tbuckley/cabot-search huggingface dataset:
Potential chemo-sensitization effect of tergenpumatucel-L immunotherapy in treated patients with advanced non-small cell lung cancer (NSCLC).
Authors: John Charles Morris, Gabriela R. Rossi, Nancy Harold, Lucinda Tennant, William Jay Ramsey, Nicholas N. Vahanian, Charles J. Link
Journal: Journal of Clinical Oncology (2013)

8094 Background: Lung cancer is the leading cause of cancer-related mortality. Tumor progression after initial chemotherapy has a poor prognosis. A major obstacle is chemo-resistance, thus targeted therapies that enhance cancer cell sensitivity to chemotherapeutic agents with limited toxicities are needed. We report that tergenpumatucel-L (HyperAcute-Lung immunotherapy, HAL) shows signs of chemo-sensitization to follow-up treatment after progression in immunized patients. This drug exploits a potent innate immune mechanism that normally functions to destroy cells expressing a common xenoantigen (αGal). HAL immunotherapy consists of injecting patients with genetically modified allogeneic NSCLC cells bearing αGal moieties on their cell surface. Methods: This phase II study included 28 patients with metastatic or recurrent NSCLC, age ≥18, ECOG PS ≤2, ≤2 prior systemic therapies. Trial objectives were response rate, safety and immunogenicity. Patients received 300 x 10 6 HAL cells q2wks x 8 doses. Adverse events were assessed using CTCAE v3. Immunogenicity was assessed by changes in serum anti-αGal titers and IFN-γ response. Patients progressing on study trial (n=16) received follow up chemotherapy. Response was evaluated using RECIST criteria. Results: Twenty-eight (28) patients were evaluable for response and 16 progressing patients received salvage chemotherapy. Median overall survival (OS) was 11.3 months (95% CI 3.8-21.9). Eight of 28 patients demonstrated stable disease (SD) ≥16 wks including one patient that progressed and later regressed to survive &gt;50 months. Fifty six percent (9/16) of the progressing patients receiving follow up chemotherapy showed a response. Five (31%) achieved a PR and 25% (4/16) had SD after initial progression during the trial suggesting a chemo-sensitization effect of tergenpumatucel-L. Conclusions: HAL immunotherapy is safe and feasible. The median OS compared favorably to that reported in patients receiving 2 nd line chemotherapy for relapsed or advanced NSCLC. The potential chemo-sensitization effect of tergenpumatucel-L is highly encouraging and currently being studied in a phase IIB/III trial. Clinical trial information: NCT00073398.
A trial of autologous ex vivo expanded NK cell-enriched lymphocytes with docetaxel in patients with advanced NSCLC as second- or third-line treatment: Phase IIa study.
Authors: Suk-Young Park
Journal: Journal of Clinical Oncology (2013)

3045 Background: Cancer immunotherapy has been attractive for a long time with diverse clinical attempts and results. In particular, NK cells have received considerable attention because of their potential role in immune surveillance in vivo. MICA/B on tumor cells, known as the representative ligand for NKG2D receptor on NK cell, has been reported to be modulated by a variety of stresses including some chemotherapeutic agents and it is anticipated that enhancing MICA/B expression is contributory to anti-cancer treatment. With recent development of expanding autologous ex-vivo NK cell enriched lymphocytes (NKL), we designed a trial to augment the anti-cancer effect by co-administering NKL and docetaxel (D), one of the second-line agents in patients with advanced NSCLC. Methods: We first identified some chemotherapeutic agents, such as cisplatin and D, that induce peak MICA/B expression on HeLa cell during the 24-36 hours and designed a trial of combination of NKL with D administered within the same day. Eligible patients were 20-75 years old, ECOG PS 0-2, previously received one chemotherapy, and had stage IIIB/IV histologically proven NSCLC with measurable lesions. NKL were prepared and provided from NKBIO CO. Feasibility, adverse effect, and PFS were evaluated and compared with historical control of weekly D. Results: 19 patients were enrolled before early closure. NKL production and administration were feasible in all cases even with disseminated disease. No additional AE was observed in addition to that reported in D alone. PFS 3M and RR 10.5% with 2 PR were observed and similar to historical control (PFS 2.9M, RR 8.8%). Conclusions: To our knowledge, it seems to be the first report on the combination of NKL with D in patients with advanced NSCLC. Autologous NKL production and co-administration with D were feasible without further toxicity or complication. Benefit in PFS and RR, as compared with historical control, was not detected in this study population with advanced NSCLC, but further study to see whether the combination of NKL and chemotherapy has anti-cancer effect is desirable to be performed in low tumor burden state, such as less advanced or remission induced state.
Impact of alcohol dehydrogenase gene 4 polymorphisms on esophageal squamous-cell carcinoma risk in a Chinese population.
Authors: Xiao-Ling Xu, Jiwen Wang, Shuang-Mei Zhu, Ming Yang, Yun Fang, An Zhao, Qian Song, Weimin Mao
Journal: Journal of Clinical Oncology (2015)

e15021 Background: Esophageal squamous-cell carcinoma (ESCC) is very common in China and is also one of the most common cancers worldwide. The purpose of this study was to examine the associations between genetic variants of various cancer-related genes and the risk of ESCC. Methods: In this study, we first examined the association between 18 potentially disruptive genetic variants of 17 genes, including alcohol dehydrogenase (ADH4) and checkpoint kinase 2 (CHEK2), and ESCC risk in a Hangzhou population of 617 patients matched with 534 controls. Among the 18 single nucleotide polymorphisms (SNPs), two were validated in a Jinan population of 540 patients matched with 550 controls. Results: Sixteen SNPs in 15 genes including CHEK2 showed no significantly different allele frequency distributions between ESCC patients and control subjects. A significantly increased risk of developing ESCC was revealed in subjects with the AA genotype for rs3805322 (ADH4) compared with those with the AG or GG genotype by unconditional univariate logistic regression analysis. Using a dominant model, the CC genotype of rs4822983 (CHEK2) had a marginally significant protective effect compared to CT and TT genotypes. The association of ESCC risk with these two SNPs (rs3805322 and rs4822983) was further validated in a Jinan case-control set. Individuals with the ADH4 rs3805322 AA or AG genotype had ORs of 1.10 (95% CI = 0.81 - 1.49, P = 0.000) or 1.86 (95% CI = 1.33 - 2.59, P = 0.559) for developing ESCC, respectively, compared with individuals with the GG genotype. CHEK2 rs4822983 CC carriers showed a marginally significantly decreased ESCC risk compared with those carrying the CT and TT genotypes in the validation set (95% CI = 0.61 - 1.01, P = 0.064). However, no evidence of interaction existed between the two SNPs and smoking or drinking in the Jinan case-control set. Conclusions: In conclusion, this current study provides substantial evidence that genetic polymorphisms of rs3805322 in the ADH4 gene are associated with increased risk of developing ESCC in two Chinese Han populations. However, future studies to address the biological function of this polymorphism in the development of ESCC are warranted.
Neoadjuvant chemoradiation for potentially resectable gastric cancer.
Authors: Michael E. Barfield, Brian R. Untch, Justin T. Arcury, Brian G. Czito, Christopher Willett, Theodore N. Pappas, Rebekah Ruth White, Douglas S. Tyler, Dan G. Blazer
Journal: Journal of Clinical Oncology (2012)

e14724 Background: Outcomes are poor in patients with gastric cancer, and recurrence is common. Perioperative chemotherapy and adjuvant chemoradiation therapy (CRT) improve survival in patients with resectable disease. Experience with neoadjuvant CRT for potentially resectable disease is limited, and its role remains undefined. We report our experience using neoadjuvant CRT for potentially resectable gastric cancer. Methods: An IRB-approved, retrospective review from 1994 to 2007 identified 23 patients with biopsy-proven, potentially resectable gastric cancer. Patients had T2/T3 and/or N1 disease and no evidence of metastatic disease by endoscopic ultrasound and cross-sectional imaging. All underwent neoadjuvant external beam radiation with concurrent 5-FU or platinum-based chemotherapy followed by restaging and surgery if appropriate. Results: Of the 23 patients, 20 completed neoadjuvant CRT and surgical exploration. Two patients (n=2) had radiographic disease progression during neoadjuvant CRT and did not undergo resection. One patient (n=1) developed a perforated gastric ulcer during CRT and underwent emergent resection. The median time from diagnosis to surgery and completion of neoadjuvant CRT to surgery was 104 days and 37.5 days, respectively. Gastrectomy was performed in 17 (85%) patients who completed neoadjuvant CRT. Metastatic disease was identified in the remaining 3 (15%) patients. Following gastrectomy, a complete pathologic response was observed in 4 (23.5%) patients, a partial response in 11 (64.7%) patients, and no response was identified in 2 (11.8%) patients. One (6%) patient had microscopic positive margins, and 9 (53%) had positive lymph nodes. There was no perioperative mortality. Two (11.8%) patients had anastomotic leaks, which were managed non-operatively. The median length of stay was 10 days. The median disease-free survival was 10.5 months, and median overall survival was 19.6 months. Conclusions: Gastric cancer carries a poor prognosis. Surgical resection after neoadjuvant CRT has low treatment-associated morbidity and mortality. Survival and complete response rates are comparable to published series. Further evaluation of this treatment strategy is warranted to assess its efficacy.
Prognostic factors in patients with pancreatic metastases from renal cell carcinoma (PM-RCC): Room for thinking about the role of surgery?
Authors: Matteo Santoni, Alessandro Conti, Camillo Porta, Linda Cerbone, Giuseppe Procopio, Umberto Basso, Ugo De Giorgi, Mimma Rizzo, Cinzia Ortega, Francesco Massari, Roberto Iacovelli, Cristina Masini, Michele Milella, Giuseppe di Lorenzo, Maria Pagano, Sebastiano Buti, Massimo Falconi, Luciano Burattini, Daniele Santini, Stefano Cascinu
Journal: Journal of Clinical Oncology (2014)

e15563 Background: Metastases to the pancreas from renal cell carcinoma (PM-RCC) are clinically uncommon and use to be an incidental finding detected on radiological follow-up of these patients and quite often lead to resection. Aim of our study was to evaluate the outcome of patients with PM-RCC and the presence of prognostic factors in this population. Methods: Data were retrospectively collected from 19 Italian centers involved in the treatment of metastatic RCC. Kaplan-Meier and log-rank test methods were used to evaluate the overall survival (OS). Clinical variables considered in the study were sex, age, concomitant metastasis to other sites, surgical resection of PM-RCC, time to PM-RCC occurrence. A subsequent univariate and backward multivariate Cox regression model was fitted to the data to correct for the effect of covariates. Results: 103 patients were enrolled in the analysis. Sixty-six of them were males. Median age was 67y (range 43−85y). PM-RCC were synchronous only in 3 patients (3%). In 56 patients (54%), pancreas was the only metastatic site, whereas in the other 47 patients lung (57%), lymph nodes (28%) and liver (21%) were the most common concomitant metastatic sites. Median time for PM-RCC occurrence was 9.6y (range 0−24y) after nephrectomy. Surgical resection of PM-RCC was performed in 40 patients (39%) and consisted in total (21%), distal (71%) or central pancreatectomy (8%). Median OS was not reached in patients who underwent surgical resection of PM-RCC and 11.1y in the other patients (p<0.001). At univariate analysis, only the presence of concomitant metastases to other sites (p=0.008) was significant associated with a poor prognosis, whereas none of the evaluated variables were an independent prognostic factor at multivariate analysis. Conclusions: The presence of PM-RCC is associated with long survival, and surprisingly is independently associated withsurgical resection, time of PM-RCC occurrence and the presence of concomitant metastases to other sites, although these data should be confirmed in a larger population. A better understanding of the biological behaviour of PM-RCC is strongly required in order to optimize patient therapeutic approach.
Bevacizumab for recurrent WHO grade III anaplastic glioma (AG).
Authors: Anna Maria Delios, Cameron W Brennan, Jason T. Huse, Kara Colevas, Antonio Marcilio Padula Omuro
Journal: Journal of Clinical Oncology (2012)

2028 Background: Salvage treatment with bevacizumab (BEV) has been increasingly used in grade III AG, but limited data are available, with conflicting results reported. Because of differences in molecular characteristics, angiogenesis mechanisms, growth rate and chemosensitivity, results observed in glioblastoma (GBM) treated with BEV may not apply to AG, and may differ between anaplastic astrocytomas (AA) and oligodendrogliomas (AO). Methods: IRB approved retrospective review of all pts with recurrent WHO grade III AG treated with BEV at MSKCC. Response and progression were determined by RANO criteria. Results: BEV was given to 39 pts with recurrent grade III AG (AA: 26; AO: 10; anaplastic oligoastrocytoma [AOA]: 3); median (med) age: 49 (range 20-75); med KPS: 80 (60-100). MGMT promoter methylation was determined in 17 pts (methylated 8, unmethylated 9). Amongst AO/AOA, 1p/19q co-deletion was present in 6 and absent in 5. IDH1/ IDH2 mutations were present in 3/5 tested tumors. Med time from diagnosis of AG to BEV treatment was 11.5m (3 – 112.5). The med number of previous recurrences was 1 (range 1-4). BEV was given as single agent to 16 pts and combined with a cytotoxic agent in 23. Objective response rate (ORR) was 41% (complete response: 5; partial: 11). The med progression-free survival (PFS) was 4.8m (6-m PFS: 35% [95% CI 20-50]). The med overall survival (OS) was 11.5 m (1y-OS: 45% [95% CI 29-61]). In pts achieving ORR, med OS was 13 m vs 4 m in pts with stable/progressive disease (P=0.02). Pts at first recurrence fared better than pts with more than one recurrence (med PFS: 6 vs 3.4 months, P=0.04). AO/AOA tended to fare worse than AA (med PFS 3 vs 5.5 m, P=0.07). There were no differences in PFS (P=0.8) or OS (P=0.4) between single agent vs BEV + cytotoxic agent. Toxicity included one grade 4 brain hemorrhage. Conclusions: In this relatively large series, BEV was associated with higher ORR and PFS as compared to historical controls, although improvements in those endpoints were of a lower magnitude than in GBM. While ORR predicted OS, improvements in OS were not apparent; results in AO were particularly disappointing. The use of BEV in this population requires reappraisal in a randomized study with adequate stratification for histology and number of previous recurrences.
Whole-Exome Sequencing and Targeted Deep Sequencing of cfDNA Enables a Comprehensive Mutational Profiling of Multiple Myeloma
Authors: Salomon Manier, Jihye Park, Samuel Freeman, Gavin Ha, Marzia Capelletti, Sarah Reed, Gregory Gydush, Denisse Rotem, Justin Rhoades, Karma Salem, Claudia Freymond, Daisy Huynh, Antonio Sacco, Houry Leblebjian, Adriana Perilla Glen, Amir Yosef, Antonio Palumbo, Laurent Garderet, Shaji Kumar, Aldo M. Roccaro, Thierry Facon, Eliezer Van Allen, J. Christopher Love, Gad Getz, Viktor Adalsteinsson, Irene M. Ghobrial
Journal: Blood (2016)
BMA urges government to grant permanent residence to European doctors working in UK
Authors: Gareth Iacobucci
Journal: BMJ (2017)

Healthcare leaders have urged the government to grant permanent residence as soon as possible to doctors from other European countries working in the UK to mitigate the potential effect of Brexit on the NHS.

After the government triggered Article 50 this week to start the process for the UK to leave the European Union, the BMA said that it was vital for the government to remove uncertainty by securing the rights of doctors from the European Economic Area to remain in the UK. The association also urged ministers to guarantee that a future immigration system would be flexible enough to ensure the recruitment and retention of …
Adjuvant chemotherapy (AC) in elderly patients with stage II colon cancer: A single institute experience.
Authors: Dawn Elizabeth Armstrong, Jennifer L. Spratlin, Christina Kim, Karen E. Mulder
Journal: Journal of Clinical Oncology (2014)

e20526 Background: The number of North Americans over the age 65 is growing rapidly, and as a result, the number of elderly patients presenting for colorectal cancer care is quickly rising. Very little is known about how many elderly Stage II colon cancer patients are offered, and proceed with, AC. The objective of this study was to review the demographics, high risk features, treatments and toxicities of AC for Stage II colon cancer patients ≥ 65 years old. Methods: Patients ≥ 65 years old, diagnosed with stage II colon cancer from 2004-2010 were identified from the provincial cancer registry. A retrospective analysis of electronic and paper patient records was performed to identify baseline characteristics, AC used, toxicities and dose reductions/delays. Results: 457 patients ≥ 65 years old, with Stage II colon cancer were diagnosed and seen by a medical oncologist at our institution from 2004-2010. 63 patients (14%) were treated with AC, of which 4 (6%) had no known high risk features. The median age of treated patients was 71, with 24% being ≥ 75. The most common AC regimen was capecitabine [n=49 (78%)]. Other AC regimens were oxaliplatin based chemotherapy [n=8 (13%)] and fluorouracil/folinic acid [n=6 (9%)]. The most common recorded reason for choosing single agent AC was patient preference (51%). 84% of patients required a dose reduction or delay in treatment. Only 4 patients were reported to have hematological toxicities. The most common recorded toxicities were hand-foot syndrome [n=30 (48%)] and diarrhea [n=9 (14%)]. Both median progression free survival and overall survival was 70 months. Conclusions: Few elderly Stage II colon cancer patients are treated with AC. Single agent AC is used more frequently than combination AC, based mostly on patient choice, and not chronologic age. Toxicity with AC in elderly patients is high, but may carry a potential survival benefit for those who receive it. Further studies are needed to compare elderly Stage II colon cancer patients who do or do not receive treatment.
Adjuvant thalidomide improves disease specific survival for patients with renal cell carcinoma at high risk for relapse following surgery
Authors: R. Sanchez-Ortiz, P. Tamboli, M. L. Lozano, S. Matin, C. G. Wood
Journal: Journal of Clinical Oncology (2006)

14586 Background: Observation is the standard of care for locally advanced renal cell carcinoma (RCC) after surgery. No adjuvant therapy for RCC exists. Thalidomide has shown activity in metastatic RCC. We studied thalidomide in the adjuvant setting for patients with locally advanced RCC. Methods: This phase III trial has enrolled 46 patients to date. All patients underwent resection of all disease. Eligible patients included T2N0M0 grade 3–4, T3a-cN0M0, T4N0M0, TanyN1–2M0, and TanyN0M0 bilateral disease completely resected. All RCC histologies were included. Patients were randomized to observation or thalidomide, 300 mg daily for 2 years. Dose reductions were allowed for toxicity. The primary endpoint was recurrence free survival. Secondary endpoints were disease specific survival and toxicity. Results: Twenty-three patients randomized to thalidomide and 23 were observed. In the thalidomide arm, one patient refused therapy and two stopped within one month due to toxicity. Only 1 patient tolerated therapy for 2 years without dose reduction. With a median follow-up of 18 months, there were 6 recurrences and 5 disease related deaths in the observation arm and 7 recurrences and 2 disease related deaths in the thalidomide arm. Using an intent to treat principle in our multivariate analysis, adjusting for grade, stage, and nodal status, we noted no significant difference in recurrence free survival between observation (mean 31 months; median not reached (NR)) and the thalidomide arm (mean 24.7 months; median NR) (Hazard ratio = 1.04, 95% CI 0.34 to 3.14, p = 0.945). Interestingly, disease specific survival was significantly better in the thalidomide arm (mean 40.1 months; median NR), as compared to the observation arm (mean 37.1 months; median NR) (Hazard ratio = 0.086, 95% CI 0.008 to 0.981, p = 0.048). Conclusions: In this limited experience with surgically resected RCC at high risk for relapse, thalidomide did not impact time to recurrence but significantly improved disease specific survival in the adjuvant setting. Despite this clinical benefit, significant toxicity limited tolerability of the drug. These data suggest that derivatives of thalidomide, with different toxicity profiles, might warrant testing in the adjuvant setting for RCC. No significant financial relationships to disclose.
Prospective identification of potentially actionable molecular alterations in cancers of unknown primary.
Authors: Anna M. Varghese, David Michael Hyman, Ahmet Zehir, Efsevia Vakiani, David S. Klimstra, Marc Ladanyi, Michael F. Berger, David B. Solit, Leonard Saltz
Journal: Journal of Clinical Oncology (2015)

4110 Background: Patients with cancers of unknown primary (CUP) represent a heterogeneous population, and the frequency of actionable molecular alterations in their tumors remains unknown. These patients are frequently excluded from most Phase II/III studies as most require a histologic diagnosis with a primary site of disease; consequently, little progress has been made in developing targeted therapies for these patients. Methods: We prospectively identified patients with CUP seen for initial consultation at MSKCC from 01/2013 through 11/2014. We excluded patients with a likely primary disease site based on subsequent pathologic and radiographic tests. Tumors and matched normal samples underwent testing by MSK-IMPACT, a comprehensive molecular profiling platform performed in a CLIA-compliant laboratory using targeted deep sequencing of 341 cancer-associated genes to identify sequence mutations, copy number alterations, and select rearrangements. We collected tumor histology and defined potentially actionable molecular alterations as those for which investigational or FDA-approved targeted agents exist. Results: Of 34 patients identified with CUP, pathologic review demonstrated 44% adenocarcinoma (15/34) and others, including carcinoma (Ca), squamous cell Ca, neuroendocrine Ca, and sarcoma. 334 alterations were identified with a median 7 alterations / patient (range 0-41). Alterations were seen most commonly in TP53 (19/34), CDKN2A (7/34), ARID1A (7/34), KRAS (7/34), and SMARCA4 (7/34). Potentially actionable alterations were present in 41% (14/34) of patients and included BRAF V600E, AKT1 E17K, and ERBB2 S310F, among others. Actionable alterations identified in 10 patients made them eligible for inclusion in targeted therapy studies available at our institution. Updated treatment and response information will be presented at the meeting. Conclusions: CUPs harbor potentially actionable mutations. Patients with CUPs might benefit from expanded treatment opportunities and possibly improved outcomes through increased access to clinical trials in which eligibility criteria is based on molecular status rather than histologic diagnosis based on a primary site of disease.