A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma.

The heterogeneity of cellular states in cancer has been linked to drug resistance, cancer progression and the presence of cancer cells with properties of normal tissue stem cells. Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration. Here we show that mouse and human lung adenocarcinomas display hierarchical features with two distinct subpopulations, one with high Wnt signalling activity and another forming a niche that provides the Wnt ligand. The Wnt responder cells showed increased tumour propagation ability, suggesting that these cells have features of normal tissue stem cells. Genetic perturbation of Wnt production or signalling suppressed tumour progression. Small-molecule inhibitors targeting essential posttranslational modification of Wnt reduced tumour growth and markedly decreased the proliferative potential of lung cancer cells, leading to improved survival of tumour-bearing mice. These results indicate that strategies for disrupting pathways that maintain stem-like and niche cell phenotypes can translate into effective anti-cancer therapies.

Recent Training Trends in Independent Plastic Surgery Graduates: American Board of Surgery Certification and Academic Priorities.

BACKGROUND: Among independent plastic surgery graduates, most have general surgery training, but the utility of American Board of Surgery (ABS) certification in plastic surgery practice is unclear. We elucidated attitudes and trends of ABS certification in American Board of Plastic Surgery diplomates. METHODS: American Board of Plastic Surgery diplomates from 2018 to 2020 were reviewed to identify independent plastic surgery graduates. These graduates were anonymously surveyed regarding demographics, employment, fellowships, practices, and attitudes toward ABS certification. RESULTS: Of 568 American Board of Plastic Surgery diplomates, 223 independent graduates (39%) were identified. Sixty-eight percent of these graduates were ABS certified, 80% of whom achieved certification during the beginning of plastic and reconstructive surgery training; 41% were fellowship trained. About half are in private practice, 25% are part of a hospital group, and 17% work in universities. Of 223 independent graduates, 54 (24.4%) completed the survey; 85.2% reported ABS certification, and 21.7% perform general surgery procedures. Most stated that general surgery training was valuable to their career, regardless of certification. Most agreed that ABS certification benefited their career; 63% plan to recertify. Of those surveyed, 59.3% had completed a plastic surgery fellowship. Non-fellowship-trained surgeons felt more strongly that ABS certification was beneficial (P = 0.014) and valued by patients (P = 0.026) compared with fellowship-trained surgeons. CONCLUSIONS: American Board of Surgery certification is a priority to independent plastic surgery trainees, despite potential disruption to training, personal costs, and unclear utility to their practice. Although few perform general surgery procedures, most plan to recertify. Future studies should investigate recertification among surgeons later in their careers and the impacts of dual board certification on plastic surgery practice.

Eptifibatide-induced profound thrombocytopaenia: a rare complication.

Drug-induced immune thrombocytopaenia (DITP) is a type of thrombocytopaenia caused by medications. It is one of the common causes of unexplained thrombocytopaenia. It is caused by the formation of autoantibodies against a particular drug and is commonly observed with medications like heparin and beta-lactam antibiotics. One of the rare causes of DITP is eptifibatide, a widely used antiplatelet agent for pretreatment in cardiac catheterisation. These patients can be asymptomatic or develop complications like skin bruising, epistaxis and even intracranial haemorrhage. We present a case of a 64-year-old man who developed eptifibatide-induced profound thrombocytopaenia leading to extensive skin bruising. He was treated with platelet transfusions followed by prompt improvement in platelet count.

Surgical Debulking of Persistent Orofacial Swelling in a Patient with Melkersson-Rosenthal Syndrome.

Melkersson-Rosenthal syndrome (MRS) is a rare neuro-mucocutaneous granulomatous disorder that is likely underdiagnosed due to its variability on presentation. Few patients present with the characteristic triad of orofacial swelling, recurrent facial palsy, and lingua plicata; in fact, most patients present with only one or two of the symptoms. Additionally, patients are evaluated by a variety of specialists, including ophthalmologists, otolaryngologists, dermatologists, and plastic surgeons, depending on their particular symptom. There is no consensus standard of care for MRS due to a limited understanding of the disease. We describe a case of a patient with a 5-year history of persistent orofacial edema in the setting of Melkersson-Rosenthal syndrome refractory to medical management, who was treated with surgical debulking of the upper lip. We encourage increased clinical suspicion for Melkersson-Rosenthal syndrome when evaluating persistent orofacial edema in the plastic surgery clinic and highlight the importance of obtaining a full patient history. Surgical debulking can correct for aesthetic deformity while sparing oral function.

Safety of Programmed Death-1 Pathway Inhibitors Among Patients With Non-Small-Cell Lung Cancer and Preexisting Autoimmune Disorders.

Purpose Although programmed death (PD)-1 pathway inhibitors are now used in nearly all patients with advanced non-small-cell lung cancer (NSCLC), the large number of patients with NSCLC and concurrent autoimmune disease (AID) have been universally excluded from immunotherapy clinical trials. Therefore, the safety of PD-1 and PD-ligand 1 (PD-L1) inhibitors in patients with NSCLC and underlying AID is currently unknown. Methods As part of a multi-institutional effort, we retrospectively collected clinicopathologic data from patients with NSCLC and a history of AID who received monotherapy with either a PD-1 or a PD-L1 (herein referred to as PD-[L]1) inhibitor. Qualifying AIDs included but were not limited to: rheumatologic, neurologic, endocrine, GI, and dermatologic conditions. Results We identified 56 patients with NSCLC and an AID who received a PD-(L)1 inhibitor. At the time of treatment initiation, 18% of patients had active AID symptoms and 20% were receiving immunomodulatory agents for their AID. A total of 55% of patients developed an AID flare and/or an immune-related adverse event (irAE). Exacerbation of the AID occurred in 13 patients (23% of the whole cohort), four of whom required systemic corticosteroids. Immune-related adverse events occurred in 21 patients (38%). Among irAEs, 74% were grade 1 or 2 and 26% were grade 3 or 4; eight patients required corticosteroids for irAE management. PD-(L)1 therapy was permanently discontinued in eight patients (14%) because of irAEs. The overall response rate to immunotherapy in this population was 22%. Conclusion In patients with NSCLC with AID treated with a PD-(L)1 inhibitor, exacerbation of AID occurred in a minority of patients. The incidence of irAEs was similar to reported rates in clinical trials where patients with AID were excluded. Adverse events were generally manageable and infrequently led to permanent discontinuation of immunotherapy.

Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts.

Small cell lung cancer (SCLC) patient-derived xenografts (PDX) can be generated from biopsies or circulating tumor cells (CTC), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a 2-year timeframe, at 89% and 38% efficiency, respectively. Whole-exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. In vivo treatment with etoposide and platinum (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP-naïve patients, and resistance to EP corresponded to increased expression of a MYC gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient's disease. Collectively, this work highlights the translational potential of this strategy.Significance: Effective translational research utilizing SCLC PDX models requires both efficient generation of models from patients and fidelity of those models in representing patient tumor characteristics. We present approaches for efficient generation of PDXs from both biopsies and CTCs, and demonstrate that these models capture the mutational landscape and functional features of the donor tumors. Cancer Discov; 8(5); 600-15. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 517.

In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis.

In vivo interrogation of the function of genes implicated in tumorigenesis is limited by the need to generate and cross germline mutant mice. Here we describe approaches to model colorectal cancer (CRC) and metastasis, which rely on in situ gene editing and orthotopic organoid transplantation in mice without cancer-predisposing mutations. Autochthonous tumor formation is induced by CRISPR-Cas9-based editing of the Apc and Trp53 tumor suppressor genes in colon epithelial cells and by orthotopic transplantation of Apc-edited colon organoids. ApcΔ/Δ;KrasG12D/+;Trp53Δ/Δ (AKP) mouse colon organoids and human CRC organoids engraft in the distal colon and metastasize to the liver. Finally, we apply the orthotopic transplantation model to characterize the clonal dynamics of Lgr5+ stem cells and demonstrate sequential activation of an oncogene in established colon adenomas. These experimental systems enable rapid in vivo characterization of cancer-associated genes and reproduce the entire spectrum of tumor progression and metastasis.

Corrigendum: In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis.

This corrects the article DOI: 10.1038/nbt.3836.