma and positive peritoneal cytology or radiologically-occult carcinomatosis that have completed treatment with systemic chemotherapy are offered participation in the study. Type and duration of systemic chemotherapy is left to the discretion of the treating medical oncologist. Laparoscopic HIPEC consists of Mitomycin C 30 mg and Cisplatin 200 mg in 3-7 liters of infusate circulated using an extracorporeal circulation device at a flow rate of 700-1500 mL/minute for 60 minutes, performed no sooner than 3 weeks after completion of systemic chemotherapy. The Laparoscopic HIPEC procedure may be performed up to 5 times, with a minimum of 3 weeks between procedures. After laparoscopic HIPEC, subjects whose disease did not progress will proceed to surgery with diagnostic laparoscopy and possibly exploratory laparotomy to assess resectability, and if their cancer is resectable will undergo gastrectomy. After completion of study–related treatment, subjects will be followed until recurrence and/or death for up to five years. Fourteen of planned 30 patients have been enrolled (NCI-2014-01105). Clinical trial information: NCI-2014-01105.
Ongoing prospective multicenter safety study of subcutaneous cytoprotectant amifostine for head and neck carcinoma
Authors: M. Samuels, K. R. Fullmer
Journal: Journal of Clinical Oncology (2005)

5553 Background:Amifostine (Ethyol) is a radioprotectant that protects mucosal tissue from chemotherapy and radiation-induced damage. Intravenous administration is the approved route, but subcutaneous (SC) administration may offer greater ease of administration and reduced toxicity. Methods:Prospective, open-label, multicenter, safety study to determine treatment-related toxicities and safety of SC administration of amifostine in preventing radiation-induced toxicities. This report focuses on patients (pts) diagnosed with head and neck carcinoma. Results:One hundred sixty-six pts (121 men, 45 women, median age 61 y) received amifostine 500 mg SC before radiation therapy. Mean cumulative amifostine dose was 10,694 mg (range less than 5,000 to >20,000 mg); median daily dose was 500 mg and mean number of doses was 22. The most frequently reported adverse events (AEs) were nausea/vomiting (61%), radiation dermatitis (34%), local reaction (24%), hypotension (20%), and skin rash (<20%). For the majority of reports of local reaction (n=29), radiation dermatitis (n=55), and nausea/vomiting (n=54), no action was required and pts continued with study medication. Sixty-one (24%) of all targeted AEs resulted in permanent discontinuation of amifostine owing to: local injection site reaction (n=6), radiation dermatitis (n=1), skin rash (n=16), hypotension (n=8), and nausea/vomiting (n=30). The majority (87%) of targeted AEs were grade ≤ 2, and 61% of reported serious AEs were either not related or remotely related to amifostine. The majority (96%) of pts did not require a change in amifostine dose; 6 pts started with amifostine 500 mg but required a dose reduction due to AEs, and 5/6 pts decreased their dose more than once. Conclusions: SC amifostine was well tolerated by pts diagnosed with head and neck carcinoma in this prospective safety study, with a low incidence of severe (grade 3/4) targeted toxicities. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MedImmune MedImmune MedImmune
Patterns of failure following tri-modality therapy for locally advanced esophageal cancer.
Authors: Talha Shaikh, Mark A. Zaki, Michael M. Dominello, Elizabeth Handorf, Andre A. Konski, Steven J. Cohen, Walter Joseph Scott, Joshua E. Meyer
Journal: Journal of Clinical Oncology (2015)

203 Background: Although tri-modality therapy is an acceptable standard of care in patients with locally advanced esophageal cancer, data regarding patterns of failure is lacking. We report bi-institutional patterns of failure experience treating patients using tri-modality therapy. Methods: Following IRB approval, we retrospectively reviewed all pts who underwent chemoradiation followed by esophagectomy at two NCI-designated cancer centers from 2000-2013. Patient and treatment factors were analyzed for failure patterns. First failure sites were categorized as local, regional nodal, or distant. Statistical analysis was performed using Fisher’s exact test and non-parametric Wilcoxon rank-sum test. Results: A total of 132 patients met the inclusion criteria with a median age of 62 (range 36-80) and median follow-up of 28 months (range 4-128). The majority of patients had T3 (82%), N1 (64%), or M0/M1a (92%) disease. At the time of last follow-up there were a total of 6 (4.5%) local, 13 (10%) regional nodal, and 32 (23.5%) distant failures. Local failure was correlated with fewer lymph nodes assessed (p=0.01) and close or positive margins (p&lt;0.01). Regional nodal failure was correlated with fewer lymph nodes assessed (p&lt;0.01) and smaller pre-treatment tumor size (p=0.04). Distant recurrence was correlated with post-treatment nodal stage (p&lt;0.01), peri-neural invasion (p=0.03), negative margins (p=0.02), ulceration (p=0.02), incomplete response (p&lt;0.01), post-treatment PET SUV (p=0.05), 3D-CRT (0.053), metastatic disease at diagnosis (p&lt;0.01) and post-treatment metastatic disease (p&lt;0.01). No other patient, tumor, or treatment factor was correlated with treatment failure. Conclusions: Per our bi-institutional experience, patient, tumor, and treatment factors may predict for failure in patients undergoing tri-modality therapy for locally advanced esophageal cancer. Further data is needed to identify patterns of failure in these patients.
Does up-front definitive surgical resection with delayed chemotherapy in patients with stage IV rectal cancer compromise overall survival?
Authors: Bindu V. Manyam, Shlomo A. Koyfman, Davendra Sohal, Ismail Mallick, Chandana A. Reddy, Feza H. Remzi, Matthew F. Kalady, Ian C. Lavery, Ravi P. Kiran, May Abdel-Wahab
Journal: Journal of Clinical Oncology (2014)

586 Background: Definitive resection of the primary is frequently part of the management of patients (pts) with stage IV rectal cancer with good performance status and low volume of systemic metastases. It is unclear whether delaying systemic therapy for up front surgical management of the primary compromises overall survival (OS). Methods: Pts with metastatic rectal adenocarcinoma who received definitive surgical resection between 1998-2011 were identified in an IRB approved registry. The sequencing of CT and surgery, and the use of perioperative radiation therapy (RT), was at the discretion of treating physicians. Preoperative chemotherapy (Pre-CT) regimens included 5-fluorouracil (5-FU) +/- leukovorin (LV), capecitabine, 5-FU/LV/oxaliplatin +/- avastin, or 5-FU/LV/irinocetan. RT dose was typically 50.4 Gy. OS was measured from the date of diagnosis. Baseline variables were compared using the Chi-square and unpaired t-tests. OS was calculated using the Kaplan Meier method. Univariate (UVA) and multivariate analysis (MVA) were performed using Cox proportional hazards regression to identify variables associated with OS. Results: In this study of 115 pts, 75 (65%) were treated with pre-CT, while 40 (35%) were treated with up front surgery. Of the pts who received surgery up front, 3 (8%) received RT and of the pts who received pre-CT, 62 (83%) received RT. The cohort was predominantly male (70%) with a median age of 57, median KPS of 80, and median follow-up of 24.1 months. 94% of pts had T3/T4 tumors, 80% had N+ disease, and 33% had poorly differentiated tumors. Liver directed therapy (LDT) was performed in 61% of pts. There was no significant difference in OS (32.3 vs. 32 months; p = 0.24) between pts treated with pre-CT and those who received surgery up front, respectively. UVA demonstrated that pre-CT was not associated with OS (HR 1.26; p = 0.544). MVA demonstrated that pts with poorly differentiated tumors (HR 2.04; p = 0.007) and those that did not undergo LDT (HR 2.45; p = 0.001) had inferior survival. Conclusions: Delaying systemic chemotherapy in order to achieve local control with surgical resection up front does not appear to impact OS in pts with stage IV rectal cancer.
Significance of CEACAM6 expression in biliary tract carcinoma.
Authors: Flavio G. Rocha, Javierra Torres, Joanne F. Chou, Nora Katabi, Mithat Gönen, Ronald P. DeMatteo, Yuman Fong, Peter J Allen, Michael Ian D'Angelica, David S. Klimstra, William R. Jarnagin
Journal: Journal of Clinical Oncology (2012)

207 Background: The entire biliary tree is at risk for malignant change, but little is known about differences in molecular pathogenesis with respect to anatomic site. CEACAM6 is a membrane protein involved in cell adhesion and signaling that is overexpressed in pancreatic adenocarcinoma and associated with poor prognosis. This study examines CEACAM6 expression in the entire spectrum of biliary carcinomas and its relationship to outcome. Methods: Tissue microarrays containing triplicate cores of paraffin-embedded surgical specimens from patients with bile duct carcinoma (hilar, intrahepatic, distal) and control tissue were stained for CEACAM6 by immunohistochemistry. Clinical, pathologic and survival data were analyzed and correlated with CEACAM6 expression. Survival was estimated using the Kaplan-Meier method and compared with log rank test. Results: One hundred twenty cases of bile duct carcinomas from 1992-2007 were assembled in the tissue microarrays. Strong CEACAM6 signal was present in 30/60 (50%) of hilar tumors, 7/45 (16%) of intrahepatic tumors, 7/15 (47%) of distal tumors, and none of the control tissues. Overall median survival and follow-up were 36.4 months and 98.3 months, respectively. CEACAM6 staining did not correlate with sex, grade, positive lymph nodes, vascular invasion or metastases but was associated with age &gt; 65 (p&lt;0.05) and higher T stage (p&lt;0.05). After R0 resection, CEACAM6 expression was associated with disease-specific survival (DSS) only in the subset of patients with intrahepatic cholangiocarcinoma (median DSS 78 months for negative and 16 months for positive, p&lt;0.002). Vascular invasion was the sole independent predictor of survival on multivariate proportional hazards regression (HR=1.742 [1.048-2.895 95%CI], p&lt;0.03) in the entire cohort. Conclusions: CEACAM6 may serve as a marker of poor outcome in patients with intrahepatic cholangiocarcinoma and should be further evaluated as a means of selecting patients for adjuvant therapy after resection.
Retrospective Analysis of Itraconacole, Voriconazole and Posaconazole As Oral Antifungal Prophylaxis in Pediatric Patients Following Allogeneic Stem Cell Transplantation
Authors: Michaela Döring, Olivia Blume, Susanne Haufe, Ulrike Hartmann, Astrid Kimmig, Carl-Philipp Schwarze, Rupert Handgretinger, Ingo Müller
Journal: Blood (2011)