tbuckley/cabot-search huggingface dataset:
KEYNOTE-365 cohort I: Phase 1b/2 study of pembrolizumab combined with platinum-containing chemotherapy and chemotherapy alone for treatment-emergent neuroendocrine prostate carcinoma (t-NE).
Authors: Johann S. De Bono, Anthony M. Joshua, Neal D. Shore, Gero Kramer, Xin Tong Li, Christian Heinrich Poehlein, Charles Schloss, Evan Y. Yu
Journal: Journal of Clinical Oncology (2022)

TPS218 Background: In previously treated adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC), approximately 20% of patients develop t-NE PC, which is aggressive with short overall survival (OS). t-NE PC treatment includes platinum-containing chemotherapy because of t-NE’s histologic, biologic, and clinical similarity to small cell/NE lung cancer. In the open-label, multicohort, phase 1b/2 KEYNOTE-365 study (NCT02861573), pembrolizumab, when combined with several agents for treatment of adenocarcinoma mCRPC, showed clinical activity and acceptable safety. To identify new treatment options for t-NE mCRPC, cohort I will help to evaluate platinum-containing chemotherapy alone or combined with pembrolizumab for patients with t-NE. Methods: Cohort I of the KEYNOTE-365 study will enroll patients with t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review) and prior docetaxel treatment for mCRPC. Prior treatment with ≤2 next-generation hormonal agents (NHAs) for metastatic hormone-sensitive prostate cancer (mHSPC) or mCRPC and 1 other chemotherapy for mCRPC is permitted. Additionally, enrollment in cohort I requires previous prostate cancer progression within 6 months of starting an NHA (mHSPC or mCRPC) and within &lt; 6 cycles of docetaxel for mCRPC. Each arm will enroll 40-100 patients with Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1. Eligible patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg IV on day 1 of each cycle every 3 weeks + carboplatin AUC of 5 IV on day 1 + etoposide 100 mg/m 2 IV on days 1, 2, and 3 of each 21-day cycle for 4 cycles (arm 1) or the same chemotherapy regimen without pembrolizumab (arm 2). Pembrolizumab treatment will continue for up to 2 years until disease progression, unacceptable toxicity, or withdrawal of consent. Patients will be stratified by ECOG PS score (0 vs 1). Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression; duration of response (DOR) and disease control rate (DCR) per RECIST v1.1 by BICR; ORR, DOR, DCR, and radiographic progression-free survival per Prostate Cancer Working Group 3–modified RECIST v1.1 by BICR; and OS. End points will be summarized for each arm without formal hypothesis testing. This cohort of KEYNOTE-365 is enrolling in Australia, Germany, New Zealand, Spain, and the United States. Clinical trial information: NCT02861573.
Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): Long-term follow-up results from the JAVELIN Bladder 100 trial.
Authors: Thomas Powles, Se Hoon Park, Eric Voog, Claudia Caserta, Begoña Pérez-Valderrama, Howard Gurney, Yohann Loriot, Srikala S. Sridhar, Norihiko Tsuchiya, Cora N. Sternberg, Joaquim Bellmunt, Jeanny B. Aragon-Ching, Daniel P. Petrylak, Andy Blake-Haskins, Robert J Laliberte, Jing Wang, Nuno Matos Costa, Petros Grivas
Journal: Journal of Clinical Oncology (2022)

487 Background: The phase 3 JAVELIN Bladder 100 trial (NCT02603432) showed significantly longer overall survival (OS) with avelumab + best supportive care (BSC) vs BSC alone in patients (pts) with advanced UC that had not progressed with 1L platinum-containing chemotherapy. Avelumab 1L maintenance is now considered standard of care in treatment guidelines. We report trial data with ≥2-years follow-up in all pts (additional 19 months from the initial analysis). Methods: Pts with unresectable locally advanced or metastatic UC without disease progression with 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin were randomized 1:1 to receive avelumab + BSC or BSC alone. The primary endpoint was OS, assessed from randomization in all pts and in pts with PD-L1+ tumors (Ventana SP263 assay). Secondary endpoints included progression-free survival (PFS) and safety. Results: 700 pts were randomized (350 per arm); 358 (51.1%) had PD-L1+ tumors. With extended follow-up (median, ≥38 months in both arms for all pts; data cutoff, June 4, 2021), OS remained significantly longer in the avelumab + BSC vs BSC alone arm in all randomized pts and in pts with PD-L1+ tumors (Table). An OS benefit was observed across prespecified subgroups. PFS (by investigator) was longer with avelumab + BSC vs BSC alone in all randomized pts and in pts with PD-L1+ tumors (Table). In the avelumab + BSC and BSC alone arms, respectively, 185 (52.9%) vs 252 (72.0%) pts received a subsequent anticancer drug therapy, including a PD-(L)1 inhibitor in 40 (11.4%) vs 186 (53.1%) pts. Long-term safety was consistent with previous avelumab monotherapy studies, with no new safety signals. Conclusions: Long-term follow-up from the JAVELIN Bladder 100 trial continues to show prolonged OS with avelumab + BSC vs BSC alone. These results further support the standard-of-care role for avelumab as 1L maintenance in pts with advanced UC that has not progressed with 1L platinum-containing chemotherapy. Clinical trial information: NCT02603432. [Table: see text]
Craniofacial surgery.
Authors: M D Poole, M Briggs, J Rayne, H Cheng
Journal: BMJ (1985)

RANIOFACIAL SURGERYCraniofacial surgery is concerned with surgical correction of problems affecting the skull base, orbits, and upper face.These anatomical areas, in particular the skull base, were until recently a kind of "no man's land" that did not fall within the province of any particular surgical specialty.In recent years multidisciplinary teams have been formed to deal with problems in this difficult area.Because these problems are not common X .... L > -. .0 , i eR96 i ...and management is difficult craniofacial surgery is performed in only a few centres with surgical teams treating sufficient numbers of patients to maintain the required level of skill.The conditions treated in this way fall i0g+00 ;>iSU0 0!0!into three main groups: congenital anomalies, tumours, and trauma.ptient with a cranidacial deformity Congenital anomaliesCongenital craniofacial anomaliesThe craniosynostoses are a group of disorders in which one or more of the Congnia sutural joins between the cranial bones becomes prematurely ossified, Simple vault craniosynostoses impairing the growth of the skull that takes place in a direction at right Craniofacial syriostoses -Crouzon's syndrome angles to the suture.This may lead to a deformity of the cranium (and -Apert's syndrome on 18 June
Gemcitabine and carboplatin versus gemcitabine and paclitaxel chemotherapy in cisplatin ineligible advanced-stage urothelial cancers: A prospective randomized control study.
Authors: Parmod Kumar, Amit Sehrawat, Deepak sundriyal, Pankaj Sharma, Ankur Mittal, Manoj Kumar Gupta
Journal: Journal of Clinical Oncology (2022)

500 Background: Cisplatin ineligibility in metastatic urinary bladder cancer patients poses a major therapeutic challenge. The reported incidence was approximately 20-30% of metastatic urinary bladder cancer. In the absence of insurance, "the immunotherapy" can be economically draining at the current cost. Moreover, there are patients in whom immunotherapy might not be feasible due to comorbid conditions. Therefore, there persists a need to optimize chemotherapy options for gemcitabine combination with either Paclitaxel or Carboplatin are recommended chemotherapy options. However, limited prospective studies are comparing the two options. Methods: This was a non-funded, prospective, randomized, single-center study among treatment naïve cisplatin-ineligible metastatic urothelial cancer from a tertiary care institute from India. The study enrollment duration was 18 months. Patients were randomized in one of the two treatment arms. The "Arm A" received (Gemcitabine and Carboplatin) and "Arm B" received the (Gemcitabine and Paclitaxel) combination chemotherapy, respectively. The two treatment arms were compared prospectively for disease control, survival, and adverse events in an Intention to treat analysis. Results: A total of 32 eligible participants were randomized in the study. "Arm A" vs. "Arm B" had an 18.7% vs. 25% drops out rate, respectively. The ORR was 40% vs. 88.4%; median PFS and OS were 3.7 vs. 3.8 months and 7.3 vs. 14.0 months, respectively. The serious adverse events were nonoverlapping. Hospitalization was needed for the care of adverse events among 37.5% vs. 12.5% patients, respectively. Conclusions: Both groups reported that similar PFS. However, better ORR, OS (though not statically significant), and lower hospitalizations for adverse event management favor the Gemcitabine with paclitaxel combination over Gemcitabine with Carboplatin. Clinical trial information: CTRI/2020/02/023402.
Impact of primary tumor location on efficacy and safety of pembrolizumab (pembro) in patients (pts) with locally advanced or metastatic urothelial carcinoma (UC) enrolled in the phase 2 KEYNOTE-052 and phase 3 KEYNOTE-045 trials.
Authors: Peter H. O'Donnell, Arjun Vasant Balar, Daniel E. Castellano, Ronald De Wit, David J. Vaughn, Thomas Powles, Jacqueline Vuky, Jae-Lyun Lee, Yves Fradet, Joaquim Bellmunt, Lawrence Fong, Daniel P. Petrylak, Winald R. Gerritsen, David I. Quinn, Stephane Culine, Dean F. Bajorin, Jin Zhi Xu, Kentaro Imai, Blanca Homet Moreno, Petros Grivas
Journal: Journal of Clinical Oncology (2022)

516 Background: Pembro showed antitumor activity in 1L and 2L for pts with UC in the single-arm, phase 2 KEYNOTE-052 study (NCT02335424) and the randomized phase 3 KEYNOTE-045 (NCT02256436) study, respectively. This post hoc exploratory analysis evaluated whether primary tumor location affected efficacy and safety of pembro (KEYNOTE-052; KEYNOTE-045) and chemotherapy (chemo; KEYNOTE-045). Methods: KEYNOTE-052 enrolled cisplatin-ineligible pts with advanced/metastatic UC who had not previously received systemic therapy; they received pembro (200 mg IV Q3W). KEYNOTE-045 enrolled pts with advanced/metastatic UC who had received platinum-containing chemo; pts were randomly assigned 1:1 to receive pembro (200 mg IV Q3W) or investigator’s choice of chemo (paclitaxel, docetaxel, or vinflunine). Both studies required pts to have measurable disease per RECIST v1.1. Upper tract (UT) UC included primary tumors in the renal pelvis or ureter; lower tract (LT) UC included primary tumors in the bladder or urethra. Pts with UT and LT disease (UT/LT) were classified as LT. Pts receiving pembro were treated until disease progression, unacceptable toxicity, or withdrawal of consent, for up to 2y. End points were PFS, ORR, and DOR per RECIST v1.1 by central radiology assessment and OS. Results: A total of 369 pembro-treated pts (68 UT; 301 LT [79 UT/LT]) from KEYNOTE-052 plus 270 pembro-treated pts (93 UT; 177 LT [33 UT/LT]) and 272 chemo-treated pts (94 UT; 178 LT) from KEYNOTE-045 were evaluated. Median follow-up from randomization to data cutoff (09/26/20 and 10/1/20, respectively) was ≥56 mo. Both studies enrolled a similar percentage of pts with PD-L1–positive tumors (25%-30%). PFS, ORR, DOR, and OS for pembro were consistent regardless of tumor location, although ORR for KEYNOTE-045 was lower for the UT group (Table). In the chemo arm of KEYNOTE-045, similar efficacy was observed regardless of tumor location or regimen. Grade 3-5 TRAEs occurred at similar rates in KEYNOTE-052 (19.1% UT; 21.6% LT) and KEYNOTE-045 (17.2% UT; 16.8% LT). Conclusions: In this exploratory analysis, pembro showed similar clinical activity and manageable safety regardless of primary UC tumor location. Clinical trial information: NCT02256436 and NCT02335424. [Table: see text]
BAYOU: A phase II, randomized, multicenter, double-blind, study of durvalumab (D) in combination with olaparib (O) for the first-line treatment of platinum-ineligible patients with unresectable, stage IV urothelial carcinoma (UC).
Authors: Jonathan E. Rosenberg, Se Hoon Park, Tu V. Dao, Daniel E. Castellano, Jian-Ri Li, Som Mukherjee, Kathryn Howells, Hannah Dry, Mark C. Lanasa, Ross Stewart, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2022)

437 Background: The prognosis for patients (pts) with advanced UC remains poor, particularly for those unable to tolerate platinum-based chemotherapy. Defects in DNA damage repair (e.g., mutations in homologous recombination repair [HRR] genes) are common in UC and render tumor cells sensitive to poly(ADP-ribose) polymerase (PARP) inhibition. HRR gene mutations (HRRm) and PARP inhibition may enhance the antitumor response of immune checkpoint inhibitors. We conducted a randomized phase II study to evaluate D (anti–PD-L1) in combination with O (a PARP inhibitor) or placebo (P) as a first-line treatment for platinum-ineligible pts with unresectable, stage IV UC (BAYOU; NCT03459846). Methods: Eligible pts were an age of ³18 years with an ECOG performance status (PS) of 0, 1, or 2, histologically or cytologically confirmed transitional cell carcinoma, and who had not received prior systemic therapy for unresectable, stage IV disease. Pts were randomized 1:1 to receive D (1500 mg IV q4w) plus O (orally at 300 mg BID) vs D (1500 mg IV q4w) plus O-matching placebo (P). Pts were stratified according to centrally-determined HRR status (mutant vs wild-type) and Bajorin risk index (a composite of visceral metastases and ECOG PS [0, 1 vs 2]). The primary endpoint was progression-free survival (PFS) by RECIST v1.1 (investigator assessed) in the intention-to-treat (ITT) population. Secondary endpoints included overall survival (OS) in the ITT population and PFS in the subset of pts with HRRm. The data cutoff occurred on October 15, 2020. Results: A total of 154 pts were randomized to receive D+O (n = 78) or D+P (n = 76). Among all randomized pts at baseline, 17%, 42%, and 40% had an ECOG PS of 0, 1, or 2, respectively, and 20% had an HRRm. Median PFS was not significantly different between D+O and D+P in the ITT population (Table). In the subset of pts with HRRm, median PFS was 5.6 months in the D+O group and 1.8 months in the D+P group (Table). In the ITT population, median OS (95% CI) was 10.2 months (7.0–13.9) in the D+O group and 10.7 months (7.2–17.3) in the D+P group (HR 1.07, 95% CI 0.72–1.61). Among all treated pts, grade 3 or 4 treatment-related adverse events occurred in 18% and 9% in the D+O and D+P groups, respectively, with one death due to anemia in the D+P group. Conclusions: The BAYOU study did not meet its primary endpoint. However, the results of pre-planned secondary analyses suggest a potential role for PARP inhibition in UC pts harboring HRRm. No new safety signals were observed. Clinical trial information: NCT03459846. [Table: see text]
Initial results of a phase II study of nivolumab(N) and ipilimumab(I) in genitourinary malignancies with neuroendocrine differentiation.
Authors: Bradley Alexander McGregor, Wanling Xie, Mehmet Asim Bilen, Matthew T Campbell, Amir Mortazavi, Jiaming Huang, Rajitha Sunkara, Praful Ravi, Amishi Yogesh Shah, Sylvan Baca, Guru P. Sonpavde, Joaquim Bellmunt, Arlene O. Siefker-Radtke, Sabina Signoretti, Eliezer Mendel Van Allen, Himisha Beltran, Rana R. McKay, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2022)

569 Background: Patients with metastatic genitourinary malignancies with neuroendocrine have limited therapeutic options following platinum therapy. Given encouraging results in initial cohort analysis for small cell urinary tract carcinoma, a cohort of any genitourinary malignancy with neuroendocrine differentiation was added to a multicenter, single arm, multi-cohort phase II trial to evaluate the efficacy of N and I in this setting. (NCT 03333616) Methods: Eligible patients had metastatic or locally advanced genitourinary malignancy with neuroendocrine differentiation with an ECOG performance status of 0-2; they may have received any line of prior therapy excluding prior immunotherapy. Patients underwent baseline biopsy and received treatment with N 3 mg/kg and I 1 mg/kg intravenously every 3 weeks for 4 cycles with continued maintenance of N 480 mg IV every 4 weeks. Imaging was performed at 12 weeks and then every 8 weeks through month 6 and then every 12 weeks thereafter. The primary endpoint was investigator assessed objective response rate (ORR) by RECIST 1.1. Results: A total of 27 patients were enrolled between 06/27/2018 and 06/21/2021, 10 (37%) had urinary tract cancer and 17 (63%) had prostate cancer (19 in expansion cohort, 3 urinary tract and 5 prostate cancer from earlier cohorts). The majority (n=25, 93%) patients received prior systemic therapy. Nine (33%) patients received all 4 doses of N and I during the induction period. Nine (33%) patients (7 of whom received 4 cycles N+I) received N maintenance (median number of cycles 9 (range, 2-37)). Median follow-up was 6.8 (range, 0.9-37.3) months. Objective response was achieved in 8 (30%, 80% CI 18%-44%) patients (Table). Median duration of response was not reached with 4 patients maintaining response &gt;9 months. Median progression-free survival time was 2.6 (95% CI 1.8-6.5) months At time of analysis, 13 (48%) death events were reported due to progressive disease, in which 3 were bladder and 10 were prostate cancer. 8 (30%) patients developed treatment-related grade 3 or higher toxicities; one grade 5 toxicity was deemed treatment-unrelated. Conclusions: In this study we demonstrate N+I resulted in objective responses in patients with genitourinary malignancy with neuroendocrine differentiation. ORR of 50% in small cell carcinoma is bladder cancer is noteworthy and will be evaluated further in ongoing expansion cohort of bladder or upper tract carcinoma with variant histology. Clinical trial information: NCT03333616. [Table: see text]
Tissue-Specific Immunopathology in Fatal COVID-19
Authors: David A. Dorward, Clark D. Russell, In Hwa Um, Mustafa Elshani, Stuart D. Armstrong, Rebekah Penrice-Randal, Tracey Millar, Chris E. B. Lerpiniere, Giulia Tagliavini, Catherine S. Hartley, Nadine P. Randle, Naomi N. Gachanja, Philippe M. D. Potey, Xiaofeng Dong, Alison M. Anderson, Victoria L. Campbell, Alasdair J. Duguid, Wael Al Qsous, Ralph BouHaidar, J. Kenneth Baillie, Kevin Dhaliwal, William A. Wallace, Christopher O. C. Bellamy, Sandrine Prost, Colin Smith, Julian A. Hiscox, David J. Harrison, Christopher D. Lucas
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown.
Refresher Course in Radiation Therapy and Physics
Journal: JNCI Journal of the National Cancer Institute (1974)

Refresher Course in Radiation Therapy and Physics Get access JNCI: Journal of the National Cancer Institute, Volume 52, Issue 3, March 1974, Pages 124–1024, https://doi.org/10.1093/jnci/52.3.1024-a Published: 01 March 1974
Total Replacement of Mitral Valve: Results of Insertion of Starr-Edwards Valve in Five Patients
Journal: JAMA (1963)

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Tumor genomic landscape of locally advanced or metastatic urothelial carcinoma with squamous differentiation (UCS) compared to pure urothelial carcinoma (UC).
Authors: Nishita Tripathi, Yeonjung Jo, Nicolas Sayegh, Haoran Li, Roberto Nussenzveig, Benjamin Haaland, Vinay Mathew Thomas, Sumati Gupta, Benjamin L. Maughan, Umang Swami, Sumanta K. Pal, Petros Grivas, Neeraj Agarwal, Deepika Sirohi
Journal: Journal of Clinical Oncology (2022)

553 Background: UCS is a common entity and usually managed similarly to pure UC but requires focused study. Limited data are available on the genomic profile of UCS. We hypothesized that UCS would have a distinct genomic landscape compared to UC. Methods: In this IRB-approved retrospective study, pts) with advanced UCS and UC undergoing tumor based comprehensive genomic profiling from a CLIA-certified laboratory were included. An independent genitourinary pathologist reviewed all cases. Pts were determined to have UCS based on presence of any component of squamous differentiation. Pts with UC having any other secondary histology variant were excluded. Genes with alterations (GA) in less than 5% of pts and variants of unknown significance were excluded from the analysis. test was used to compare gene aberration frequency and the p-values were adjusted for false using Benjamini-Hochberg (BH) correction. Results: 87 pts were eligible and included. UCS (n=31) vs UC (n=56): median age, 66 vs 68 years; male vs female: 21/10 vs 48/8Genomic aberrations in both groups are listed in the. GA in KMT2D was found to be significantly enriched in UCS vs UC (15/31 vs 0/56, FDR &lt;0.001, p value = &lt;0.001). GA in CUL4A was numerically higher in UCS vs UC (4/31 vs 1/56, FDR= 0.444, p-value = 0.03). Tumor mutation burden the frequency of genomic aberrations per pt were not significantly different in the groups. Conclusions: While tumor GA in only KMT2D was significantly enriched in the UCS cohort, it is interesting to note that both KMT2D and CUL4A (higher frequency in UCS) are involved in epigenetic regulation. Identification of underlying molecular targets and biomarkers can guide further drug development in this population. Limitations include small sample size, selection and confounding biases. These hypothesis-generating data need external validation.[Table: see text]