tbuckley/cabot-search huggingface dataset:
Patients of a third surgeon who worked at a Spire hospital are recalled over concerns
Authors: Clare Dyer
Journal: BMJ (2020)

The private hospital group Spire Healthcare, where the jailed surgeon Ian Paterson performed many of his operations, has recalled patients of a third surgeon over concerns that he may have carried out unnecessary or inadequate procedures.

The decision to recall patients of orthopaedic surgeon Michael Walsh follows the revelation last month that Spire was reviewing the care of 217 patients who had shoulder operations performed by another orthopaedic surgeon, Habib Rahman.1

Walsh’s patients, of whom Spire said “fewer than 50” had been recalled, underwent shoulder procedures at a Spire hospital in Leeds. Walsh also operated at a Leeds hospital run by another private company, Nuffield Health. Paterson and Rahman operated at Spire hospitals in the West Midlands.

Spire suspended Walsh in …
Safety and efficacy of intravesical nadofaragene firadenovec for patients with high-grade, BCG unresponsive nonmuscle invasive bladder cancer (NMIBC): Results from a phase III trial.
Authors: Stephen A. Boorjian, Colin P.N. Dinney
Journal: Journal of Clinical Oncology (2020)

442 Background: Patients (pts) with BCG-unresponsive NMIBC are at significant risk for disease recurrence and progression. While cystectomy can be curative, many such pts are unwilling or unable given the attendant morbidity of surgery. To date, effective salvage intravesical therapies in this setting remain lacking. Nadofaragene firadenovec is a novel intravesical gene-mediated therapy that delivers the human IFNα2b gene resulting in IFNα2b expression that provided durable responses in a previous Phase 2 trial. Herein, we report the results from a follow-up Phase III trial of this agent for pts with BCG unresponsive NMIBC. Methods: This multicenter, open-label Phase 3 study investigated nadofaragene for high-grade NMIBC (CIS ± Ta/T1, or Ta/T1 alone) unresponsive to BCG. Nadofaragene (3X10 11 vp/mL [75 mL]) was administered once every 3 months for up 4 doses in the initial 12 months, with additional dosing at the investigator’s discretion. The primary endpoint was complete response (CR) at any time in pts with carcinoma in situ (CIS). Results: A total of 157 pts (safety population, n=157; efficacy population, n=151) were enrolled. Among pts with CIS (n=103), 55 (53.4%) (95% CI, 43.3-63.3) achieved CR, all by month 3 after treatment. Of these 55 CIS CR pts, 25 (45.5%) remained free of high-grade recurrence at month 12, confirmed on protocol-mandated biopsy. For pts with HG Ta/T1 alone, 35 (72.9%) and 21 (43.8%) were free from recurrence at 3 and 12mos, respectively. Most treatment-emergent adverse events (TEAEs) were transient in nature: instillation site discharge 33.1%; fatigue 23.6%; bladder spasm 19.7%; micturition urgency 17.8%; hematuria 16.6%. There were 2 Gr4 TEAEs (sepsis and anaphylactic reaction, neither related to study drug) and no Gr5 TEAEs. Conclusions: Nadofaragene achieved CR in 53.4% of pts with BCG-unresponsive CIS, and was well tolerated. Responses were noted early and remained durable to one year. These data represent a potentially significant management advancement for a historically difficult to treat disease state. Clinical trial information: NCT02773849.
HLA Haplotype DRB1*07:01-DQA1*02:01-DQB1*02:02 Predicts Pegaspargase Hypersensitivity
Authors: Yiwei Liu, Colton Smith, Wenjin Yang, Cheng Cheng, Seth Karol, Eric Larsen, Naomi Winick, William Carroll, Elizabeth Raetz, Mignon Loh, Stephen Hunger, Stuart Winter, Kimberly Dunsmore, Meenakshi Devidas, Jun Yang, William Evans, Sima Jeha, Ching-Hon Pui, Hiroto Inaba, Mary Relling
Journal: Journal of Allergy and Clinical Immunology (2020)
Patient outcomes associated with post-tuberculosis lung damage in Malawi: a prospective cohort study
Authors: Jamilah Meghji, Maia Lesosky, Elizabeth Joekes, Peter Banda, Jamie Rylance, Stephen Gordon, Joseph Jacob, Harmien Zonderland, Peter MacPherson, Elizabeth L Corbett, Kevin Mortimer, Stephen Bertel Squire
Journal: Thorax (2020)

Post-tuberculosis lung damage (PTLD) is a recognised consequence of pulmonary TB (pTB). However, little is known about its prevalence, patterns and associated outcomes, especially in sub-Saharan Africa and HIV-positive adults.Adult (≥15 years) survivors of a first episode of pTB in Blantyre, Malawi, completed the St George's Respiratory Questionnaire, 6-minute walk test, spirometry and high-resolution CT (HRCT) chest imaging at TB treatment completion. Symptom, spirometry, health seeking, TB-retreatment and mortality data were collected prospectively to 1 year. Risk factors for persistent symptoms, pulmonary function decline and respiratory-related health-seeking were identified through multivariable regression modelling.Between February 2016 and April 2017, 405 participants were recruited. Median age was 35 years (IQR: 28 to 41), 77.3% (313/405) had had microbiologically proven pTB, and 60.3% (244/403) were HIV-positive. At pTB treatment completion, 60.7% (246/405) reported respiratory symptoms, 34.2% (125/365) had abnormal spirometry, 44.2% (170/385) had bronchiectasis ≥1 lobe and 9.4% (36/385) had ≥1 destroyed lobe on HRCT imaging. At 1 year, 30.7% (113/368) reported respiratory symptoms, 19.3% (59/305) and 14.1% (43/305) of patients had experienced declines in FEV1 or FVC of ≥100 mL, 16.3% (62/380) had reported ≥1 acute respiratory event and 12.2% (45/368) had symptoms affecting their ability to work.PTLD is a common and under-recognised consequence of pTB that is disabling for patients and associated with adverse outcomes beyond pTB treatment completion. Increased efforts to prevent PTLD and guidelines for management of established disease are urgently needed. Low-cost clinical interventions to improve patient outcomes must be evaluated.
Advances in Targeting RET-Dependent Cancers
Authors: Vivek Subbiah, Gilbert J. Cote
Journal: Cancer Discovery (2020)

Abstract RET alterations have been characterized as oncogenic drivers in multiple cancers. The clinical validation of highly selective RET inhibitors demonstrates the utility of specific targeting of aberrantly activated RET in patients with cancers such as medullary thyroid cancer or non–small cell lung cancer. The remarkable responses observed have opened the field of RET-targeted inhibitors. In this review, we seek to focus on the impact of therapeutic RET targeting in cancers. Significance: Successful clinical translation of selective RET inhibitors is poised to alter the therapeutic landscape of altered cancers. Questions that clearly need to be addressed relate to the ability to maintain long-term inhibition of tumor cell growth, how to prepare for the potential mechanisms of acquired resistance, and the development of next-generation selective RET inhibitors.
Intensive alternating 6-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma in children and adolescents: Impact on survival.
Authors: Gerges Attia Demian, Hany Hussein, Emad Nabil Ebeid, Samy Elbadawy
Journal: Journal of Clinical Oncology (2012)

9566 Background: Both 5-year overall survival (OS) and event free survival (EFS) for pediatric rhabdomyosarcoma (RMS) has increased in the last 3 decades through multimodality, risk-adapted management. The reported EFS for high risk RMS in children treated at the NCI in Egypt during the 1990s was 50%. Using an intensive 6 drug alternating chemotherapy regimen in addition to local control measures was our aim to improve the outcome for this group of patients. Methods: Forty-six previously untreated patients, younger than 21 years of age, with localized high risk RMS received this regimen. High risk criteria included: (1) Localized tumors (T1) biopsied or incompletely resected, ortumors extending beyond the tissue or organ of origin (T2) completely or incompletely resected at any site (excluding orbit, uterus, vagina, and paratestis); (2)All node positive patients with primary tumor at any site; and (3) All RMS with alveolar histology at any site. Chemotherapy regimen comprised 27 weeks of alternating 6 drugs (carboplatin, doxorubicin hydrochloride, ifosfamide, actinomycin D, etoposide, vincristine). Local therapy (surgery, radiotherapy, or both) was offered at week 9. Results: Forty-six patients meeting high-risk criteria were recruited from September 2000 to November 2005. Median follow-up of survivors was 62 months. The 5-year OS and EFS for the whole group was 64% ± 10% and 47% ± 8% respectively. The EFS was significantly affected by: the size of the tumor (≤5 cm vs. &gt; 5 cm, p= 0.03), SIOP UICC clinical stage (p = 0.004), IRS stage (p = 0.01), lymph node status (p = 0.02), surgery vs. incisional biopsy (p=0.01) and overall duration of time in which therapy was delivered (p = 0.04). There was significant toxicity, mainly hematologic, but only one treatment related fatality. Conclusions: The use of intensified alternating 6-drug CT did not improve the EFS compared with historical control although it was feasible to be delivered safely in a variety of outpatient settings. Surgical resection of the tumor is essential. Delivering therapy in a timely fashion appears to impact outcome and future investigations will focus on impediments to administering chemotherapy as scheduled.
Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Rα antibody, is required to broadly inhibit type 2 inflammation
Authors: Audrey Le Floch-ramondou, Kirsten Nagashima, George Scott, Dylan Birchard, Seblewongel Asrat, Yu Bai, Wei Keat Lim, Andrew Murphy, Matthew Sleeman, Jamie Orengo
Journal: Journal of Allergy and Clinical Immunology (2020)
Virological suppression and clinical management in response to viremia in South African HIV treatment program: A multicenter cohort study
Authors: Lucas E. Hermans, Sergio Carmona, Monique Nijhuis, Hugo A. Tempelman, Douglas D. Richman, Michelle Moorhouse, Diederick E. Grobbee, Willem D. F. Venter, Annemarie M. J. Wensing
Journal: PLoS Medicine (2020)

Uptake of antiretroviral treatment (ART) is expanding rapidly in low- and middle-income countries (LMIC). Monitoring of virological suppression is recommended at 6 months of treatment and annually thereafter. In case of confirmed virological failure, a switch to second-line ART is indicated. There is a paucity of data on virological suppression and clinical management of patients experiencing viremia in clinical practice in LMIC. We report a large-scale multicenter assessment of virological suppression over time and management of viremia under programmatic conditions.Linked medical record and laboratory source data from adult patients on first-line ART at 52 South African centers between 1 January 2007 and 1 May 2018 were studied. Virological suppression, switch to second-line ART, death, and loss to follow-up were analyzed. Multistate models and Cox proportional hazard models were used to assess suppression over time and predictors of treatment outcomes. A total of 104,719 patients were included. Patients were predominantly female (67.6%). Median age was 35.7 years (interquartile range [IQR]: 29.9-43.0). In on-treatment analysis, suppression below 1,000 copies/mL was 89.0% at month 12 and 90.4% at month 72. Suppression below 50 copies/mL was 73.1% at month 12 and 77.5% at month 72. Intention-to-treat suppression was 75.0% and 64.3% below 1,000 and 50 copies/mL at month 72, respectively. Viremia occurred in 19.8% (20,766/104,719) of patients during a median follow-up of 152 (IQR: 61-265) weeks. Being male and below 35 years of age and having a CD4 count below 200 cells/μL prior to start of ART were risk factors for viremia. After detection of viremia, confirmatory testing took 29 weeks (IQR: 16-54). Viral resuppression to below 1,000 copies/mL without switch of ART occurred frequently (45.6%; 6,030/13,210) but was associated with renewed viral rebound and switch. Of patients with confirmed failure who remained in care, only 41.5% (1,872/4,510) were switched. The median time to switch was 68 weeks (IQR: 35-127), resulting in 12,325 person-years spent with a viral load above 1,000 copies/mL. Limitations of this study include potential missing data, which is in part addressed by the use of cross-matched laboratory source data, and the possibility of unmeasured confounding.In this study, 90% virological suppression below the threshold of 1,000 copies/mL was observed in on-treatment analysis. However, this target was not met at the 50-copies/mL threshold or in intention-to-treat analysis. Clinical management in response to viremia was profoundly delayed, prolonging the duration of viremia and potential for transmission. Diagnostic tools to establish the cause of viremia are urgently needed to accelerate clinical decision-making.
The Personalized Medicine for Prostate Cancer (PMPC) Study: The role of race, genomics, and patient complexity in treatment outcomes.
Authors: Sheldon Greenfield, Edward M. Uchio, Mark S. Litwin, Gregory Gin, Isla Garraway, Timothy J. Daskivich, Harwood Garland, Sherrie H. Kaplan
Journal: Journal of Clinical Oncology (2020)

302 Background: Matching of patients with optimal treatment for localized prostate cancer (PCa) requires accurate estimates of risk for progression or recurrence. Traditional risk assessment methods may underestimate risk for certain patient subgroups, (e.g. minorities). In the PMPC study, we replicated an expanded risk model, adding genomic data to improve risk prediction and optimize treatment assignment for PCa. Methods: A prospective cohort of 660 patients with early PCa was identified from 3 teaching hospitals and 2 VA Hospitals in Southern California. Risk model data were collected from electronic medical records, patient questionnaires and tissue-based genomic data provided by GenomeDx. Complexity variables included demographic characteristics, clinical markers (PSA levels, Gleason score), patient-reported health status measures (e.g. comorbidity burden, depression, stress) and Decipher score. We compared individual components of the complexity score for 425 Non-Hispanic White (NHW) and 104 African American (AA) men using t-tests. Composite complexity scores were derived from weights from general linear models. Mean complexity scores were compared using t-tests. Results: Compared with NHW men, AA men had statistically significantly more comorbidity, poorer health ratings, poorer physical functioning, more depression, less energy, more fatigue, more stress and less resilience. More AA men had Gleason scores &gt;6 (60.0%) than NHW men (46.6%), p=.0134. Fewer AA men (41.5%) had ‘low risk’ Decipher scores compared to NHW men (53.8%). More AA men had high complexity scores compared with NHW men (63.4% vs. 45.1%, p=.008), however, there were no statistically significant differences in the proportion of NHW vs. AA men on active surveillance, 46.0% vs. 40.7%, p=.384. Using clinical variables alone there were no significant differences in low risk between NHW and AA men. Conclusions: The addition of genomic data improved the complexity model developed earlier. AA men may be at higher risk for suboptimal treatment than predicted by clinical variables alone. Data from the longitudinal cohort will test accuracy of model prediction for disease progression or recurrence. Clinical trial information: NCT03770351.
Differences in the exposure to sunitinib in the immediate and deferred cytoreductive nephrectomy (CN) arms of the randomized controlled trial SURTIME.
Authors: Yasmin Abu-Ghanem, Johannes V. Van Thienen, Christian U. Blank, Thomas Powles, Bertrand F. TOMBAL, Laurence Collette, John B. A. G. Haanen, Axel Bex
Journal: Journal of Clinical Oncology (2020)

703 Background: SURTIME compared immediate CN followed by sunitinib 50mg/day (4/2 weeks on-off) 4 weeks after surgery (n=50) versus 3 cycles sunitinib followed by CN in the absence of progression and continued sunitinib 4 weeks after surgery (n=49). In the intention to treat analysis, the hazard ratio of the secondary endpoint overall survival (OS) favored deferred CN [0.57 (CI: 0.34–0.95, p=0.032)] with a median OS of 32.4 (CI: 14.5-65.3) versus only 15.0 months (CI: 9.3–29.5), following immediate CN. We investigated differences in exposure to systemic therapy between the two arms. Methods: Post-hoc exploratory analysis of number of patients receiving sunitinib, overall response rate (ORR) by RECIST 1.1, length of drug exposure and dose intensity in the immediate and deferred arm. Descriptive methods and 95% confidence intervals (CI) were used. Results: In the deferred arm, 97.7% (CI: 89.3-99.6; n=48) received sunitinib versus only 80% (CI: 66.9-88.7, n=40) in the immediate arm. Following immediate CN, 19.6% had confirmed progression at an interval CT scan 4 weeks after CN compared to baseline and 25% started with sunitinib &gt; 4 weeks after surgery. At week 16, 46.0% had progressed at metastatic sites in the immediate CN arm versus 32.7% in the deferred arm, who had a per-protocol recommendation against nephrectomy. In the deferred arm, 83% completed 3 cycles sunitinib with 77.1% at &gt;90%-120% relative dose intensity and an ORR of 29%, reducing the median sum of target lesions from 162 to 127 mm prior to planned CN.Of the patients who started with sunitinib in the immediate (n=40) or continued in the deferred arm after CN (n=29) median duration of treatment was 140 versus 351 days. Conclusions: With immediate CN fewer patients receive systemic therapy, which is administered later and shorter compared to the deferred approach. Starting systemic therapy with sunitinib leads to early and more profound control of the disease and identification of progression prior to planned CN which may translate into the observed survival benefit. Clinical trial information: NCT01099423.
Comparative response of bladder cancer models to interferon alpha: Recombinant protein versus adenoviral delivery.
Authors: Jennifer Green, Robin Osterhout, Scott McDonnell, Amy Klova, Adeela Kamal
Journal: Journal of Clinical Oncology (2020)

531 Background: Adenoviral delivery of the IFNα2b gene to the bladder urothelium enables prolonged exposure to high levels of IFNα2b protein, relative to intravesically-instilled IFNα protein treatments where short bladder dwell time limits exposure. As such, adenoviral-delivered IFNα2b has demonstrated clinical efficacy in patients with BCG-unresponsive NMIBC. The pleiotropic anti-tumor effects of IFNα include both stimulation of the host immune system and direct cytotoxicity of tumor cells. As clinical efficacy of adenoviral-delivered IFNα2b in the context of bladder cancer could be driven by immune-mediated or direct effects, or both, characterizing the cellular and molecular mechanisms of these activities is warranted. Methods: Here, we investigate the molecular mechanisms of tumor-intrinsic resistance to adenoviral-delivered or recombinant IFNα2b in a panel of bladder cancer cell line and patient-derived bladder cancer organoid models. Adenoviral vectors were constructed that express IFNα2b together with a GFP reporter (Ad-IFNα2b) or GFP alone (Ad-GFP), validated, and benchmarked against in vivo data from the literature. Bladder cancer cells and organoids were treated in vitro with rhIFNα2b, Ad-IFNα2b or conditioned media produced by Ad-IFNα2b infected cells, followed by measurements of cytotoxicity and gene expression in response to treatment. Results: Some bladder cancer models exhibited dose-dependent cytotoxicity in response to IFNα2b treatments, while others were resistant to these effects. Genomic and mRNA features associated with IFNα2b sensitivity/resistance are being evaluated and may inform future investigation of the mechanism of anti-tumor activity in patients. Additional studies to evaluate immune-mediated mechanisms are being conducted. Conclusions: Together, these studies will help to define the molecular mechanisms of response and resistance to IFNa2b treatment in bladder cancer patients.
Introducing the next evolution of the small-caliber-tip transparent hood: enhancing the pocket-creation method by building on previous successes
Authors: Yoshikazu Hayashi, Tatsuma Nomura, Ralph F. Lee, Yoshimasa Miura, Satoshi Shinozaki, Keijiro Sunada, Hironori Yamamoto
Journal: Endoscopy (2020)

The pocket-creation method facilitates the procedure of endoscopic submucosal dissection (ESD) and results in high-quality resected specimens with thick and minimally burned submucosa [1] [2] [3] [4]. The small-caliber-tip transparent hood (ST hood; Fujifilm, Tokyo, Japan) is an essential component of the pocket-creation method, with a conical shape that allows the endoscope tip to enter into the submucosal space quickly and easily [5]. The small-caliber-tip transparent hood provides both traction and countertraction, stretching the submucosa and allowing it to be easily cut with minimal thermal damage. The previous conventional (DH-15GR; Fujifilm) and short small-caliber-tip transparent hoods (DH-28GR; Fujifilm) each had their own advantages and disadvantages. However, the latest hood of this type (DH-33GR; Fujifilm), launched in Japan in June 2019, incorporates the best qualities of both ([Fig. 1], [Table 1]). Features of this latest hood include: 1) a small, 7-mm diameter orifice; 2) an inner guiderail directing the tips of inserted devices to the center of the endoscopic view (similar to the conventional model); 3) a shorter, 7-mm conical protrusion; 4) double slits facilitating drainage of internal fluid; 5) an easy-to-attach silicon cylindrical base (similar to the short small-caliber-tip transparent hood); and 6) a redesigned proximal guiderail ([Fig. 2]).
An international challenge to use artificial intelligence to define the state-of-the-art in kidney and kidney tumor segmentation in CT imaging.
Authors: Nicholas Heller, Sean McSweeney, Matthew Thomas Peterson, Sarah Peterson, Jack Rickman, Bethany Stai, Resha Tejpaul, Makinna Oestreich, Paul Blake, Joel Rosenberg, Keenan Moore, Edward Walczak, Zachary Rengel, Zach Edgerton, Ranveer Vasdev, Arveen Kalapara, Niranjan J. Sathianathen, Nikolaos Papanikolopoulos, Christopher J. Weight
Journal: Journal of Clinical Oncology (2020)

626 Background: The 2019 Kidney and Kidney Tumor Segmentation challenge (KiTS19) was an international competition held in conjunction with the 2019 International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI) and sought to stimulate progress on this automatic segmentation frontier. Growing rates of kidney tumor incidence led to research into the use of artificial inteligence (AI) to radiographically differentiate and objectively characterize these tumors. Automated segmentation using AI objectively quantifies complexity and aggression of renal tumors to better differentiate and describe the tumors for improved treatment decision making. Methods: A training set of over 31,000 CT images from 210 patients with kidney tumors was publicly released with corresponding semantic segmentation masks. 106 teams from five continents used this data to develop automated deep learning systems to predict the true segmentation masks on a test set of an additional 13,500 CT images in 90 patients for which the corresponding ground truth segmentations were kept private. These predictions were scored and ranked according to their average Sørensen-Dice coefficient between kidney and tumor across the 90 test cases. Results: The winning team achieved a Dice of 0.974 for kidney and 0.851 for tumor, approaching the human inter-annotator performance on kidney (0.983) but falling short on tumor (0.923). This challenge has now entered an “open leaderboard” phase where it serves as a challenging benchmark in 3D semantic segmentation. Conclusions: Results of the KiTS19 challenge show deep learning methods are fully capable of reliable segmentation of kidneys and kidney tumors. The KiTS19 challenge attracted a high number of submissions and serves as an important and challenging benchmark in 3D segmentation. The publicly available data will further propel the use of automated 3D segmentation analysis. Fully segmented kidneys and tumors allow for automated calculation of all types of nephrometry, tumor textural variation and discovery of new predictive features important for personalized medicine and accurate prediction of patient relevant outcomes.