tbuckley/cabot-search huggingface dataset:
Antibiotics prescription to decrease progression-free survival (PFS) and overall survival (OS) in patients with advanced cancers treated with PD1/PDL1 immune checkpoint inhibitors.
Authors: Lisa Derosa, Bertrand Routy, Laura Mezquita, Charles Naltet, David Enot, Marine Fidelle, Anne-Gaëlle Goubet, Jean-Charles Soria, Christophe Massard, Francois Goldwasser, Laurence Zitvogel, Solenn Brosseau, Bernard J. Escudier, Yohann Loriot, Gerard Zalcman, Benjamin Besse, Laurence Albiges
Journal: Journal of Clinical Oncology (2017)

3015 Background: Use of antibiotics (ATB) alters the gut microbiota composition and decreases bacterial diversity. Pre-clinical evidences demonstrated the impact of the microbiota in the efficacy of immune checkpoint blockades (ICB) in cancer. Interaction between ATB and ICB has not been extensively investigated in cancer patients (pts). Our study evaluated the effect of ATB in cancer pts treated with PD-1/PD-L1 inhibitors. Methods: We conducted a retrospective analysis of pts treated with PD-1/PD-L1 inhibitors for advanced Renal Cell Carcinoma (RCC), Urothelial Cancer (UC) and Non-Small Cell Lung Cancer (NSCLC) and data on ATB use were collected. ATB(+)/(-) groups were defined as pts treated or not with ATB before (2 months period) or within the first month of ICB. PFS and OS were compared between both groups among all pts and then according to tumor site. Statistical analyses were performed using the Kaplan-Meier method. Cox regression analyses were performed separately for each cancer type adjusting for its specific risk factors. Results: Among 175 pts included, 51 (29%) received ATB (mostly beta-lactamases and fluoroquinolones). ATB(+) group had shorter PFS and OS when compared to ATB(-) group: 3.4 vs. 5.2 months, p &lt; 0.013, and 12.2 vs. 20.8 months, p &lt; 0.001, respectively. According to tumor type, ATB(+) group translated into decrease OS (7.0 vs. 13.8 months, p &lt; 0.038) in NSCLC. In RCC and UC pts, ATB (+) group had shorter PFS when compared to ATB(-) group (4.3 vs. 7.4 months, p &lt; 0.013 and 1.8 vs. 4.3 months, p = 0.048, respectively). The negative impact of ATB was maintained after multivariate analyses adjusting for risk factors in each tumor type. Conclusions: ATB prescription preceding or concomitant to the first injection of PD-1/PD-L1 inhibitors impaired the outcome in patients with advanced cancers. This reduction in efficacy seems to be independent of classical prognostic factors in RCC, UC and NSCLC. These data should be validated in larger cohort. In addition, the role of gut composition to explain this interaction is ongoing, as well as novel diagnosis tools based on microbiota to predict response/resistance to ICB.
Mammography screening and detection of early stage breast cancer in Hispanic and African American women at a Minnesota safety net healthcare system.
Authors: Daniel Fellows Pease, David T. Gilbertson, Andres Wiernik
Journal: Journal of Clinical Oncology (2017)

e18074 Background: Approximately 12% of breast cancer cases occur in women younger than 50 years, per SEER data from 2012. Hispanic women are known to present at a younger age and African American women with more advanced stage disease. In this study, we describe the impact of age and race on the initial presentation of breast cancer among minority women treated at the Hennepin Healthcare System (HHS) in the state of Minnesota. Methods: A single-institution retrospective analysis of data from our electronic health record of all breast cancer diagnoses from 2010-2015. Cases were compared by age ( &lt; 50 or &gt; 50 years), race (Caucasian, African American, Hispanic, other), stage (AJCC 7th edition), and method of diagnosis (self-reported mass or screening mammography). Results: A total of 315 breast cancer diagnoses occurred at HHS from 2010-2015. In our cohort, 29% of all breast cancer cases were diagnosed in women &lt; 50yrs. Hispanic and African American women had higher rates of diagnosis at &lt; 50yrs compared to Caucasian women (38.9% vs 37.1% vs 18.1 respectively, p &lt; 0.05). Early stage cancer (stage 0 or I) accounted for most diagnoses in those &gt; 50yrs (54.8%), while advanced stage (stage II-IV) was more prevalent in the &lt; 50yrs age group (59.5%) (p &lt; 0.05). Of all women diagnosed with breast cancer, 63% presented with a self-reported mass and 37% were diagnosed by screening mammography. Hispanics and African American women had a higher rate of presentation with a self-reported mass (74% and 66% respectively) compared to Caucasian women (55%). Women with breast cancer &lt; 50yrs were more likely to present with a self-reported mass than women &gt; 50yrs (80% vs 55%, p &lt; 0.05). 92% of Hispanic and 80% of African American women &lt; 50yrs presented with a self-reported mass, compared to 62% of Caucasian women (p = 0.095). Conclusions: At our institution, Hispanic and African American women are diagnosed at a significantly younger age than Caucasian women, and those diagnosed at a younger age have more advanced disease. Presenting with a self-reported mass is very common for young non-Caucasian women. Whether screening mammography can be better utilized to change these trends requires further study.
Long-term survival comparison of stereotactic radiotherapy versus surgery for elderly patients with clinical stage T1-T2 non-small cell lung cancer.
Authors: Feng-Ming Spring Kong, Chunyu He, Yong Zang, Sandra K. Althouse, Lautenschlaeger Tim, Kenneth Kesler
Journal: Journal of Clinical Oncology (2018)

8511 Background: There are several matched-paired analysis reports of comparing the long-term outcome between Stereotactic Body Radiation Therapy (SBRT) and surgical resection. Most of them are small series. This study aimed to compare the long-term overall survival (OS) after SBRT and surgery from a single medical center with surgery performed with the same group of surgeons. Methods: We used our cancer registry of 2005-2015. Patients with clinical staged T1 and T2 N0 diseases treated with either primary surgery or SBRT . Only patients elder than 65 years. The log rank p-value was used for overall survival comparison between the groups. Cox regression was used for univariate test for age, gender, race, smoking history, alcohol use, primary site location, laterality, T stage, and histology grade. Variables with p < 0.05 from univariate analysis were then used for propensity score based matching to compare the effect of surgery or SBRT on overall survival. Results: A total 1244 patients with clinically staged T1-T2 N0 NSCLC, 774 patients were elder than 65 years and matched: 508 patients with surgery and 266 patients with SBRT. The median age was 73 years (range: 65-96 years), 50% were male, and 67% had T1 disease. Median follow-up was 60 months.Age (p < 0.001), gender (p = 0.007), primary lobar location, middle and lower lobe (p < 0.001), grade of 1, 2, 3, and 4 (p< 0.001) and treatment modality of surgery versus SBRT (P < 0.001) were all significantly associated with OS under univariate analysis. The median OS and survival rates at one-, three- and five years were 81 months (95%CI:66-92), 85%, 70% and 58% after surgery, and 37 months (95%CI:28-46), 83%, 50% and 29% after SBRT, respectively (log-rank p< 0.001). Conclusions: This matched analysis, representing the largest one in the literature, demonstrated that patients treated with surgery have significantly better long-term survival than that of SBRT in elderly patients. This result varies from some of previous reports showing similar survival between SBRT and surgery. Prospective randomized study is needed to determine whether SBRT can present as an alternative for operable patients.
Breast cancer and survival among older women.
Authors: Rottenberg Yakir, Jeremy M Jacobs, Beatrice Uziely, Tamar Peretz, Arash Naeim
Journal: Journal of Clinical Oncology (2016)

10035 Background: Despite growing numbers of older people with cancer, treatment decisions are often challenging, since evidence-based survival data according to staging and treatment progressively declines with increasing age, particularly among the oldest old. The aim of this study was to describe the association of increasing age and disease staging at presentation, on survival among women aged over 65 years, diagnosed with breast cancer. Methods: This was a nested case control study, comparing 3,270 patients with breast cancer to 13,163 non-cancer age-matched controls. Baseline characteristics and cancer data (followed up from 2000-2011) were gathered from the Israeli Central Bureau of Statistics 1995 census and the Israel Cancer Registry. Survival curves and Hazards Ratios adjusted for ethnicity and socioeconomic status were stratified for 5-year age groups. Results: The poor survival of metastatic cancer progressively deteriorated with increasing age; among patients age 80 years old and more, the median survival in the upper quartile was less than a year. On the other hand, women with early stage cancer had similar survival compared to the non-cancer controls, even showing a trend to improved survival among the oldest old. Similarly, the magnitude of the decreased survival among intermediate stage cancer was seen to attenuate beyond the age of 80. Compared to non-cancer controls, early breast cancer subjects had a non-significant decreased risk of death throughout follow-up, which actually achieved a borderline significance beyond age 85 with an adjusted HR = 0.60 (95%CI:0.358-1.009). The increased risk of death associated with Intermediate stage breast cancer gradually declined with rising age, falling from adjusted HR 3.26 (95%CI: 2.58-4.12) at age 65-69, to an adjusted HR of 1.20 (95%CI: 1.22-2.09) at age 80-84, slightly rising again beyond age 85. Metastatic disease was strongly associated with mortality at all ages. Conclusions: Elderly women with breast cancer presenting with localized disease have a comparable expectancy of life compared to non-cancer healthy controls irrespective of advancing age. In contrast, the poor prognosis of patients diagnosed with metastatic disease was seen to deteriorate with advancing age.
Gene expression profiling using Nanostring technology to predict surgical outcome in advanced primary high grade serous ovarian cancer (HGSOC) patients (pts). Study of the Tumor Bank Ovarian Cancer (TOC).
Authors: Elena Ioana Braicu, Hagen Kulbe, Felix Dreher, Silvia Darb-Esfahani, Eliane T Taube, Radoslav Chekerov, Thomas Kessler, Mustafa Zelal Muallem, Christoph Wierling, Carsten Denkert, Hedwig Lammert, Michael Hummel, Jalid Sehouli
Journal: Journal of Clinical Oncology (2018)

5569 Background: Ovarian cancer has the highest mortality rates among gynecological cancer. Residual tumor mass after primary debulking surgery (PDS) is one of the most important prognostic factors. There are no accurate predictive tools to identify pts who won't benefit from upfront surgery. Aim was to discover and validate a debulking signature to predict surgical outcome in advanced HGSOC. Methods: Using in silico data analysis of publicly available data, we developed a 200 gene signature to differentiate between optimal vs. suboptimal debulked pts. Optimal debulking was defined as no macroscopical residual mass after PDS. The mRNA expression levels of the top 25% genes were validated in an independent cohort of 246 HGSOC pts, using Nanostring nCounter Analysis System. Only advanced stage, chemonaive HGSOC pts were included in the study. FFPEs and clinical data were provided by TOC (www.toc-network.de). Residual mass and clinical-histological parameters were documented prospectively. Surgery was performed by an experienced gynecological oncologist, between 2002-2013. The validation was performed using unsupervised hierarchical clustering (distance metric:1-correlation, complete linkage). Pts stratification in the two main clusters was assessed by Pearson's Chi-squared test with Yates' continuity correction. Results: 152 (61.7%) pts presented no residual mass after PDS. Median age at diagnosis was 59 years. The own generated data showed 29 differentially expressed genes between suboptimal and optimal debulked pts (Mann-Whitney U-test, p < 0.05). MYCN, PTCH1, MMP11, GREM1, PMEPA1, FABP4, ASPN and TGFB3 were the top differentially expressed genes (p < 0.05 and abs(log2FoldChange) > 0.5) between the two cohorts. Unsupervised hierarchical clustering of all measured genes, the 29 genes and the 8 top genes, showed significant phenotypical separation (p = 0.04, p = 0.00011 and p = 0.00022, respectively). Conclusions: Our debulking signature predicts macroscopical residual mass after PDS in advanced HGSOC. This will more likely allow pts selection for primary vs. interval debulking surgery.
Implementation of single-cell genomics as a translational tool in patients with metastatic melanoma.
Authors: Benjamin Izar, Itay Tirosh, Sanjay Prakadan, Marc Wadsworth, Asaf Rotem, John Trombetta, Parin Shah, Ken Dutton-Regester, Mohammad Fallahi, Jia Ren-Lin, George Murphy, Christine Lian, Peter Sorger, Monica M. Bertagnolli, Orit Rozenblatt-Rosen, Charles H. Yoon, Alex Shalek, Aviv Regev, Levi A. Garraway
Journal: Journal of Clinical Oncology (2016)

11503 Background: Heterogeneity of malignant and non-malignant tumor components and their interactions pose tremendous clinical challenges and opportunities in clinical care. Due to technical constraints, current profiling technologies only provide average signals that do not reflect this intrinsic genetic and phenotypic variability. Methods: To overcome these barriers, we applied single-cell RNA-sequencing to 4,645 single cells isolated from 19 freshly procured melanomas, profiling malignant, immune and stromal cells. Results: Independent from their bulk-RNA signature, all tumors harbored dormant cells that are intrinsically resistant to RAF/MEK-inhibition. We confirmed this observation in six additional pairs of pre-treatment and post-relapse biopsies of patients who developed resistance to RAF/MEK-inhibition and by flow-cytometry and quantitative single-cell IF of 18 established human melanoma cell lines. We inferred distinct patterns of the tumor microenvironment that were associated with the resistant AXL-high signature indicating their interactions within the tumor ecosystem as drivers of resistance. Analysis of CD8+ T cells revealed strong co-expression of PD1, CTLA-4 and TIM-3 with cytotoxicity markers, such as perforin 1 and granzyme B, indicating a critical correlation of activation and exhaustion cell states. By controlling for cytotoxic T cell markers, we established a core gene signature of 28 genes that defined the salient exhaustion function of T cell. To identify potential T-cell clones, we classified single T-cells by their isoforms of the V and J segments of the alpha and beta TCR chains, allowing us to identify expanded T-cell clones. We found that clonally expanded T-cells expressed a strong exhaustion program. Conclusions: This analysis represents the most comprehensive single-cell genomics analysis in humans to date and begins to unravel the cellular ecosystem of tumors. Single-cell genomics offer new insights with transnational implications for targeted and immune therapies by simultaneously profiling numerous aspects of a tumor using a single assay.
Poor prognosis in patients with resectable KRAS-MUT colorectal liver metastases is improved by adjuvant hepatic arterial infusion chemotherapy.
Authors: Sepideh Gholami, Taryn Mary Boucher, Nancy E. Kemeny, Mithat Gonen, Andrea Cercek, T. Peter Kingham, Vinod P. Balachandran, Peter J. Allen, Ronald P. DeMatteo, William R. Jarnagin, Michael Ian D'Angelica
Journal: Journal of Clinical Oncology (2017)

e15161 Background: Patients with KRAS-mutated colorectal cancer liver metastases (CRLM) have worse outcomes after resection. Adjuvant hepatic artery pump chemotherapy (HAIC) improves overall survival. We investigated the impact of HAIC in relation to KRAS mutational status in patients with resected CRLM. Methods: Patients with resected CRLM treated with and without adjuvant HAIC and available KRAS status (wild-type, WT; mutated, MUT) were reviewed from a prospective institutional database. Correlations between KRAS status, adjuvant HAIC, clinical factors, and overall survival (OS) were analyzed. Cox proportional hazard model was used to adjust for confounders. Results: Between 1993-2012, 675 patients (419 KRAS-WT, 256 KRAS-MUT) with a median follow up of 6.5 years after resection were evaluated. Fifty-four percent received adjuvant HAIC. Tumor characteristics (synchronous disease, number of lesions, clinical-risk score, 2-stage hepatectomy) were significantly worse in the HAIC group, however, there were more patients with extrahepatic metastases in the no-HAIC group. Adjuvant HAIC was associated with improved OS in both KRAS-WT (5-yr OS 76% vs 57%, HR 0.51, p&lt;0.01) and KRAS-MUT (5-yr OS 59% vs 40%, HR 0.56, p&lt;0.01) patients. On multivariate analysis, HAIC remained associated with improved OS (HR 0.6, p&lt;0.001) independent of KRAS status and other clinico-pathologic factors. Conclusions: Adjuvant HAIC after resection of CRLM is independently associated with improved OS regardless of KRAS status and may abrogate the poor prognosis in resectable KRAS-MUT CRLM. [Table: see text]
PPHM 1501- An open-label, randomized, phase II trial of durvalumab (MEDI4736) with or without bavituximab in patients with previously treated metastatic non-small cell lung cancer (NSCLC): Safety report on first 18 patients.
Authors: Ronald B. Natale, David R. Spigel, Rachel E. Sanborn, Alberto Chiappori, Suresh S. Ramalingam, Konstantin H. Dragnev, Joseph Shan, Lisa Stepp, Michael McCleod, David Michael Waterhouse, David E. Gerber
Journal: Journal of Clinical Oncology (2016)

e14537 Background: The programed cell death 1/ligand 1 (PD-1/PD-L1) axis has been identified as an immunosuppressive pathway and a target for cancer immunotherapy. Durvalumab, a human monoclonal antibody (MAb) inhibits binding of PD-L1 to PD 1. Phosphatidylserine (PS) is a highly immunosuppressive molecule that becomes externalized on tumor cells and exosomes in the tumor microenvironment providing another target for cancer immunotherapy. PS binding to PS receptors leads to production of anti-inflammatory cytokines. Bavituximab, a PS-targeting monoclonal antibody, counters these effects, resulting in production of pro-inflammatory cytokines, maturation of dendritic cells and induction of tumor specific cytotoxic T lymphocyte immunity. Treatment with bavituximab in combination with a downstream immune checkpoint inhibitor such as durvalumab, may result in long-lasting antitumor immunity that improves clinical outcomes. Previously reported results from a Phase II second line trial in non-squamous, non-small cell lung cancer demonstrated 60% improvement (11.7 vs 7.3 months) in medial overall survival (OS) in the bavituximab treated group (bavituximab 3mg/kg plus docetaxel) compared to control. Methods: PPHM 1501 is a Phase II, open label, trial for patients with previously treated metastatic NSCLC. Patients are randomized in a 1:1:1 ratio. Arm A receives10 mg/kg durvalumab alone every two weeks. In Arms B and C, patients receive 3 mg/kg bavituximab weekly in combination with 10 mg/kg durvalumab every two weeks or 3 mg/kg bavituximab in combination with 10 mg/kg durvalumab both every two weeks, respectively. Patients are treated until progression or toxicity. This global trial will enroll 198 patients. The primary endpoint is ORR. Other endpoints include PFS, OS, and safety. Results: Enrollment is ongoing and initially will be limited to no more than 2 patients per arm per week. A safety committee will monitor the occurrence of dose limiting toxicities for the first 18 patients prior to enrolling the remainder of the trial. Conclusions: Analysis of the first 18 patients will be presented.
Changes in neuromuscular structure and functions of human colon during ageing are region-dependent
Authors: John Broad, Victor W S Kung, Alexandra Palmer, Shezan Elahi, Azadeh Karami, Taher Darreh-Shori, Shafi Ahmed, Mohamed Adhnan Thaha, Rebecca Carroll, Joanne Chin-Aleong, Joanne E Martin, M Jill Saffrey, Charles H Knowles, Gareth John Sanger
Journal: Gut (2018)

Objective To determine if human colonic neuromuscular functions decline with increasing age. Design Looking for non-specific changes in neuromuscular function, a standard burst of electrical field stimulation (EFS) was used to evoke neuronally mediated (cholinergic/nitrergic) contractions/relaxations in ex vivo muscle strips of human ascending and descending colon, aged 35–91 years (macroscopically normal tissue; 239 patients undergoing cancer resection). Then, to understand mechanisms of change, numbers and phenotype of myenteric neurons (30 306 neurons stained with different markers), densities of intramuscular nerve fibres (51 patients in total) and pathways involved in functional changes were systematically investigated (by immunohistochemistry and use of pharmacological tools) in elderly (≥70 years) and adult (35–60 years) groups. Results With increasing age, EFS was more likely to evoke muscle relaxation in ascending colon instead of contraction (linear regression: n=109, slope 0.49%±0.21%/year, 95% CI), generally uninfluenced by comorbidity or use of medications. Similar changes were absent in descending colon. In the elderly, overall numbers of myenteric and neuronal nitric oxide synthase-immunoreactive neurons and intramuscular nerve densities were unchanged in ascending and descending colon, compared with adults. In elderly ascending, not descending, colon numbers of cell bodies exhibiting choline acetyltransferase immunoreactivity increased compared with adults (5.0±0.6 vs 2.4±0.3 neurons/mm myenteric plexus, p=0.04). Cholinergically mediated contractions were smaller in elderly ascending colon compared with adults (2.1±0.4 and 4.1±1.1 g-tension/g-tissue during EFS; n=25/14; p=0.04); there were no changes in nitrergic function or in ability of the muscle to contract/relax. Similar changes were absent in descending colon. Conclusion In ascending not descending colon, ageing impairs cholinergic function.
Surgical resection of large anterior mediastinal masses: Results of median sternotomy approach.
Authors: Raj Mohan
Journal: Journal of Clinical Oncology (2017)

e20005 Background: Anterior mediastinal masses are a diverse group of tumors generally presenting as compressive symptoms. Larger masses require open surgical approaches including median sternotomy or sterno-thoracotomy. In this study we analyzed the surgical and pathological outcomes of large anterior mediastinal masses resected through sternotomy approach. Methods: Data of 16 patients with anterior mediastinal masses ( &gt; 10 cms) treated surgically was analyzed retrospectively. All the patients were evaluated preoperatively with MRI, CT guided biopsy and pulmonary function test followed by exploration through median sternotomy approach with/without cardiac bypass (through femoral access). Adjuvant chemo-radiation was used according to histopathological features. Results: A total of 10 male and 6 females with median age 42 years (range: 6-62) underwent resection. Three patients received neoadjuvant chemotherapy and the mean tumor size was 12.2 cms. Histopathologies included mature teratomas/dermoids (4), thymic carcinoma (3), nerve sheath tumors (3), malignant germ cell tumors (3), synovial sarcoma (1) primary mediastinal goiter (1) and inflammatory pseudo tumor (1). There was no postoperative mortality and two patients required cardiac bypass. Bovine pericardium was used in two patients for the loss of large are of pericardium. One patient required biograft for replacement of resected superior vena cava. Major morbidities included prolonged ventilation and intrathoracic collection in two patients. All the patients were disease free after a median follow up of 14 months. Conclusions: Large anterior mediastinal masses are challenging surgically. An aggressive surgical approach through median sternotomy in association with cardiac bypass helps in complete resection and may lead to optimal results.