The Proposed 9th Edition TNM Classification of Lung Cancer.

A universal nomenclature of the anatomic extent of lung cancer has been critical for individual patient care as well as research advances. As progress occurs, new details emerge that need to be included in a refined system that aligns with contemporary clinical management issues. The 9th edition TNM classification of lung cancer, which is scheduled to take effect in January of 2025, addresses this need. It is based on a large international database, multidisciplinary input and extensive statistical analyses. Key features of the 9th edition include validation of the significant changes in the T component introduced in the 8th edition, subdivision of N2 after exploration of fundamentally different ways of categorizing the N component, and further subdivision of the M component. This has led to reordering of the TNM combinations included in stage groups, primarily involving stage groups IIA, IIB, IIIA and IIIB. This paper summarizes the analyses and revisions for the TNM classification of lung cancer to familiarize the broader medical community and facilitate implementation of the 9th edition system.

Telehealth and Outcomes in Patients With Cancer: Data and Innovation.

ABSTRACT: Despite that telehealth has been crucial to the delivery of oncology care during the COVID-19 pandemic, the impact of this care delivery mechanism on outcomes in cancer care has not been rigorously studied relative standard in-person care for patients with cancer. Patient-centered outcomes such as quality of life, patient satisfaction, and symptoms are important outcomes that have been the primary focus of many of the existing studies in this space, yet only a select few have evaluated overall survival and other objective efficacy endpoints. Studies have alluded to positive effects of telehealth on mitigating financial toxicity and enhancing cost-effective care delivery in oncology. Telehealth carries much potential for advancing care for patients with cancer, but future study should focus on additional efficacy endpoints, implementation, and ways to reduce disparities.

Coil-Helix Block Copolymers Can Exhibit Divergent Thermodynamics in the Disordered Phase.

Chiral building blocks have the ability to self-assemble and transfer chirality to larger hierarchical length scales, which can be leveraged for the development of novel nanomaterials. Chiral block copolymers, where one block is made completely chiral, are prime candidates for studying this phenomenon, but fundamental questions regarding the self-assembly are still unanswered. For one, experimental studies using different chemistries have shown unexplained diverging shifts in the order-disorder transition temperature. In this study, particle-based molecular simulations of chiral block copolymers in the disordered melt were performed to uncover the thermodynamic behavior of these systems. A wide range of helical models were selected, and several free energy calculations were performed. Specifically, we aimed to understand (1) the thermodynamic impact of changing the conformation of one block in chemically identical block copolymers and (2) the effect of the conformation on the Flory-Huggins interaction parameter, χ, when chemical disparity was introduced. We found that the effective block repulsion exhibits diverging behavior, depending on the specific conformational details of the helical block. Commonly used conformational metrics for flexible or stiff block copolymers do not capture the effective block repulsion because helical blocks are semiflexible and aspherical. Instead, pitch can quantitatively capture the effective block repulsion. Quite remarkably, the shift in χ for chemically dissimilar block copolymers can switch sign with small changes in the pitch of the helix.

The Evolving Role for Systemic Therapy in Resectable Non-small Cell Lung Cancer.

During the last 2 decades, the understanding of non-small cell lung cancer (NSCLC) has evolved from a purely histologic classification system to a more complex model synthesizing clinical, histologic, and molecular data. Biomarker-driven targeted therapies have been approved by the United States Food and Drug Administration for patients with metastatic NSCLC harboring specific driver alterations in EGFR, HER2, KRAS, BRAF, MET, ALK, ROS1, RET, and NTRK. Novel immuno-oncology agents have contributed to improvements in NSCLC-related survival at the population-level. However, only in recent years has this nuanced understanding of NSCLC permeated into the systemic management of patients with resectable tumors.

Efficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations.

PURPOSE: The uncommon EGFR exon 19 deletion (ex19del), L747_A750>P, demonstrates reduced sensitivity to osimertinib compared with the common ex19del, E746_A750del in preclinical models. The clinical efficacy of osimertinib in patients with non-small cell lung cancer harboring L747_A750>P and other uncommon ex19dels is not known. EXPERIMENTAL DESIGN: The AACR GENIE database was interrogated to characterize the frequency of individual ex19dels relative to other variants, and a multicenter retrospective cohort was used to compare clinical outcomes for patients with tumors harboring E746_A750del, L747_A750>P, and other uncommon ex19dels who received osimertinib in the first line (1L) or in second or later lines of therapy and were T790M+ (≥2L). RESULTS: ex19dels comprised 45% of EGFR mutations, with 72 distinct variants ranging in frequency from 28.1% (E746_A750del) to 0.03%, with L747_A750>P representing 1.8% of the EGFR mutant cohort. In our multi-institutional cohort (N = 200), E746_A750del was associated with significantly prolonged progression-free survival (PFS) with 1L osimertinib versus L747_A750>P [median 21.3 months (95% confidence interval, 17.0-31.7) vs. 11.7 months (10.8-29.4); adjusted HR 0.52 (0.28-0.98); P = 0.043]. Osimertinib efficacy in patients with other uncommon ex19dels varied on the basis of the specific mutation present. CONCLUSIONS: The ex19del L747_A750>P is associated with inferior PFS compared with the common E746_A750del mutation in patients treated with 1L osimertinib. Understanding differences in osimertinib efficacy among EGFR ex19del subtypes could alter management of these patients in the future.

Heterocyclic Phosphenium Cations and Their Divergent Coordination Chemistry.

While they are often encountered as reaction intermediates, phosphenium cations are not commonly incorporated into π-conjugated systems. We report the synthesis and characterization of donor-stabilized phosphenium cations supported by pyridylhydrazonide ligands. The preparation of these cations relies on precise control of ligand E-Z isomerism. The heterocycles were treated with a variety of transition metals, with [Rh(COD)Cl]2 yielding the only well-defined organometallic products. The optoelectronic properties of the phosphenium heterocycles and their transition-metal complexes were examined using UV-vis absorption spectroscopy, cyclic voltammetry, and modeling by density functional theory (DFT). Computations support the description of these compounds as phosphenium cations and corroborate our observation of a weak P-Npyridine bond, which was manifested experimentally as the Rh adducts undergo selective insertion of Rh into the P-Npyridine bond, depending on the substituent at phosphorus. The reported compounds provide a framework for further study of π-conjugated, N,N'-chelated phosphenium cations and their transition-metal adducts.

Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations.

Tyrosine kinase inhibitors (TKIs) are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). TKI responses vary across tumors driven by the heterogeneous group of exon 19 deletions and mutations, but the molecular basis for these differences is not understood. Using purified TKDs, we compared kinetic properties of several exon 19 variants. Although unaltered for the second generation TKI afatinib, sensitivity varied significantly for both the first and third generation TKIs erlotinib and osimertinib. The most sensitive variants showed reduced ATP-binding affinity, whereas those associated with primary resistance retained wild type ATP-binding characteristics (and low KM, ATP). Through crystallographic and hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies, we identify possible origins for the altered ATP-binding affinity underlying TKI sensitivity and resistance, and propose a basis for classifying uncommon exon 19 variants that may have predictive clinical value.

Forming the Hematology-Oncology Collaborative Videoconferencing (CO-VID) Learning Initiative: Experiential Lessons Learned From a Novel Trainee-Led Multidisciplinary Virtual Learning Platform.

PURPOSE: COVID-19 challenged medical practice and graduate medical education. Building on previous initiatives, we describe and reflect on the formative process and goals of the Hematology-Oncology Collaborative Videoconferencing Learning Initiative, a trainee-led multi-institutional virtual COVID-19 learning model. METHODS: Clinical fellows and faculty from 13 US training institutions developed consensus needs, goals, and objectives, recruited presenters, and generated a multidisciplinary COVID-19 curriculum. Weekly Zoom conferences consisted of two trainee-led instructional segments and a trainee-moderated faculty Q&A panel. Hematology-oncology training program faculty and trainees were the targeted audience. Leadership evaluations consisted of anonymized baseline and concluding mixed methods surveys. Presenter evaluations consisted of session debriefs and two structured focus groups. Conference evaluations consisted of attendance, demographics, and pre- or postmultiple-choice questions on topic learning objectives. RESULTS: In 6 weeks, the initiative produced five conferences: antivirals, anticoagulation, pulmonology, provider resilience, and resource scarcity ethics. The average attendance was 100 (range 57-185). Among attendees providing both pre- and postconference data, group-level knowledge appeared to increase: antiviral (n = 46) pre-/postcorrect 82.6%/97.8% and incorrect 10.9%/2.2%, anticoagulation (n = 60) pre-/postcorrect 75%/93.3% and incorrect 15%/6.7%, and pulmonary (n = 21) pre-/postcorrect 66.7%/95.2% and incorrect 33.3%/4.8%. Although pulmonary management comfort appeared to increase, comfort managing of antivirals and anticoagulation was unchanged. At the conclusion of the pilot, leadership trainees reported improved self-confidence organizing multi-institutional collaborations, median (interquartile range) 58.5 (50-64) compared with baseline 34 (26-39), but did not report improved confidence in other educational or leadership skills. CONCLUSION: During crisis, trainees built a multi-institutional virtual education platform for the purposes of sharing pandemic experiences and knowledge. Accomplishment of initiative goals was mixed. Lessons learned from the process and goals may improve future disaster educational initiatives.

Prolonged Complete Response of Early Stage Primary Adenocarcinoma of the Lung to Nivolumab Monotherapy.

Immune checkpoint inhibitors are currently employed for the treatment of various malignancies, including advanced melanoma and non-small cell lung cancer. As more patients are treated with checkpoint inhibitors, situations will arise in which early-stage disease may be subjected, intentionally or unintentionally, to these agents. This is especially relevant for patients presenting with multiple primary malignant tumors (MPMTs). Here we report the case of a patient presenting synchronously with metastatic melanoma to multiple regional lymph nodes and stage I lung adenocarcinoma with high Programmed-Death Ligand 1 (PD-L1) expression. Given the high-risk nature of his melanoma, he was treated with nivolumab monotherapy, and had a durable response of both malignancies to a PD-1 inhibitor. He remains disease-free, off therapy sixteen months after completing a 19-month course of treatment. This highlights the complexity of treating patients with MPMTs in the era of effective immunotherapy and raises the possibility of treating primary lung cancer with systemic immunotherapy in situations in which surgery is not feasible due to comorbidities or other circumstances.

Selecting the optimal immunotherapy regimen in driver-negative metastatic NSCLC.

The treatment landscape of driver-negative non-small-cell lung cancer (NSCLC) is rapidly evolving. Immune-checkpoint inhibitors, specifically those targeting PD-1 or PD-L1, have demonstrated durable efficacy in a subset of patients with NSCLC, and these agents have become the cornerstone of first-line therapy. Approved immunotherapeutic strategies for treatment-naive patients now include monotherapy, immunotherapy-exclusive regimens or chemotherapy-immunotherapy combinations. Decision making in this space is complex given the absence of head-to-head prospective comparisons, although a thorough analysis of long-term efficacy and safety data from pivotal clinical trials can provide insight into the optimal management of each subset of patients. Indeed, histological subtype and the extent of tumour cell PD-L1 expression are paramount to regimen selection, although other clinicopathological factors and patient preferences might also be relevant in certain scenarios. Finally, several emerging biomarkers and novel therapeutic strategies are currently under investigation, and these might further refine the current treatment paradigm. In this Review, we discuss the current treatment landscape and detail our approach to first-line immunotherapy regimen selection for patients with advanced-stage, driver-negative NSCLC.

Treatment with Foscarnet after Allogeneic Hematopoietic Cell Transplant (Allo-HCT) Is Associated with Long-Term Loss of Renal Function.

Despite a well-established risk of chronic kidney disease (CKD) after allogeneic hematopoietic cell transplant (allo-HCT), the benefits of using nephrotoxic anti-infective agents to treat serious peritransplant infections often outweigh this risk. While there is no consensus on the optimal management of post-allo-HCT human herpes virus 6 (HHV6) reactivation, the nephrotoxic drug foscarnet is often used, although its long-term impact on renal function has not been established. We retrospectively reviewed 987 adult patients who underwent transplantation between 2002 and 2016, of whom 45.3% (n = 447) were exposed to foscarnet. The most frequent indications for foscarnet treatment were cytomegalovirus (n = 257, 57.5%) and HHV6 (n = 139, 31.1%). In the first 3 months post-transplant, patients exposed versus unexposed had similar rates of acute kidney injury and acute kidney failure (defined as 3 times baseline creatinine or <75% baseline estimated glomerular filtration rate [eGFR], 61.6% versus 58.7%, P = .42 and 28.1% versus 26.6%, P = .64, respectively). There was no difference in the eGFR at 3 months (P = .36), but patients treated with foscarnet had significantly lower median eGFRs (mL/min/1.73 m2) at 6 months (69.3, interquartile range [IQR] 51.4 to 92.8 versus 77.4, IQR 57.3 to 99.3; P = .009) and 12 months (67.8, IQR 52.7 to 85.0 versus 80.7, IQR 63.1 to 102.0; P < .001), respectively. There was also a significant difference in the decline in eGFR from baseline to 12 months (median 32.8, IQR 14.6 to 53.2 versus 21.9, IQR 6.4 to 37.4; P < .001), irrespective of the duration of foscarnet treatment. Multivariate analysis revealed that patients treated with foscarnet were more likely to experience a >30% decrease in eGFR from baseline to 12 months compared to those who were not (odds ratio, 2.30; 95% CI, 1.40 to 3.78; P = .001). We conclude that foscarnet use following allo-HCT had a profound impact on long-term renal function independent of other transplant-related factors.

The Use of Percutaneous Screw Fixation Without Fracture Site Preparation in the Treatment of Fifth Metatarsal Base Nonunion.

Nonunion after a proximal fifth metatarsal fracture can cause considerable pain, with high morbidity and loss of work. Although many authors advocate early surgical management of zone 3 injuries (Jones fractures), zone 1 and 2 fractures are generally expected to heal with conservative management. Uncommonly, zone 1 and 2 fractures can develop nonunions. The aim of this study was to evaluate the efficacy of closed intramedullary screw fixation for nonunions of the fifth metatarsal base. We performed a prospective study involving all fifth metatarsal base nonunions treated in our department over 2 years. Only minimally displaced adult fractures were considered for this study. The fracture pattern was categorized using the Dameron classification (zone 1, styloid process; zone 2, metadiaphyseal area; zone 3, proximal diaphysis). All nonunions were fixed percutaneously under radiographic guidance, without fracture site preparation. Zone 1 injuries were fixed using a 3-mm headless compression screw, and those of zones 2 and 3, with an intramedullary 4-mm screw. Of 30 patients included in this study, a minimum 6-month clinical follow-up was obtained. The average time from injury to treatment was 5.9 months (range 3 to 36). There were no smokers in this patient cohort. There were 12 zone 1 injuries, 9 zone 2 injuries, and 9 zone 3 injuries. All patients achieved union by 3 months after screw fixation, with 29 of 30 achieving union by 6 weeks. All patients had resolution of symptoms. There were no complications. We conclude that percutaneous fixation of fifth metatarsal base nonunions, without fracture site preparation, achieves excellent results. We believe that the screw alters the strain of the fracture, thus promoting fibrous-to-osseous conversion and therefore union.

Vibration as an adjunct to exercise: its impact on shoulder muscle activation.

PURPOSE: There is an interest within elite sport in understanding the impact of a vibrating platform as an adjunct to exercise in the training and rehabilitation of throwing athletes. However, there has been no comprehensive evaluation of its impact on the rotator cuff muscles or its effect on the timing of shoulder muscle recruitment more globally. METHODS: Twenty healthy participants were recruited with EMG recorded from 15 shoulder girdle muscles. Isometric shoulder flexion at 25% maximal voluntary contraction was performed in three testing scenarios [no vibration; whole body vibration (WBV); and arm vibration (AV)]. A press up and triceps dips with and without vibration were also performed. Muscular recruitment was assessed pre- and post-vibration exposure as participants initiated forward flexion. RESULTS: Activation of the anterior deltoid (p = 0.002), serratus anterior (p = 0.004), and rotator cuff muscles (p = 0.004-0.022) occurred significantly earlier following exposure to vibration. Significantly greater activation was seen in the anterior, middle and posterior deltoid, upper, middle and lower trapezius, serratus anterior, teres major, latissimus dorsi, supraspinatus, and infraspinatus when the isometric contraction was performed with either WBV and/or AV (p = < 0.001-0.040). Similarly, increased activation was also demonstrated during the press up and triceps dips when performed with vibration. CONCLUSION: The use of vibration as an adjunct to exercise provokes a near global increase in shoulder muscle activation level. Furthermore, exposure to vibration alters muscular recruitment improving readiness for movement. This has potential implications within elite sport for both training and game preparation; however, further longitudinal work is required.

Checkpoint inhibitor use in two heart transplant patients with metastatic melanoma and review of high-risk populations.

Due to the unique side-effect profile of immune checkpoint inhibitors (ICIs), groups of patients deemed to be at high risk of complications were excluded from trials that proved the efficacy and safety of these agents in patients with various malignancies. Among these excluded patients were those with prior solid organ transplantation, chronic viral infections and pre-existing autoimmune diseases including paraneoplastic syndromes. We present follow-up on a patient from a previously published case report with an orthotopic heart transplantation who was treated with both cytotoxic T-lymphocyte antigen 4 and PD-1 inhibition safely, without organ rejection. Additionally, we describe the case of a patient with a cardiac allograft who also did not experience organ rejection after treatment with pembrolizumab. Through smaller trials, retrospective analyses, case series and individual case reports, we are accumulating initial data on how these agents are tolerated by the aforementioned groups. Our survey of the literature has found more evidence of organ transplant rejection in patients treated with PD-1 inhibitors than those treated with inhibitors of cytotoxic T-lymphocyte antigen 4. Patients with chronic viral infections, especially hepatitis C, seem to have little to no risk of treatment-related increase in serum RNA levels. The literature contains few documented cases of devastating exacerbations of pre-existing autoimmune disease during treatment with ICIs, and flares seem to be easily controlled by immunosuppression in the vast majority of cases. Last, several cases allude to a promising role for disease-specific antibodies and other serum biomarkers in identifying patients at high risk of developing certain immune-related adverse events, detecting subclinical immune-related adverse event onset, and monitoring treatment response to immunosuppressive therapy in patients treated with ICIs. Though these excluded populations have not been well studied in randomized placebo-controlled trials, we may be able to learn and derive hypotheses from the existing observational data in the literature.

HSCT-GAVE as a Manifestation of Chronic Graft versus Host Disease: A Case Report and Review of the Existing Literature.

Gastric antral vascular ectasia or "watermelon stomach" is a significant cause of nonvariceal upper GI bleeding and is characterized by red, tortuous ectatic vessels along longitudinal folds in the gastric antrum. The existing literature links GAVE to patients with cirrhosis, scleroderma, bone marrow transplantation, and chronic renal failure among other associations, but its pathophysiology remains ill-defined. Over 30 cases of hematopoietic stem cell transplant-related GAVE (HSCT-GAVE) have been reported in the literature to date and there are likely many more that go undiagnosed or are attributed to another cause of upper gastrointestinal bleeding. Interestingly, a busulfan-containing conditioning regimen has been the primary factor implicated in the etiology of HSCT-GAVE because this was common to all cases in the literature to date. Here, we present the first case of HSCT-GAVE in a patient that was treated with a non-busulfan-containing conditioning regimen. We propose a link between chronic GVHD and the development of HSCT-GAVE that is supported by a similar development of GAVE in patients with systemic sclerosis.

Radiation-induced liver disease as a mimic of liver metastases at serial PET/CT during neoadjuvant chemoradiation of distal esophageal cancer.

PURPOSE: To determine the frequency and appearance of radiation-induced liver disease on PET/CT in patients undergoing serial imaging during neoadjuvant chemoradiation of distal esophageal cancer. MATERIALS AND METHODS: In this IRB-approved, HIPAA-compliant retrospective analysis, we identified 112 patients with distal esophageal cancer treated by neoadjuvant chemoradiation who had serial PET/CT imaging available for review. Two readers reviewed all studies in consensus and recorded those cases where new foci of visually detectable increased FDG avidity appeared in the liver during therapy. The etiology of such foci was determined from corresponding findings at CT or MRI, by hepatic biopsy during surgery, by characteristic evolution on post-operative imaging, or by a combination of these methods. RESULTS: New foci of FDG avidity developed in the liver during neoadjuvant therapy in 10 of 112 (9%) patients, of whom nine (8%) were determined to have radiation-induced liver disease based on further imaging and/or biopsy and one of whom had developed interval metastatic disease based on biopsy. In the cases of radiation-induced liver disease, the abnormal foci were found only in the caudate and left hepatic lobes, near the primary tumor, while the patient who developed interval metastatic disease had involvement of the inferior right hepatic lobe, remote from the radiation therapy field. CONCLUSION: New foci of increased FDG avidity are commonly seen in the caudate and left hepatic lobes of the liver during neoadjuvant chemoradiation of distal esophageal cancer, and these findings generally reflect radiation-induced liver disease rather than metastatic disease.