Randomized Phase 2 Trial of Tremelimumab and Durvalumab in Combination Versus Sequentially in Recurrent Platinum-Resistant Ovarian Cancer

BACKGROUND: Single-agent immune checkpoint inhibitors (ICIs) have demonstrated limited responses in recurrent ovarian cancer; however, 30%-40% of patients achieve stable disease. The primary objective was to estimate progression-free survival (PFS) after sequential versus combination cytotoxic T-lymphocyte antigen 4 and programmed death ligand 1 ICIs in patients with platinum-resistant high-grade serous ovarian cancer (HGSOC). METHODS: Patients were randomized to a sequential arm (tremelimumab followed by durvalumab on progression) or a combination arm (tremelimumab plus durvalumab, followed by durvalumab) via a Bayesian adaptive design that made it more likely for patients to be randomized to the more effective arm. The primary end point was immune-related PFS (irPFS). RESULTS: Sixty-one subjects were randomized to sequential (n = 38) or combination therapy (n = 23). Thirteen patients (34.2%) in the sequential arm received durvalumab. There was no difference in PFS in the sequential arm (1.84 months; 95% CI, 1.77-2.17 months) compared with the combination arm (1.87 months; 95% CI, 1.77-2.43 months) (p = .402). In the sequential arm, no responses were observed, although 12 patients (31.6%) demonstrated stable disease. In the combination arm, two patients (8.7%) had partial response, whereas one patient (4.4%) had stable disease. Adverse events were consistent with those previously reported for ICIs. Patient-reported outcomes were similar in both arms. CONCLUSIONS: There was no difference in irPFS for combination tremelimumab plus durvalumab compared to tremelimumab alone (administered as part of a sequential treatment strategy) in a heavily pretreated population of patients with platinum-resistant HGSOC. Response rates were comparable to prior reports, although the combination regimen did not add significant benefit, as has been previously described

Evaluation of screening and risk-reducing surgery for women followed in a high-risk breast/ovarian cancer clinic: it is all about the tubes in BRCA mutation carriers

The objectives of this study were to determine both surgical and subsequent cancer outcomes for high-risk women from the University of Virginia's High-Risk Breast/Ovarian Cancer clinic undergoing ovarian cancer risk-reducing surgery. Retrospective review identified high risk women who had ovarian risk reducing surgery over the past decade and surgical outcomes, pathology, pre-operative screening results, and pre-/post-operative cancer diagnoses were evaluated. One hundred and eighty-three high-risk women had risk reducing surgery at a mean age of 50.1 years and with a mean BMI of 28.9 kg/m2 at the time of surgery. Most women (103; 56.3%) had a strong family history of cancer concerning for a hereditary syndrome without an identified mutation, 35.5% of women carried a known deleterious mutation and 7.7% of women had a personal history of breast or ovarian cancer. The most common procedure was a risk-reducing bilateral salpingo-oophorectomy with or without hysterectomy (RRBSO, 89.1%). All women underwent the Sectioning and Extensively Examining the Fimbriated End (SEE-FIM) pathology protocol which found two (1.1%) invasive ovarian cancers (one ovarian/tubal carcinosarcoma, one granulosa cell ovarian cancer), three (1.6%) serous tubal intraepithelial carcinomas (STIC), and one (1.1%) invasive fallopian tube cancer. Subsequent cancer diagnoses included one (0.5%) primary peritoneal cancer, four (2.2%) DCIS, and seven (3.8%) invasive breast cancers. Ultimately, among all high-risk women undergoing RR surgery, about 3.3% were diagnosed with a STIC or an ovarian cancer none of which were identified on screening. All STIC and tubal cancers were diagnosed in women with BRCA mutations (6.6% rate for this group). Keywords: BRCA, Risk-reducing surgery, Serous tubal intraepithelial carcinoma, High-risk cance

Double Protonation of Amino-Substituted Pyridine and Pyrimidine Tungsten Complexes: Friedel–Crafts-like Coupling to Aromatic Heterocycles

2-(Dimethylamino)­pyridine (2-DMAP) and 2-(dimethylamino)­pyrimidine derivatives form η²-bound complexes with the dearomatization agent {TpW­(NO)­(PMe₃)} that are each capable of undergoing a double protonation. In the case of 2-DMAP, the resulting π-allyl species reacts with the α-carbon of thiophene or 2-methylfuran, thereby coupling the heterocyclic rings. In the case of the thiophene-derived product, subsequent oxidative decomplexation using ceric ammonium nitrate affords a novel organic amidine derivative. Examples of tungsten-promoted acetylation and fluorination of the aminopyridine ring are also described

Tungsten-Mediated Selective Ring Opening of Vinylcyclopropanes

The complexes TpW­(NO)­(PMe₃)­(L), where L = 2<i>H</i>-phenol, 2<i>H</i>-<i>p</i>-cresol, 2<i>H</i>-5,6,7,8-tetrahydro-2-naphthol, 2<i>H</i>-<i><i>N,N</i>-</i>dimethylanilinium were cyclopropanated using Simmons–Smith conditions. Cyclopropanated derivatives of 2<i>H</i>-<i>N,N</i>-dimethylanilinium were selectively ring-opened with HOTf/MeCN to form allylic species, which could be coupled with various nucleophiles. The nucleophilic addition occurs <i>anti</i> to the metal fragment, as determined by X-ray crystallography. Moreover, the cyclopropane ring opening occurs regioselectively, owing to the stabilization of the allylic cation by the metal fragment. The resulting ligands can, in some cases, be removed from the metal by oxidative decomplexation using ceric ammonium nitrate (CAN)

Tungsten-Mediated Selective Ring Opening of Vinylcyclopropanes

The complexes TpW­(NO)­(PMe₃)­(L), where L = 2<i>H</i>-phenol, 2<i>H</i>-<i>p</i>-cresol, 2<i>H</i>-5,6,7,8-tetrahydro-2-naphthol, 2<i>H</i>-<i><i>N,N</i>-</i>dimethylanilinium were cyclopropanated using Simmons–Smith conditions. Cyclopropanated derivatives of 2<i>H</i>-<i>N,N</i>-dimethylanilinium were selectively ring-opened with HOTf/MeCN to form allylic species, which could be coupled with various nucleophiles. The nucleophilic addition occurs <i>anti</i> to the metal fragment, as determined by X-ray crystallography. Moreover, the cyclopropane ring opening occurs regioselectively, owing to the stabilization of the allylic cation by the metal fragment. The resulting ligands can, in some cases, be removed from the metal by oxidative decomplexation using ceric ammonium nitrate (CAN)

International consensus statement on allergy and rhinology: Sinonasal tumors

BACKGROUND: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represents a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field. METHODS: In accordance with prior ICAR documents, ICSNT assigned each topic as an Evidence-Based Review with Recommendations, Evidence-Based Review, and Literature Review based on level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses format, and completed sections underwent a thorough and iterative consensus-building process. The final document underwent rigorous synthesis and review prior to publication. RESULTS: The ICNST document consists of 4 major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology-based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention. CONCLUSION: As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses

International consensus statement on allergy and rhinology: Sinonasal tumors.

BACKGROUND: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represents a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field. METHODS: In accordance with prior ICAR documents, ICSNT assigned each topic as an Evidence-Based Review with Recommendations, Evidence-Based Review, and Literature Review based on level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses format, and completed sections underwent a thorough and iterative consensus-building process. The final document underwent rigorous synthesis and review prior to publication. RESULTS: The ICNST document consists of 4 major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology-based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention. CONCLUSION: As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses. This article is protected by copyright. All rights reserved

International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors

BACKGROUND: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represents a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field. METHODS: In accordance with prior ICAR documents, ICSNT assigned each topic as an Evidence-Based Review with Recommendations, Evidence-Based Review, and Literature Review based on level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses format, and completed sections underwent a thorough and iterative consensus-building process. The final document underwent rigorous synthesis and review prior to publication. RESULTS: The ICNST document consists of 4 major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology-based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention. CONCLUSION: As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses