tbuckley/cabot-search huggingface dataset:
Minimally invasive or open oesophagectomy for localized oesophageal cancer: Results of the ROMIO phase 3 randomized controlled trial.
Authors: Jane M. Blazeby
Journal: Journal of Clinical Oncology (2021)

e16057 Background: Patients with localised oesophageal adenocarcinoma or squamous cell cancer are frequently offered surgery, usually with neoadjuvant treatment. Whether minimally invasive surgical approaches are superior to standard open procedures in terms of patient recovery and survival benefit is unclear. Well-designed and well-conducted pragmatic trials are limited. The ROMIO study compared laparoscopic abdominal surgery and thoracotomy (LAO) with open oesophagectomy (OO), to test the hypothesis that LAO allows faster recovery than OO whilst maintaining the survival benefit of surgery. Methods: A pragmatic multi-centre randomised controlled trial (1:1 LAO vs. OO) was conducted in 9 major cancer centres in the UK. Included were patients with localised adenocarcinoma or squamous cell cancer selected by a multi-disciplinary team for oesophagectomy with or without neoadjuvant treatment. Surgery was quality assured by provision of a protocol, pre-operative video assessment of the 40 participating surgeons and intra-operative photographs of key agreed surgical components. The primary outcome was the physical function scale of the EORTC QLQ-C30 assessed during the first 3 months. Results: At enrolment to ROMIO 447 (85%) of 526 participants were male, mean age was 67 years (SD 9), 469 (89%) had an adenocarcinoma, 368 (70%) had a clinically staged T3 or T4a tumour, 295 (56%) had clinically positive nodes, and 438 (83%) underwent neoadjuvant treatment. 263 were randomly allocated to each of the two procedures, with 241 (92%) undergoing their allocated open surgery and 237 (91%) undergoing their allocated LAO (hybrid) surgery. Analyses are underway and this presentation will include the primary outcome measure and other short-term clinical outcomes including key complications and survival during the first 90 days (clinical data &gt;95% complete). Conclusions: ROMIO is the largest multi-centre randomised controlled surgical trial of minimal access versus open surgical approaches for oesophageal cancer. The provision of a surgical quality assessment tool will supplement trial data to provide for the first-time evidence of surgical standards of both approaches. Clinical trial information: ISRCTN10386621.
Acute thromboembolic events (TE) within 30 days of COVID-19 infection in cancer patients.
Authors: Phaedon D. Zavras, Rafi Kabarriti, Vikas Mehta, Sanjay Goel, Henny Heisler Billett
Journal: Journal of Clinical Oncology (2021)

e18691 Background: Increased rates of TE have been reported in patients (pts) with coronavirus disease (COVID-19), even without prior predisposition to thrombosis. Patients with cancer are already predisposed to a hypercoagulable state. We aimed to assess whether COVID-19 further increased the risk of TE in pts with active cancer at Montefiore Medical Center, Bronx, NY. Methods: The EMR of 90 cancer pts diagnosed with COVID-19 from March 15 th to April 10 th , 2020 were reviewed. COVID-19 testing was performed by PCR of nasal swab samples. Active cancer was defined as disease treated &lt;1 year. Reports of imaging studies performed &lt;30 days of the COVID-19+ test, either for new symptoms or for other reasons, were reviewed for new arterial (ATE) and/or venous thromboses (VTE). Patient were followed for 30 days from the date of COVID-19+ test for development of TE, hospital length of stay (LOS) and mortality. Results: Of 90 pts, 11 (12.2%) were found to have 13 new TE within 30 days of COVID-19+ test, 8 (8.9%) arterial and 5 (5.6%) venous. Of the 8 ATE, 7 were new strokes and/or microvascular cerebral disease (MCD) and 1 was a spleen infarct (SI). Of the 5 VTE, 3 were deep venous thrombosis, 1 pulmonary embolism (PE) and 1 patient presented with a superficial VTE. Two patients had 2 new TE each; stroke/PE and MCD/SI, respectively. Peak D-dimer (DD) value was higher in the TE group; mean DD (SD), TE vs no TE, 7.1 (3.4) vs 6.4 (7) ug/mL, p=0.03. Pts on either prophylactic or therapeutic anticoagulation (AC) had less TE; AC vs no AC, 9.1% vs 90.9%, p=0.0003. Only 1 pt on Enoxaparin prophylaxis developed TE. Of the 20 pts on therapeutic AC, 25% were newly started due to concern for thrombosis; the rest were already receiving AC for other reasons. Mortality was higher in the TE group; HR, TE vs no TE, 2.6, 95% CI (1.2 - 5.6), p=0.009. There was no correlation of cancer type, disease stage (metastatic or not), administration of prior chemotherapy or immunotherapy, common comorbidities, patient setting (inpatient, ICU, outpatient, ED visit), LOS or ventilation status with increased incidence of TE. Conclusions: Pts with COVID-19 have high rates of TE, and this is true for our pts with cancer. A high incidence of ATE was noted. TE was associated with increased mortality.[Table: see text]
Interaction effect between mutational events on predicting efficacious immunotherapy in nonsquamous NSCLC: Results from 1,083 patients.
Authors: Fan Zhang, Lei Zhao, Tao Li, Yu Xu, Chengcheng Li, Guoqiang Wang, Shangli Cai, Yi Hu, Jinliang Wang
Journal: Journal of Clinical Oncology (2021)

e21100 Background: Despite that the biomarkers of single mutational events predicting efficacy of immune checkpoint inhibitors (ICIs) have been intensively studied in non-squamous NSCLC, the interaction effects between mutations on prediction were scarcely investigated due to the limited sample size. Deeper understanding of these inter-relations could optimize the prediction model and provide insights for basic research on anti-tumor immunity. Methods: In total, 1083 patients with non-squamous NSCLC were included. 288 patients with both PFS and OS data receiving monotherapy from the MSKCC, DFCI, and SNCC cohorts were included in the training set-1. 304 and 294 patients from the POPLAR/OAK cohort treated with atezolizumab or docetaxel were included in the training set-2 and the control set respectively. Validation set-1 and validation set-2 respectively consists of 104 patients receiving monotherapy with only OS data and 93 patients treated with combination therapy from the MSKCC cohort. Risk models using single mutations (uni-model) and both single mutations and interactions (inter-model) were developed via multivariable Cox proportional hazards regression model. Results: By cross-validation in training set-1/2, five single mutational events, including mutations of EGFR, STK11, PTPRD, members in PI3K pathway, and members in HRR pathway, and five interactions ( EGFR* PI3K pathway, TP53* KRAS, TP53* ERBB4, cell cycle pathway*HRR pathway, and PI3K pathway*chromatin remodeling pathway) were identified as predictive biomarkers. The score of inter-model exhibited higher correlation with immunotherapeutic PFS in the training sets, compared to the uni-model ( Dxy: 0.173 vs. 0.139). Uni-score low was moderately associated with longer OS in the validation set-1 (HR = 0.62, 95% CI 0.35-1.08, P = 0.092), and PFS in the validation set-2 (HR = 0.32, 95% CI 0.18-0.60, P &lt; 0.001). Inter-score low showed better predictive utility in the validation set-1 (HR = 0.53, 95% CI 0.30-0.94, P = 0.030), and the validation set-2 (HR = 0.23, 95% CI 0.10-0.50, P &lt; 0.001). On the contrary, inter-score low was associated with worse PFS and OS in the control set, indicating that inter-score low might be a negative prognostic biomarker, but positive predictive biomarker to efficacious immunotherapy. Conclusions: Our study suggests that the predictive biomarkers might not be similarly predictive in every single subpopulation, and they might be merely valid under certain circumstances, which is termed by “interaction effect”. Given this, the future researches probing into immunotherapeutic predictor should focus on the mutual influence between distinct biomarkers, for instance, adding an interaction term in the Cox proportional hazards regression model.
Patient quality criteria for a multidisciplinary integrated care pathway for von Hippel-Lindau syndrome.
Authors: Rachel H. Giles, Koen Dreijerink, Rachel van Leeuwaarde, Wendy Wolters, Wouter Zandee, Patricia Zondervan, Thera P. Links
Journal: Journal of Clinical Oncology (2021)

e13534 Background: The objective was to establish a comprehensive set of patient-driven recommendations for specialists and allied healthcare professionals for the care of individuals with the multiple neoplasia syndrome von Hippel-Lindau (VHL). VHL patients require multiple surgeries during the course of their lifetimes, due to cysts and tumors in various organs including the kidney, brain, eye, spine, pancreas, adrenal glands, and broad ligament/epididymis. Screening and care from multiple specialists form the backbone of their care, yet this is rarely coordinated in an optimal manner. Methods: The Dutch VHL patient organization (Belangenvereniging VHL) initiated this process, and approached specialists and expert patients for input. Using components of consensus methodology, a 20-member multidisciplinary panel produced an integrated care pathway relating to the provision of care for VHL patients by patients, medical specialists, specialist nurses and allied healthcare professionals. Items were developed by 3 rounds of email correspondence in which the basis was formed for a consensus meeting which constituted the third round of review. The fourth and final round was an email review of the consensus output. Results: The panel agreed on recommendations for the optimal quality of care for VHL patients, in the form of a decision tree, which is supervised by a nurse specialist as a main contact point. These items were grouped under categories of "Diagnosis" and "Patient Pathway" and included recommendations on training, communication, and quality assessment as well as specific items related to VHL diagnosis clinics, non-academic treatment clinics, and follow-up survivor groups. The Netherlands has 3 official Expert Reference Centers for VHL care (Groningen, Utrecht, Nijmegen), and the patient organization and allied specialists are planning to publish this protocol, while implementing its practice in those 3 sites. Conclusions: Medical specialists (internists, endocrinologists, urologists, neurosurgeons, ophthalmologists, geneticists, etc) and specialist nurses play a vital role alongside allied healthcare professionals to provide care to people with VHL and their families. Yet VHL patients and their families are the experts most acquainted with their own unmet needs. We present a set of standards and consensus recommendations from the patient perspective for the roles for these practitioners to provide optimal VHL care. These recommendations could form the basis for facilitated development of comprehensive integrated pathways for any pleiotropic neoplasia syndrome, and represent best-practice collaboration between patient organizations and national expertise centers to provide value-based healthcare.
Prem Nath Satsangi
Authors: Jack Satsangi
Journal: BMJ (2021)

Prem Nath Satsangi was born in Basti in eastern Uttar Pradesh, at a time when life expectancy in the area was 35 years, and infant mortality up to 50%.

He studied medicine at King George’s Medical College, Lucknow, completing the degree of MBBS in 1954. He was awarded MS in general surgery two years later in respect of his thesis on amino acid content in skin, and its relation to …
MVX-ONCO-1 in advanced refractory cancers: Safety, feasibility, and preliminary efficacy results from all HNSCC patients treated in two ongoing clinical trials.
Authors: Eugenio Fernandez, Remi Vernet, Emily Charrier, Denis Migliorini, Markus Joerger, Marie-Claude Belkouch, Muriel Urwyler, Olivier Von Rohr, Valentin Saingier, Virginie Ancrenaz, Nicole Grandjean, Emmanuel Lavalliere, Elisabeth Lafferma, Olivier Rubin, Jean Villard, Julien Grogg, Nicolas Mach
Journal: Journal of Clinical Oncology (2021)

e18005 Background: MVX-ONCO-1 is an active, personalized cancer immunotherapy combining irradiated autologous tumor cells and encapsulated, genetically engineered allogeneic cells producing GM-CSF. The immunostimulant cytokine is released locally in a sustained manner over one week at the immunization site. All cancer types are potential candidates and more than 40 patients have been treated in two clinical trials. Here we report the data on all HNSCC patients treated, as of 31 st January 2021. Methods: Eleven (11) patients with locally advanced/metastatic HNSCC relapsing after at least one line of systemic therapy were enrolled in 2 open-label, single-arm clinical trials (NCT02193503 and NCT02999646) evaluating the safety, feasibility and efficacy of MVX-ONCO-1. All patients were treated with at least 5 administrations of MVX-ONCO-1 over 8 weeks (W1,2,3,4,6,8). Each administration consists of the subcutaneous implantation in healthy skin of 2 capsules containing each 8x10 5 cells, producing &gt; 20ng/24h of GM-CSF, and an injection of 4x10 6 irradiated autologous tumor cells between the 2 capsules. Results: Eleven (11) patients are evaluable for safety and feasibility. Ten patients (91%) with at least 6 months, respectively 9 patients (82%) with 12 months follow-up are evaluable for efficacy analysis. Eight patients (80%) failed both Cisplatin based chemotherapy and anti-PD1 therapies prior to enrolment. The most common treatment-related adverse event (AE) was local hematoma at implantation site in 3 patients (27%). None experienced &gt; grade 2 treatment-related AE. Overall Survival is 70% (7/10pts) at 6 months, and 56% (5/9pts) at 12 months. Eight patients (80%) presented some degree of disease control with 4SDs, 2PRs and 2CRs. Both CRs are longstanding, with both patients not any longer on anticancer therapy for 24 and 6 months respectively. While 1 PR was observed on MVX-ONCO-1, 1PR and 1CR were observed on subsequent Nivolumab therapy (both CPS0), and 1 CR was observed after carboplatin-cetuximab. Two patients had progressive disease as best overall response. Conclusions: Treatment with MVX-ONCO-1 is feasible, safe and well tolerated. Preliminary efficacy data shows an encouraging rate of tumor control including prolonged CR in patients subsequently treated with nivolumab or chemotherapy. Efficacy of the concurrent use of anti-PD-1 and MVX-ONCO will be assessed in a planned clinical trial. Clinical trial information: NCT02999646.
Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases
Authors: Anna Maria Di Giacomo, Vanna Chiarion-Sileni, Michele Del Vecchio, Pier Francesco Ferrucci, Michele Guida, Pietro Quaglino, Massimo Guidoboni, Paolo Marchetti, Ornella Cutaia, Giovanni Amato, Alessia Covre, Roberto Camerini, Luana Calabrò, Monica Valente, Diana Giannarelli, Mario Mandalà, Michele Maio
Journal: Clinical Cancer Research (2021)

Phase II trials have shown encouraging activity with ipilimumab plus fotemustine and ipilimumab plus nivolumab in melanoma brain metastases. We report the primary analysis and 4-year follow-up of the NIBIT-M2 study, the first phase III trial comparing these regimens with fotemustine in patients with melanoma with brain metastases.This phase III study recruited patients 18 years of age and older with BRAF wild-type or mutant melanoma, and active, untreated, asymptomatic brain metastases from nine centers, randomized (1:1:1) to fotemustine, ipilimumab plus fotemustine, or ipilimumab plus nivolumab. The primary endpoint was overall survival (OS).From January, 2013 to September, 2018, 27, 26, and 27 patients received fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab. Median OS was 8.5 months [95% confidence interval (CI), 4.8-12.2] in the fotemustine arm, 8.2 months (95% CI, 2.2-14.3) in the ipilimumab plus fotemustine arm (HR vs. fotemustine, 1.09; 95% CI, 0.59-1.99; P = 0.78), and 29.2 months (95% CI, 0-65.1) in the ipilimumab plus nivolumab arm (HR vs. fotemustine, 0.44; 95% CI, 0.22-0.87; P = 0.017). Four-year survival rate was significantly higher for ipilimumab plus nivolumab than fotemustine [(41.0%; 95% CI, 20.6-61.4) vs. 10.9% (95% CI, 0-24.4; P = 0.015)], and was 10.3% (95% CI, 0-22.6) for ipilimumab plus fotemustine. In the fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab arms, respectively, 11 (48%), 18 (69%), and eight (30%) patients had treatment-related grade 3 or 4 adverse events, without treatment-related deaths.Compared with fotemustine, ipilimumab plus nivolumab significantly improved overall and long-term survival of patients with melanoma with asymptomatic brain metastases.
Proteome and phospho-proteome profiling for deeper phenotype characterization of colorectal cancer heterogeneity.
Authors: Jakob Vowinckel, Thomas Corwin, Jonathan Woodsmith, Tobias Treiber, Roland Bruderer, Lukas Reiter, Eike-Christin von Leitner, Karel Novy, Hartmut Juhl, Oliver Rinner
Journal: Journal of Clinical Oncology (2021)

e15536 Background: The rise of precision oncology therapeutics requires deep understanding of the molecular mechanisms implicated in cancer biology. Colorectal cancer (CRC) is one of the first solid tumors to be molecularly characterized by defined genes and pathways. Advances in tumor profiling have revealed a profound molecular heterogeneity in CRC leading to the definition of several consensus molecular subtypes (CMS). However, this molecular heterogeneity is still largely defined on the genomic and transcriptomics level. To complement the understanding of genetically defined molecular subgroups, we performed large-scale deep proteomic and phospho-proteomic profiling of CRC patient biopsies and adjacent healthy control tissue, which has enabled to explore the phenotype and obtain more functional insights in cancer biology. Methods: Sample processing from 5-10 mg of tissue per sample was performed using a liquid handling robot. Phospho-peptide enrichment was carried out with a Kingfisher Flex device and MagReSyn Ti-IMAC magnetic beads. Data-Independent Acquisition (DIA) LC-MS/MS was performed on multiple platforms consisting of a Thermo Scientific Q Exactive HF-X mass spectrometer coupled to a Waters M-Class LC. Chromatography was operating at 5 µL/min, and separation was achieved using 45 min (whole proteome) and 60 min (phospho-proteome) gradients. Results: Indivumed has built IndivuType, the world’s first multi-omics database for individualized cancer therapy, analyzing the highest quality cancer biospecimens to generate the most comprehensive dataset, including genomics, transcriptomics, proteomics, and clinical outcome information. Enabled by the DIA technology, a mass spectrometric method developed by Biognosys that obtains peptide fragmentation data in a highly parallelized way with high sensitivity, more than 7,000 proteins in the whole proteome and 20,000 phospho-peptides in the phospho-proteome workflow were profiled across more than 900 resected tissue samples of various CMS of CRC. The resulting proteome and phospho-proteome data were integrated into the IndivuType database and cross-analyzed with genomic and transcriptomic markers. Through this combined analysis, novel insights in clinically relevant signaling pathways in CRC subtypes were revealed. Conclusions: The deep phenotypic profiling of cancer samples, using next generation proteomics and phospho-proteomics, has enabled us to go beyond the genomic level in the characterization of tumor molecular heterogeneity. This multi-omics approach provides a solid foundation to advance the understanding of cancer biology, unravel key molecular events, and support the identification of novel therapeutic targets for precision medicine in CRC.
Ending AIDS as a public health threat by 2030: Time to reset targets for 2025
Authors: Paul R. De Lay, Adèle Benzaken, Quarraisha Abdool Karim, Sani Aliyu, Carolyn Amole, George Ayala, Kalipso Chalkidou, Judy Chang, Michaela Clayton, Aleny Couto, Carl Dieffenbach, Mark Dybul, Wafaa El Sadr, Marelize Gorgens, Daniel Low-Beer, Smail Mesbah, Jorge Saveedra, Petchsri Sirinirund, John Stover, Omar Syarif, Aditia Taslim, Safiatou Thiam, Lucy Wanjiku Njenga, Peter D. Ghys, Jose Antonio Izazola-Licea, Luisa Frescura, Erik Lamontagne, Peter Godfrey-Faussett, Christopher Fontaine, Iris Semini, Shannon Hader
Journal: PLoS Medicine (2021)

Paul De Lay and co-authors introduce a Collection on the design of targets for ending the AIDS epidemic.
The temporal evaluation of RAS and BRAF mutation by liquid biopsy at progression after bevacizumab combinations in patients with metastatic colorectal cancer (mCRC).
Authors: Irem Bilgetekin, Mehmet Dogan, Cengiz Karacin, Fatma Bugdayci Basal, Ece Esin, Gokhan Ucar, Ozlem Aydin Isak, Goksen Inanc Imamoglu, Gul Sema Yildiran Keskin, Ismail Erturk, Burak Yasin Aktas, Naziyet Kose Baytemur, Kubra Aydin, Selcuk Cemil Ozturk, Bulent Aksel, Nuri Karadurmus, Olcay Kandemir, Berna Oksuzoglu, Umut Demirci
Journal: Journal of Clinical Oncology (2021)

e15587 Background: Expanded RAS analysis is essential for the selection of biologic agents in mCRC. RAS mutations indicates anti-EGFR unresponsiveness. In this study, we aimed to investigate RAS and BRAF mutations by liquid biopsy at progression in patients with RAS mutant mCRC. Methods: Sixty patients with mCRC who harbored tissue RAS mutations were prospectively analyzed between July 2019 and April 2020. All the patients treated with chemotherapy plus bevacizumab combinations . The plasma samples of the patients were analyzed after progression of bevacizumab combinations. RAS mutation profile was evaluated in plasma using Idylla PCR-based molecular diagnostics method, which enables rapid detection of common mutations in RAS and BRAF genes in circulating tumor DNA (ctDNA). Kaplan-Meier method was used for survival analysis and log-rank test was performed for comparison of groups. Results: The median age of the patients was 60 years (IQR:35-83 years) and female was (n=23, 38.3%). Primary tumor was located in the left colon in 81.7% of all patients. There were 95.0% KRAS and 5% NRAS mutations in baseline tissue biopsy. As a result of liquid biopsy after progression, 55.0% of the patients had KRAS, 3.3% NRAS and 3.3% had BRAF mutations. The RAS mutation detected in 58.3% of the patients. While there was no significant difference in terms of clinicopathological features between wild type (RAS/BRAF) and mutant type (RAS/BRAF) determined by liquid biopsy, the overall survival (OS) of the wild type group was significantly longer than mutant group (43.8 vs. 20.4 months, p= 0.002). Conclusions: This study demonstrated that there may be changes in RAS/BRAF mutation from plasma analysis after progression in patients with mCRC. Since better survival in the patient group with wild type was detected compared to the RAS concordance group, the evaluation of RAS mutation status at the time of progression may be important in terms of disease prognosis and treatment options.
A muscle fatigue-like contractile decline was recapitulated using skeletal myotubes from Duchenne muscular dystrophy patient-derived iPSCs
Authors: Tomoya Uchimura, Toshifumi Asano, Takao Nakata, Akitsu Hotta, Hidetoshi Sakurai
Journal: Cell Reports Medicine (2021)

Duchenne muscular dystrophy (DMD) is a muscle degenerating disease caused by dystrophin deficiency, for which therapeutic options are limited. To facilitate drug development, it is desirable to develop in vitro disease models that enable the evaluation of DMD declines in contractile performance. Here, we show MYOD1-induced differentiation of hiPSCs into functional skeletal myotubes in vitro with collagen gel and electrical field stimulation (EFS). Long-term EFS training (0.5 Hz, 20 V, 2 ms, continuous for 2 weeks) mimicking muscle overuse recapitulates declines in contractile performance in dystrophic myotubes. A screening of clinically relevant drugs using this model detects three compounds that ameliorate this decline. Furthermore, we validate the feasibility of adapting the model to a 96-well culture system using optogenetic technology for large-scale screening. Our results support a disease model using patient-derived iPSCs that allows for the recapitulation of the contractile pathogenesis of DMD and a screening strategy for drug development.