Citations

ABSTRACT Background and hypothesis Podocytopathy associated with likely pathogenic/pathogenic variants of Transient receptor potential cation channel subfamily C member 6 (TRPC6) (TRPC6-AP) has been recognized for about 20 years. As a result of its rarity however, the spectrum of clinical phenotypes and genotype–phenotype correlation of TRPC6-AP remains poorly understood. Here, we characterized clinical, histological and genetic correlates of familial and sporadic patients with TRPC6-AP. Methods In this multicentre observational study, an online questionnaire followed by a systematic literature review was performed to create a cohort with comprehensive data on genetic and clinical outcomes [age of onset, clinical presentation, treatment response, kidney biopsy findings and progression to kidney failure (KF)]. Logistic regression, Cox proportional hazards model and Kaplan–Meier analyses investigated the associations between genetic variants and disease progression. Results Among 87 families (96 familial and 45 sporadic cases), 31 distinct missense TRPC6 variants (including 2 novel) were identified, with c.2683C>T p.(Arg895Cys) and c.523C>T p.(Arg175Trp) the commonest variants. Proteinuric kidney disease/nephrotic syndrome was the most common clinical presentation (83.7%), while focal segmental glomerulosclerosis was the most common histological finding (89.4%). By 33 (interquartile range 17–40) years, 48.9% (69/141) of patients had progressed to KF. Sporadic TRPC6-AP demonstrated an earlier progression to KF than familial cases (P = .001) and were more likely to present with nephrotic syndrome [odds ratio 4.34 (1.85–10.15); P = .001]. Gain-of-function TRPC6 variants were more frequent in familial than sporadic TRPC6-AP (70.8% vs 44.4%; P = .004). Compared with patients with other TRPC6 variants, patients with TRPC6 p.R175W and p.R895C variants progressed to KF earlier [median kidney survival of 21 years, hazard ratio 2.985 (95% confidence interval 1.40–5.79); and 38 years, hazard ratio 1.65 (95% confidence interval 1.01–2.81), respectively, log-rank P = .005]. Conclusion Our study shows unique clinical and genetic correlations of TRPC6-AP, which may enable personalized care and promising novel therapies.

ABSTRACT Objective There is limited consensus on endoscopic skull base surgery (ESBS) reconstruction principles. This study aims to generate comprehensive themes regarding ESBS reconstruction by pooling the experiences of ESBS experts, with comparison to a literature review of current published evidence. Methods Structured qualitative interviews of ESBS experts regarding postoperative management and reconstruction of various defect locations were conducted. Results A total of 68 experts comprising 40 academic teams across 13 countries with an average of 18 years of ESBS experience were included. We propose 10 stepwise algorithms for common skull base reconstruction scenarios based on these expert interviews. When available, the nasoseptal flap is used for all high_flow cerebrospinal leak defects. Multilayered reconstruction is favored at all anatomical subsites with increasing number of layers for increasing defect size and complexity. Heterogeneity exists in terms of inlay technique and materials, free grafting versus various pedicled flap options for low‐flow defects or in the absence of a nasal septum, nasal packing, tissue sealant, lumbar drain use, and postoperative management. Commonalities and discrepancies between experts were summarized. Conclusion Skull base reconstruction and post‐ESBS management is highly complex with a wide variety of practice patterns and expert strategies. Further research of higher quality evidence is warranted to identify optimal management patterns, though the current work aims to inform surgeons on these controversial areas by drawing from numerous experiences.

Background: Skin cancer patients who undergo Mohs surgery may require subsequent reconstructive rhinoplasty for large nasal defects. Autologous cartilage is the primary source of supporting cartilage grafts, but carries the risk of potential donor-site complications. In this study, we demonstrate the safety and efficacy of nonterminally irradiated fresh frozen human costal cartilage allografts (CCAs) in reconstructive rhinoplasty after skin cancer removal. Methods: A retrospective chart review of 25 patients who underwent reconstructive rhinoplasties using human CCA after basal cell carcinoma resection was conducted. Human CCA undergoes a process of sterilization without terminal irradiation and is stored frozen (−40°C to −80°C). Anthropometric measurements were taken on pre- and postoperative photographs to evaluate nasal tip projection. Adverse events were evaluated. Results: There were 25 participants, with an average age of 71 years at the time of surgery (range: 42–90). The average follow-up duration was 12 months (range: 3–66 mo). Types of grafts used included alar batten graft (n = 17, 68%), nasal tip graft (n = 7, 28%), and alar batten graft with nasal tip graft (n = 1, 4%). Measurements on the 2-dimensional photographs of the patients showed no significant resorption or deviation at the 6- or 12-month follow-up. No significant complications related to the use of the cartilage were noted. Conclusions: Our data highlight the low complication rate and aesthetically positive outcomes from using nonterminally irradiated human CCA for reconstructive rhinoplasties in post-Mohs surgery for older patients. This approach offers a reliable source of high-quality cartilage for reconstruction.

Abstract Introduction Rheumatoid arthritis (RA) is a systemic autoimmune rheumatic disease (SARD) primarily associated with articular involvement, but is often associated with lung involvement, sometimes preceding articular symptoms. Common pulmonary manifestations include interstitial lung disease (ILD), airway, and serosal involvement. RA-related pleural disease can mimic empyema due to the pleural fluid's green, pus-like appearance, exudative nature, low pH, markedly low glucose, and elevated lactate dehydrogenase (LDH) levels. Empyema sometimes yields negative cultures which can accentuate the diagnostic challenge in such cases. This report presents a patient with RA-related pleural lung disease who was referred to our hospital with trapped lung presumed to be secondary to empyema in the setting of pleural-based pulmonary abscess. Case Report A 66-year-old female with a 22-year history of RA presented with recurrent right-sided pleural effusions and progressive dyspnea over three years. Her initial presentation in 2022 involved a large right-sided pleural effusion, suspected to result from a ruptured pleural-based pulmonary abscess that led to empyema and subsequently a trapped lung. Pleural fluid analysis showed elevated LDH (1364 U/L), low glucose (45 mg/dL), high cholesterol (121 mg/dL), and low triglycerides (79 mg/dL). Due to refractory exudative effusion and a comprehensive negative infectious evaluation (bacterial, mycobacterial, and fungal cultures), RA-related pleural disease was suspected. The patient underwent video-assisted thoracoscopic surgery (VATS), which revealed pleural-based rheumatoid nodules and pleural thickening. (figure1) Lung and pleural biopsies confirmed RA-associated fibrinous pleuritis, RA-associated follicular bronchiolitis, and usual interstitial pneumonitis. Given the complexity of the infection, a thoracotomy with decortication and pleurectomy was planned and conducted in stages. Immunosuppressive regimen was switched from leflunomide to rituximab. Discussion This case underscores the diagnostic complexity in distinguishing RA-associated pleural effusion from empyema. Features such as pleural nodularity resembling a pulmonary abscess, unilateral exudative effusion, grossly purulent pleural fluid, low pH and glucose, and elevated LDH levels led to an initial misdiagnosis of empyema. Characteristic pleural fluid, along with persistent negative cultures and absence of sepsis pointed towards RA-related pleural disease. VATS and biopsy were instrumental in establishing the final diagnosis through characteristic histopathological findings of RA-associated pleural, parenchymal and airway involvement. Conclusion For RA patients with pleural effusion suggestive of empyema, especially in the context of negative cultures and no signs of sepsis, RA-related pleural disease should be a consideration. Early recognition and timely immunosuppressive therapy escalation can prevent complications such as trapped lungs and reduce the necessity for extensive surgical interventions. Figure1:

Abstract Introduction Unilateral pulmonary vein atresia (UPVA) is a rare congenital anomaly involving absent or obstructed pulmonary veins (PV), often leading to chronic pulmonary venous stasis, recurrent infections, and hemoptysis. Although typically diagnosed in infancy, UPVA can present in adulthood. This report presents a 63-year-old male referred as a case of chronic thromboembolic pulmonary disease (CTEPD) who was diagnosed with UPVA. We describe the diagnostic complexities and potential explanation for loss of pulmonary artery (PA) perfusion in such cases. Case Presentation A 63-year-old man was referred to rule out CTEPD. His past medical history included coronary artery disease and sleep apnea. He presented with chronic cough, repeated hemoptysis, recurrent pneumonias requiring prolonged antibiotics use, and progressive exertional dyspnea. Physical examination was unremarkable. Pulmonary function tests showed moderate restriction and moderately-reduced diffusion capacity. A ventilation-perfusion (V/Q) scan revealed complete absence of perfusion in the left lung. [figure1] High-resolution CT revealed a straight left atrial border sign with absent left superior and inferior PVs, left pulmonary arterial tree hypoplasia, hypoplastic left lung with fibrotic changes due to chronic venous-lymphatic engorgement and pulmonary hypoperfusion. CT also showed compensatory right lung hyperinflation and bronchial artery collaterals. Echocardiography indicated an atrial septal defect (ASD) with no pulmonary vascular disease. Based on CT angiography, UPVA was considered the leading diagnosis. Discussion UPVA is a congenital disease rarely presenting in adulthood with recurrent infections, hemoptysis, and fibrosis. It often accompanies congenital cardiac conditions, like ASD in our case. Pulmonary angiography may reveal ipsilateral PA hypoplasia and atrophied peripheral vessels. The absence of perfusion in the V/Q scan could be explained by reversed blood flow in the PA from congestion caused by the atretic PVs and ipsilateral backflow from the bronchial arteries collaterals. Differential diagnosis like CTEPD was excluded due to atypical complete loss of perfusion of the left lung, and lack of the other radiological stigmata. Swyer-James-MacLeod syndrome was excluded due to a mismatched perfusion defect. Proximal Interruption of the PA was also excluded due to normally developed proximal left and right PAs. Imaging is crucial in showing absent PVs and hypoplastic ipsilateral lung. Conservative management for UPVA is recommended. Given recurrent infections and hemoptysis, pneumonectomy can be considered. Conclusion This case illustrates the atypical presentation of UPVA as a CTEPD mimicker, presenting with absent pulmonary perfusion unilaterally, which can be explained by reversed pulmonary flow secondary to venous engorgement and backflow from bronchial artery collaterals. Figure1:

Abstract Rationale: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a pulmonary condition characterised by neuroendocrine cell proliferation along respiratory bronchioles resulting in tumourlet formation which may progress to pulmonary carcinoid. DIPNECH is a rare and under-recognised condition that predominantly affects females, with an estimated worldwide incidence of 5-6 people per million population. Given it's rarity and the poor understanding around the pathogenesis and treatment of this condition, we undertook the largest international case series to date of DIPNECH patients. We aim to further characterise this patient cohort to better understand the clinical features, identify common pulmonary function test (PFT) patterns and radiographic findings and describe current treatment practices. Methods: We collated data from 17 centres across 8 different countries comprising a total of 258 patients. Data collected included patient demographics, smoking history, symptoms, co-morbidities, pathological diagnosis, imaging findings, PFT pattern and therapies. Results: In total 258 patients were identified. The median age was 65 (SD+/- 10.6). 241 (93%) were female. 39% (n= 94/243) were ex-smokers. 79% (n=186/234) of patients reported pulmonary symptoms with cough being the most common symptom reported in 81% (n=151/186) of patients. Many patients were polysymptomatic, with cough and dyspnoea being the most common combination of symptoms described. (50.54%; n=94/186). Complete spirometry pattern was documented for 180 patients (69.78%) with an obstructive pattern being the most commonly observed (n=76/180; 42%). 27.5% (n=41/139) had clinically significant FEV1 reversibility post bronchodilator administration. Pathology specimens were available in 219 cases. Most common pathological features were neuroendocrine hyperplasia which was observed in 75% (n=165/219) and tumourlets in 74% (n=162/219) of cases. Carcinoid, either typical or atypical, was observed in 64% (n=141/219) of samples. 252 patients had computed tomography (CT) imaging performed. Pulmonary nodules were the most common feature identified in 99.60% of cases (248/250). Mosaic attenuation (69.30%; n=50/173) and airway dilatation (28.90%; n=50/173) were also frequently reported. There was no significant correlation between symptoms (cough, dyspnoea, wheeze) and airway dilatation (p=0.496), mosaic attenuation (p=0.496) and PFT pattern (p=0.837). There was a significant association between presence of symptoms and mosaic attenuation on CT (p=0.003). Conclusions: DIPNECH, while a rare disorder, is understudied. This international case series is the largest performed to date and highlights the complexity in management of these patients.

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more. PURPOSE To develop a clinical practice guideline and recommendations for symptom management of patients with well-differentiated grade 1 to grade 3 metastatic gastroenteropancreatic neuroendocrine tumors. METHODS ASCO convened an Expert Panel to develop a clinical practice guideline by reviewing the literature for relevant guidelines, systematic reviews, randomized controlled trials (RCTs), and observational studies to develop recommendations for clinical practice. RESULTS The literature review identified eight guidelines, 19 systematic reviews, and three RCTs that informed the development of guideline recommendations. RECOMMENDATIONS Recommendations are included for carcinoid syndrome, carcinoid heart disease and carcinoid crisis, and functional pancreatic neuroendocrine tumor syndromes. Recommendations are provided for surgical management, liver-directed therapy, and systemic therapy options, as well as palliative care. Limited guidance is provided for sequencing of interventions. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Importance A subset of Union for International Cancer Control ( UICC )/ American Joint Committee on Cancer ( AJCC ) eighth edition TNM stage I and II human papillomavirus–positive oropharyngeal carcinoma has undesirable outcomes, which might have contributed to a lack of success in phase III deintensification trials. Refining clinical stage groups, especially in the overabundant cN1/stage I group, has become important for treatment selection. Objective To assess the prognostic importance of pretreatment lymph node (LN) characteristics to optimize case distribution and outcome homogeneity within the N classification system. Design, Setting, and Participants This is an international multi-institutional retrospective prognostic cohort study. Analysis of human papillomavirus–positive oropharyngeal carcinoma treated curatively from 4 institutions (International Collaboration of Oropharyngeal Cancer Network for N-Classification [ICON-N] dataset) provided a refined clinical staging proposal; an independent dataset (Centre Hospitalier de l’Université de Montréal [CHUM] dataset) validated the proposal. Neuroradiologists reviewed pretreatment computed tomography and/or magnetic resonance imaging for nodal features, including presence or absence of abnormal LN(s), retropharyngeal LN, laterality, number of abnormal LN, and imaging-detected extranodal extension (iENE). Data were collected from February to May 2023, and data were analyzed from June to July 2023. Exposures Definitive chemoradiotherapy/radiotherapy or definitive surgery with or without postoperative chemoradiotherapy/radiotherapy. Main Outcomes and Measures The primary end point was overall survival. A Cox proportional hazards multivariable model was used to estimate adjusted hazard ratios (AHRs) and to derive an optimal clinical TNM stage classification (AHR-stage schema) incorporating the strongest prognostic nodal features within the UICC/AJCC eighth edition TNM framework after confirming the prognostication of iENE status. The performance (according to overall normalized scores and ranking) of the AHR-stage schema against the current UICC/AJCC eighth edition TNM staging system was evaluated for hazard consistency, hazard discrimination, prognostic importance, and sample size balance. Validation was performed in the CHUM dataset. Results The ICON-N dataset comprised 2053 patients, including 1898 (92.5%) with cN-positive disease and 155 (7.5%) with cN0 disease; a total of 298 (14.5%) were female, and the mean (SD) age was 60.6 (9.3) years. iENE-positive disease was identified in 710 of 1898 patients with cN-positive disease (37.4%). The median (range) follow-up was 5.1 (0.1-14.7) years. iENE was the strongest prognostic nodal feature in multivariable analysis; the AHR for iENE-positive vs iENE-positive disease was 2.43 (95% CI, 1.96-3.03) in the ICON-N dataset and 2.04 (95% CI, 1.28-3.23) in the CHUM dataset (n = 451). Reclassifying iENE-positive cases 1 stratum higher for N categorization without altering iENE-negative cases yielded an AHR-stage schema that outperformed the current TNM staging system in disease-free and overall survival with a lower (ie, better) overall normalized score (2 vs 3). Conclusions and Relevance In this study, reclassifying each N category 1 stratum higher for iENE-positive disease resulted in better disease-free and overall survival. The proposed new classification outperformed the currently TNM staging system in risk stratification and may facilitate future clinical trial design, outcomes research, and patient care.