Survival and Toxicity in Patients With Unresectable or Inoperable Biliary Tract Cancers With Ablative Radiation Therapy Versus Nonablative Chemoradiation.

Purpose: Conventional chemoradiation (CCRT) is inadequately effective for the treatment of unresectable or inoperable biliary tract cancers (UIBC). Ablative radiation therapy (AR), typically defined as a biologically effective dose (BED) ≥80.5 Gy, has shown some promise in terms of local control and survival in these patients. We compare the efficacy and toxicity of AR to non-AR in UIBC patients. Methods and Materials: Patients with UIBC treated with stereotactic body radiation therapy (SBRT; n = 18) or CCRT (n = 28) between 2006 and 2021 were retrospectively analyzed. The associations of treatment, BED groups, selected characteristics with overall survival (OS), progression-free survival (PFS), and local control were estimated separately using Cox proportional hazards regression. Toxicity was scored using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: Median dose fractionation was 60 Gy in 5 fractions (median BED, 127 Gy) for SBRT and 50 Gy in 25 fractions (median BED, 64 Gy) for CCRT. The median follow-up of the entire cohort was 11.5 months. The 1-year OS rate was 62% for BED <80.5 versus 66% for BED ≥80.5 (P = .069). The 1-year PFS rate was 24% for BED <80.5 and 29% for BED ≥80.5 (P = .050). The 1-year local control rate was 20% for BED <80.5 and 41% for BED ≥80.5 (P = .097). BED as a continuous variable (P = .013), BED ≥100 Gy (P = .044), and race (white versus nonwhite) (P = .037) were associated with improved overall mortality. BED ≥80.5 Gy (P = .046), smaller tumor size (<5 cm; P = .038) and N0 disease (P <.0001) were associated with improved disease progression rates. Local control was improved in patients with N0 disease compared with N1 disease (P <.0001). Both treatments were well tolerated; there was no difference in acute and late toxicity between AR and non-AR. Conclusions: In this review, there was improved PFS with BED ≥80.5 Gy with a trend toward OS benefit. BED ≥80.5 Gy was achieved mostly through SBRT and was well tolerated. AR could be considered a more effective treatment modality than CCRT in patients with UIBC.

Design and Construction of a Multi-Tiered Minimal Actin Cortex for Structural Support in Lipid Bilayer Applications.

Artificial lipid bilayers have revolutionized biochemical and biophysical research by providing a versatile interface to study aspects of cell membranes and membrane-bound processes in a controlled environment. Artificial bilayers also play a central role in numerous biosensing applications, form the foundational interface for liposomal drug delivery, and provide a vital structure for the development of synthetic cells. But unlike the envelope in many living cells, artificial bilayers can be mechanically fragile. Here, we develop prototype scaffolds for artificial bilayers made from multiple chemically linked tiers of actin filaments that can be bonded to lipid headgroups. We call the interlinked and layered assembly a multiple minimal actin cortex (multi-MAC). Construction of multi-MACs has the potential to significantly increase the bilayer's resistance to applied stress while retaining many desirable physical and chemical properties that are characteristic of lipid bilayers. Furthermore, the linking chemistry of multi-MACs is generalizable and can be applied almost anywhere lipid bilayers are important. This work describes a filament-by-filament approach to multi-MAC assembly that produces distinct 2D and 3D architectures. The nature of the structure depends on a combination of the underlying chemical conditions. Using fluorescence imaging techniques in model planar bilayers, we explore how multi-MACs vary with electrostatic charge, assembly time, ionic strength, and type of chemical linker. We also assess how the presence of a multi-MAC alters the underlying lateral diffusion of lipids and investigate the ability of multi-MACs to withstand exposure to shear stress.

Factors Associated With Racial and Ethnic Disparities in Locally Advanced Rectal Cancer Outcomes.

Importance: Hispanic and non-Hispanic Black patients receiving neoadjuvant therapy and surgery for locally advanced rectal cancer (LARC) achieve less favorable clinical outcomes than non-Hispanic White patients, but the source of this disparity is incompletely understood. Objective: To assess whether racial and ethnic disparities in treatment outcomes among patients with LARC could be accounted for by social determinants of health and demographic, clinical, and pathologic factors known to be associated with treatment response. Design, Setting, and Participants: The National Cancer Database was interrogated to identify patients with T3 to T4 or N1 to N2 LARC treated with neoadjuvant therapy and surgery. Patients were diagnosed between January 1, 2004, and December 31, 2017. Data were culled from the National Cancer Database from July 1, 2022, through December 31, 2023. Exposure: Neoadjuvant therapy for rectal cancer followed by surgical resection. Main Outcomes and Measures: The primary outcome was the rate of pathologic complete response (pCR) following neoadjuvant therapy. Secondary outcomes were rate of tumor downstaging and achievement of pN0 status. Results: A total of 34 500 patient records were reviewed; 21 679 of the patients (62.8%) were men and 12 821 (37.2%) were women. The mean (SD) age at diagnosis was 59.7 (12.0) years. In terms of race and ethnicity, 2217 patients (6.4%) were Hispanic, 2843 (8.2%) were non-Hispanic Black, and 29 440 (85.3%) were non-Hispanic White. Hispanic patients achieved tumor downstaging (48.9% vs 51.8%; P = .01) and pN0 status (66.8% vs 68.8%; P = .02) less often than non-Hispanic White patients. Non-Hispanic Black race, but not Hispanic ethnicity, was associated with less tumor downstaging (odds ratio [OR], 0.86 [95% CI, 0.78-0.94]), less frequent pN0 status (OR, 0.91 [95% CI, 0.83-0.99]), and less frequent pCR (OR, 0.81 [95% CI, 0.72-0.92]). Other factors associated with reduced rate of pCR included rural location (OR, 0.80 [95% CI, 0.69-0.93]), lack of or inadequate insurance (OR for Medicaid, 0.86 [95% CI, 0.76-0.98]; OR for no insurance, 0.65 [95% CI, 0.54-0.78]), and treatment in a low-volume center (OR for first quartile, 0.73 [95% CI, 0.62-0.87]; OR for second quartile, 0.79 [95% CI, 0.70-0.90]; OR for third quartile, 0.86 [95% CI, 0.78-0.94]). Clinical and pathologic variables associated with a decreased pCR included higher tumor grade (OR, 0.58 [95% CI, 0.49-0.70]), advanced tumor stage (OR for T3, 0.56 [95% CI, 0.42-0.76]; OR for T4, 0.30 [95% CI, 0.22-0.42]), and lymph node-positive disease (OR for N1, 0.83 [95% CI, 0.77-0.89]; OR for N2, 0.73 [95% CI, 0.65-0.82]). Conclusions and Relevance: The findings of this cohort study suggest that disparate treatment outcomes for Hispanic and non-Hispanic Black patients are likely multifactorial in origin. Future investigation into additional social determinants of health and biological variables is warranted.

Pulsed low-dose-rate radiation (PLDR) reduces the tumor-promoting responses induced by conventional chemoradiation in pancreatic cancer-associated fibroblasts.

Pancreatic cancer is becoming increasingly deadly, with treatment options limited due to, among others, the complex tumor microenvironment (TME). This short communications study investigates pulsed low-dose-rate radiation (PLDR) as a potential alternative to conventional radiotherapy for pancreatic cancer neoadjuvant treatment. Our ex vivo research demonstrates that PLDR, in combination with chemotherapy, promotes a shift from tumor-promoting to tumor-suppressing properties in a key component of the pancreatic cancer microenvironment we called CAFu (cancer-associated fibroblasts and selfgenerated extracellular matrix functional units). This beneficial effect translates to reduced desmoplasia (fibrous tumor expansion) and suggests PLDR's potential to improve total neoadjuvant therapy effectiveness. To comprehensively assess this functional shift, we developed the HOST-Factor, a single score integrating multiple biomarkers. This tool provides a more accurate picture of CAFu function compared to individual biomarkers and could be valuable for guiding and monitoring future therapeutic strategies. Our findings support the ongoing NCT04452357 clinical trial testing PLDR safety and TME normalization potential in pancreatic cancer patients. The HOST-Factor will be used in samples collected from this trial to validate its potential as a key tool for personalized medicine in this aggressive disease.

Source, co-occurrence, and prognostic value of PTEN mutations or loss in colorectal cancer.

Somatic PTEN mutations are common and have driver function in some cancer types. However, in colorectal cancers (CRCs), somatic PTEN-inactivating mutations occur at a low frequency (~8-9%), and whether these mutations are actively selected and promote tumor aggressiveness has been controversial. Analysis of genomic data from ~53,000 CRCs indicates that hotspot mutation patterns in PTEN partially reflect DNA-dependent selection pressures, but also suggests a strong selection pressure based on protein function. In microsatellite stable (MSS) tumors, PTEN alterations co-occur with mutations activating BRAF or PI3K, or with TP53 deletions, but not in CRC with microsatellite instability (MSI). Unexpectedly, PTEN deletions are associated with poor survival in MSS CRC, whereas PTEN mutations are associated with improved survival in MSI CRC. These and other data suggest use of PTEN as a prognostic marker is valid in CRC, but such use must consider driver mutation landscape, tumor subtype, and category of PTEN alteration.

Confirming Silent Translocation through Nanopores with Simultaneous Single-Molecule Fluorescence and Single-Channel Electrical Recordings.

Most of what is known concerning the luminal passage of materials through nanopores arises from electrical measurements. Whether nanopores are biological, solid-state, synthetic, hybrid, glass-capillary-based, or protein ion channels in cells and tissues, characteristic signatures embedded in the flow of ionic current are foundational to understanding functional behavior. In contrast, this work describes passage through a nanopore that occurs without producing an electrical signature. We refer to the phenomenon as "silent translocation." By definition, silent translocations are invisible to the standard tools of electrophysiology and fundamentally require a simultaneous ancillary measurement technique for positive identification. As a result, this phenomenon has been largely unexplored in the literature. Here, we report on a derivative of Cyanine 5 (sCy5a) that passes through the α-hemolysin (αHL) nanopore silently. Simultaneously acquired single-molecule fluorescence and single-channel electrical recordings from bilayers formed over a closed microcavity demonstrate that translocation does indeed take place, albeit infrequently. We report observations of silent translocation as a function of time, dye concentration, and nanopore population in the bilayer. Lastly, measurement of the translocation rate as a function of applied potential permits estimation of an effective energy barrier for transport through the pore as well as the effective charge on the dye, all in the absence of an information-containing electrical signature.

NCI Rectal-Anal Task Force consensus recommendations for design of clinical trials in rectal cancer.

The optimal management of locally advanced rectal cancer is rapidly evolving. The National Cancer Institute Rectal-Anal Task Force convened an expert panel to develop consensus on the design of future clinical trials of patients with rectal cancer. A series of 82 questions and subquestions, which addressed radiation and neoadjuvant therapy, patient perceptions, rectal cancer populations of special interest, and unique design elements, were subject to iterative review using a Delphi analytical approach to define areas of consensus and those in which consensus is not established. The task force achieved consensus on several areas, including the following: 1) the use of total neoadjuvant therapy with long-course radiation therapy either before or after chemotherapy, as well as short-course radiation therapy followed by chemotherapy, as the control arm of clinical trials; 2) the need for greater emphasis on patient involvement in treatment choices within the context of trial design; 3) efforts to identify those patients likely, or unlikely, to benefit from nonoperative management or minimally invasive surgery; 4) investigation of the utility of circulating tumor DNA measurements for tailoring treatment and surveillance; and 5) the need for identification of appropriate end points and recognition of challenges of data management for patients who enter nonoperative management trial arms. Substantial agreement was reached on priorities affecting the design of future clinical trials in patients with locally advanced rectal cancer.

Comparing Lifestyle Modifications and the Magnitude of Their Associated Benefit on Cancer Mortality.

Many cancers are associated with poor diet, lack of physical activity, and excess weight. Improving any of these three lifestyle factors would likely reduce cancer deaths. However, modifications to each of these-better nutrition, enhanced activity and fitness, and loss of extra body fat-have different effect sizes on cancer mortality. This review will highlight the relative benefit that each lifestyle change, enacted prior to a diagnosis of cancer, might impart on cancer-related deaths, as well as attempt to quantify the changes required to derive such a benefit. The review relies primarily on epidemiological data, with meta-analyses serving as the backbone for comparisons across interventions and individual studies within the larger meta-analyses providing the data necessary to form more quantitative conclusions. The reader can then use this information to better understand, recommend, and implement behaviors that might ultimately reduce cancer mortality. Of all the interventions, it seems clear that exercise, specifically improving cardiorespiratory fitness, is the best way to decrease the risk of dying from cancer.

Understanding the Challenges Faced by Esophageal and Gastroesophageal Junction Cancer Survivors.

The primary aim of this study is to characterize long-term quality of life (QOL) in patients with esophageal and gastroesophageal junction (EGEJ) cancers who underwent curative intent treatment. EGEJ survivors were recruited to participate in a one-time cross-sectional survey study using validated questionnaires assessing QOL. Chart review was conducted for patient demographics and clinical characteristics. Spearman correlation coefficients, Wilcoxon signed-rank test, and Fisher's exact test were used to assess relationships between patient characteristics and long-term outcomes. QOL was relatively high in this sample, as evidenced by high median scores on the functional scales and low median scores in the symptom domains of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, with an overall median global health score of 75.0 (range 66.7-83.3). Patients using opiates at the time of survey reported lower role functioning (P = .004), social functioning (P = .052), and overall global health (P = .041). Younger patients had significantly higher rates of reflux (P = .019), odynophagia (P = .045), choking (P = .005), and cough (P = .007). Patients using opiates or of younger age had lower QOL and higher symptoms in this cohort of long-term EGEJ survivors.

Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society for the management of high grade gastroenteropancreatic and gynecologic neuroendocrine neoplasms.

High-grade neuroendocrine neoplasms are a rare disease entity and account for approximately 10% of all neuroendocrine neoplasms. Because of their rarity, there is an overall lack of prospectively collected data available to advise practitioners as to how best to manage these patients. As a result, best practices are largely based on expert opinion. Recently, a distinction was made between well-differentiated high-grade (G3) neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas, and with this, pathologic details, appropriate imaging practices and treatment have become more complex. In an effort to provide practitioners with the best guidance for the management of patients with high-grade neuroendocrine neoplasms of the gastrointestinal tract, pancreas, and gynecologic system, the North American Neuroendocrine Tumor Society convened a panel of experts to develop a set of recommendations and a treatment algorithm that may be used by practitioners for the care of these patients. Here, we provide consensus recommendations from the panel on pathology, imaging practices, management of localized disease, management of metastatic disease and surveillance and draw key distinctions as to the approach that should be utilized in patients with well-differentiated G3 neuroendocrine tumors vs poorly differentiated neuroendocrine carcinomas.

Association of Radiotherapy Duration With Clinical Outcomes in Patients With Esophageal Cancer Treated in NRG Oncology Trials: A Secondary Analysis of NRG Oncology Randomized Clinical Trials.

Importance: For many types of epithelial malignant neoplasms that are treated with definitive radiotherapy (RT), treatment prolongation and interruptions have an adverse effect on outcomes. Objective: To analyze the association between RT duration and outcomes in patients with esophageal cancer who were treated with definitive chemoradiotherapy (CRT). Design, Setting, and Participants: This study was an unplanned, post hoc secondary analysis of 3 prospective, multi-institutional phase 3 randomized clinical trials (Radiation Therapy Oncology Group [RTOG] 8501, RTOG 9405, and RTOG 0436) of the National Cancer Institute-sponsored NRG Oncology (formerly the National Surgical Adjuvant Breast and Bowel Project, RTOG, and Gynecologic Oncology Group). Enrolled patients with nonmetastatic esophageal cancer underwent definitive CRT in the trials between 1986 and 2013, with follow-up occurring through 2014. Data analyses were conducted between March 2022 to February 2023. Exposures: Treatment groups in the trials used standard-dose RT (50 Gy) and concurrent chemotherapy. Main Outcomes and Measures: The outcomes were local-regional failure (LRF), distant failure, disease-free survival (DFS), and overall survival (OS). Multivariable models were used to examine the associations between these outcomes and both RT duration and interruptions. Radiotherapy duration was analyzed as a dichotomized variable using an X-Tile software to choose a cut point and its median value as a cut point, as well as a continuous variable. Results: The analysis included 509 patients (median [IQR] age, 64 [57-70] years; 418 males [82%]; and 376 White individuals [74%]). The median (IQR) follow-up was 4.01 (2.93-4.92) years for surviving patients. The median cut point of RT duration was 39 days or less in 271 patients (53%) vs more than 39 days in 238 patients (47%), and the X-Tile software cut point was 45 days or less in 446 patients (88%) vs more than 45 days in 63 patients (12%). Radiotherapy interruptions occurred in 207 patients (41%). Female (vs male) sex and other (vs White) race and ethnicity were associated with longer RT duration and RT interruptions. In the multivariable models, RT duration longer than 45 days was associated with inferior DFS (hazard ratio [HR], 1.34; 95% CI, 1.01-1.77; P = .04). The HR for OS was 1.33, but the results were not statistically significant (95% CI, 0.99-1.77; P = .05). Radiotherapy duration longer than 39 days (vs ≤39 days) was associated with a higher risk of LRF (HR, 1.32; 95% CI, 1.06-1.65; P = .01). As a continuous variable, RT duration (per 1 week increase) was associated with DFS failure (HR, 1.14; 95% CI, 1.01-1.28; P = .03). The HR for LRF 1.13, but the result was not statistically significant (95% CI, 0.99-1.28; P = .07). Conclusions and Relevance: Results of this study indicated that in patients with esophageal cancer receiving definitive CRT, prolonged RT duration was associated with inferior outcomes; female patients and those with other (vs White) race and ethnicity were more likely to have longer RT duration and experience RT interruptions. Radiotherapy interruptions should be minimized to optimize outcomes.

Use of the Toxicity Index in Evaluating Adverse Events in Anal Cancer Trials: Analysis of RTOG 9811 and RTOG 0529.

Novel toxicity metrics that account for all adverse event (AE) grades and the frequency of may enhance toxicity reporting in clinical trials. The Toxicity Index (TI) accounts for all AE grades and frequencies for categories of interest. We evaluate the feasibility of using the TI methodology in 2 prospective anal cancer trials and to evaluate whether more conformal radiation (using Intensity Modulated Radiation Therapy) results in improved toxicity as measured by the TI. Patients enrolled on NRG/RTOG 0529 or nonconformal RT enrolled on the 5-Fluorouracil/Mitomycin arm of NRG/RTOG 9811 were compared using the TI. Patients treated on NRG/RTOG 0529 had lower median TI compared with patients treated with nonconformal RT on NRG/RTOG 9811 for combined GI/GU/Heme/Derm events (3.935 vs 3.996, P=0.014). The TI methodology is a feasible method to assess all AEs of interest and may be useful as a composite metric for future efforts aimed at treatment de-escalation or escalation.

EyeScreen: Development and Potential of a Novel Machine Learning Application to Detect Leukocoria.

Purpose: Early diagnosis and treatment of retinoblastoma are of paramount importance for a positive clinical outcome. The most common sign of retinoblastoma is leukocoria, or white pupil. Effective, easy-to-perform, community-based screening is needed to improve outcomes in lower-income regions. The EyeScreen (developed by Joshua Meyer from the University of Michigan) Android (Google LLC) smartphone application is an important step toward addressing this need. The purpose of this study was to examine the potential of the novel use of low-cost technologies-a cell phone application and machine learning-to identify leukocoria. Design: A cell phone application was developed and refined with the feedback from on-site, single-population use in Ethiopia. Application performance was evaluated in this technology validation study. Participants: One thousand four hundred fifty-seven participants were recruited from ophthalmology and pediatric clinics in Addis Ababa, Ethiopia. Methods: Photographs obtained with inexpensive Android smartphones running the EyeScreen Application were used to train an ImageNet (ResNet) machine learning model and to measure the performance of the app. Eighty percent of the images were used in training the model, and 20% were reserved for testing. Main Outcome Measures: Performance of the model was measured in terms of sensitivity, specificity, receiver operating characteristic (ROC) curve, and precision-recall curve. Results: Analyses of the participant images resulted in the following at the participant level: sensitivity, 87%; specificity, 73%; area under the ROC curve, 0.93; and area under the precision-recall curve, 0.77. Conclusions: EyeScreen has the potential to serve as an effective screening tool in the areas of the world most affected by delayed retinoblastoma diagnosis. The relatively high initial performance of the machine learning model with small training datasets in this early-phase study can serve as a proof of concept for future use of machine learning and artificial intelligence in ophthalmic applications.

Real-world Use of Radiation for Newly Diagnosed Brain Metastases in Patients With ALK-positive Lung Cancer Receiving First-line ALK Inhibitor.

PURPOSE: Management paradigms now allow for systemic targeted drugs before central nervous system (CNS)-directed radiation therapy (RT) in selected asymptomatic patients with non-small cell lung cancer (NSCLC) and brain metastases (BM). We aimed to quantify how novel targeted agents with improved CNS activity, such as second-generation anaplastic lymphoma kinase (ALK) inhibitors (eg, alectinib), might affect the role of CNS-directed RT. METHODS AND MATERIALS: This retrospective, observational, real-world, patterns-of-care study used a nationwide, electronic, health record-derived, de-identified, longitudinal database. A random sample of patients with ALK+ advanced NSCLC and BM on first-line ALK-inhibitor monotherapy between January 1, 2014 and August 31, 2019 were included. Using an index date of the first instance of BM, the outcome was brain-directed local treatment within 4 months. Trends over time were reported and tested using multivariable modified Poisson regression with robust error variance, including an indicator during or after 2017 (when alectinib was approved). RESULTS: Of the 352 included patients, 146 had BM. In addition, 104 patients received CNS-directed local therapy, and 42 did not. The majority of patients (89.4%) were treated with RT alone. Of those receiving RT, stereotactic radiosurgery monotherapy was the most common (53%), followed by whole brain RT alone (39%). On multivariable analysis, patients who had their first BM during or after 2017 had a decreased rate of receiving local BM treatment versus those before 2017 with an adjusted incidence rate ratio of 0.63 (95% confidence interval [CI], 0.41-0.95; P = .026). We found no change in the proportion of BM treated with whole brain RT during or after 2017 versus before (adjusted incidence rate ratio: 0.70; 95% CI: 0.24-2.06; P = .517). CONCLUSIONS: We found decreasing use of CNS-directed RT in patients with NSCLC with new BM on first-line ALK inhibitors. Clinical outcomes for these patients require continued investigation, because physicians may become increasingly comfortable deferring upfront local therapy for BM in lieu of novel targeted agents with improved CNS activity.

Identifying Bone Matrix Impairments in a Mouse Model of Neurofibromatosis Type 1 (NF1) by Clinically Translatable Techniques.

Three-to-four percent of children with neurofibromatosis type 1 (NF1) present with unilateral tibia bowing, fracture, and recalcitrant healing. Alkaline phosphatase (ALP) enzyme therapy prevented poor bone mineralization and poor mechanical properties in mouse models of NF1 skeletal dysplasia; but transition to clinical trials is hampered by the lack of a technique that (i) identifies NF1 patients at risk of tibia bowing and fracture making them eligible for trial enrollment and (ii) monitors treatment effects on matrix characteristics related to bone strength. Therefore, we assessed the ability of matrix-sensitive techniques to provide characteristics that differentiate between cortical bone from mice characterized by postnatal loss of Nf1 in Osx-creTet-Off ;Nf1flox/flox osteoprogenitors (cKO) and from wild-type (WT) mice. Following euthanasia at two time points of bone disease progression, femur and tibia were harvested from both genotypes (n ≥ 8/age/sex/genotype). A reduction in the mid-diaphysis ultimate force during three-point bending at 20 weeks confirmed deleterious changes in bone induced by Nf1 deficiency, regardless of sex. Pooling females and males, low bound water (BW), and low cortical volumetric bone mineral density (Ct.vBMD) were the most accurate outcomes in distinguishing cKO from WT femurs with accuracy improving with age. Ct.vBMD and the average unloading slope (Avg-US) from cyclic reference point indentation tests were the most sensitive in differentiating WT from cKO tibias. Mineral-to-matrix ratio and carbonate substitution from Raman spectroscopy were not good classifiers. However, when combined with Ct.vBMD and BW (femur), they helped predict bending strength. Nf1 deficiency in osteoprogenitors negatively affected bone microstructure and matrix quality with deficits in properties becoming more pronounced with duration of Nf1 deficiency. Clinically measurable without ionizing radiation, BW and Avg-US are sensitive to deleterious changes in bone matrix in a preclinical model of NF1 bone dysplasia and require further clinical investigation as potential indicators of an onset of bone weakness in children with NF1. © 2022 American Society for Bone and Mineral Research (ASBMR).

ECOG-ACRIN Guideline for Contouring and Treatment of Early Stage Anal Cancer Using IMRT/IGRT.

PURPOSE: Previous anal cancer guidelines delineate target volumes similarly for all patients with squamous cell carcinoma of the anal canal and/or perianal skin (SCCA), regardless of disease stage. The purpose of this guideline is to provide customized radiation treatment recommendations for early stage (T1-2 N0 M0) anal cancer treated with intensity modulated and image guided radiation therapy (RT). METHODS AND MATERIALS: A contouring atlas and radiation treatment recommendations for the ongoing, randomized phase II trial of deintensified chemoradiation for early stage SCCA (EA2182) was created by an expert panel of radiation oncologists. A literature search was conducted to update and expand these recommendations into a guideline for routine clinical use. RESULTS: For the majority of cases, we recommend treatment in the supine, frog leg position with the use of a customized immobilization device and daily image guided RT to ensure optimal bone and soft tissue alignment. Vaginal dilators can be used daily during RT to maximize genitalia sparing. We recommend use of a 10-mm margin on the gross tumor plus including the anal complex to create the primary clinical target volume. To define the elective lymph node clinical target volume, we recommend starting with a 7-mm expansion on blood vessels, but then further refining these volumes based on the anatomic location. A 5- to 10-mm planning target volume (PTV) margin is suggested based on institutional setup and patient-specific factors. When using a simultaneous integrated boost technique, a dose of 50.4 Gy to primary PTV and 42 Gy to lymph node PTV, both delivered over 28 fractions, with chemotherapy is appropriate for early stage anal cancer. CONCLUSIONS: This guideline provides anatomic, clinical, and technical instructions to guide radiation oncologists in the planning and delivery of intensity modulated and image guided RT for early stage SCCA.

The American Brachytherapy Society consensus statement for permanent implant brachytherapy using Yttrium-90 microsphere radioembolization for liver tumors.

PURPOSE: To develop a multidisciplinary consensus for high quality multidisciplinary implementation of brachytherapy using Yttrium-90 (90Y) microspheres transarterial radioembolization (90Y TARE) for primary and metastatic cancers in the liver. METHODS AND MATERIALS: Members of the American Brachytherapy Society (ABS) and colleagues with multidisciplinary expertise in liver tumor therapy formulated guidelines for 90Y TARE for unresectable primary liver malignancies and unresectable metastatic cancer to the liver. The consensus is provided on the most recent literature and clinical experience. RESULTS: The ABS strongly recommends the use of 90Y microsphere brachytherapy for the definitive/palliative treatment of unresectable liver cancer when recommended by the multidisciplinary team. A quality management program must be implemented at the start of 90Y TARE program development and follow-up data should be tracked for efficacy and toxicity. Patient-specific dosimetry optimized for treatment intent is recommended when conducting 90Y TARE. Implementation in patients on systemic therapy should account for factors that may enhance treatment related toxicity without delaying treatment inappropriately. Further management and salvage therapy options including retreatment with 90Y TARE should be carefully considered. CONCLUSIONS: ABS consensus for implementing a safe 90Y TARE program for liver cancer in the multidisciplinary setting is presented. It builds on previous guidelines to include recommendations for appropriate implementation based on current literature and practices in experienced centers. Practitioners and cooperative groups are encouraged to use this document as a guide to formulate their clinical practices and to adopt the most recent dose reporting policies that are critical for a unified outcome analysis of future effectiveness studies.

Delineating the RAS Conformational Landscape.

Mutations in RAS isoforms (KRAS, NRAS, and HRAS) are among the most frequent oncogenic alterations in many cancers, making these proteins high priority therapeutic targets. Effectively targeting RAS isoforms requires an exact understanding of their active, inactive, and druggable conformations. However, there is no structural catalog of RAS conformations to guide therapeutic targeting or examining the structural impact of RAS mutations. Here we present an expanded classification of RAS conformations based on analyses of the catalytic switch 1 (SW1) and switch 2 (SW2) loops. From 721 human KRAS, NRAS, and HRAS structures available in the Protein Data Bank (206 RAS-protein cocomplexes, 190 inhibitor-bound, and 325 unbound, including 204 WT and 517 mutated structures), we created a broad conformational classification based on the spatial positions of Y32 in SW1 and Y71 in SW2. Clustering all well-modeled SW1 and SW2 loops using a density-based machine learning algorithm defined additional conformational subsets, some previously undescribed. Three SW1 conformations and nine SW2 conformations were identified, each associated with different nucleotide states (GTP-bound, nucleotide-free, and GDP-bound) and specific bound proteins or inhibitor sites. The GTP-bound SW1 conformation could be further subdivided on the basis of the hydrogen bond type made between Y32 and the GTP γ-phosphate. Further analysis clarified the catalytic impact of G12D and G12V mutations and the inhibitor chemistries that bind to each druggable RAS conformation. Overall, this study has expanded our understanding of RAS structural biology, which could facilitate future RAS drug discovery. SIGNIFICANCE: Analysis of >700 RAS structures helps define an expanded landscape of active, inactive, and druggable RAS conformations, the structural impact of common RAS mutations, and previously uncharacterized RAS inhibitor-binding modes.

Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers.

Loss of expression or activity of the tumor suppressor PTEN acts similarly to an activating mutation in the oncogene PIK3CA in elevating intracellular levels of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), inducing signaling by AKT and other pro-tumorigenic signaling proteins. Here, we analyze sequence data for 34,129 colorectal cancer (CRC) patients, capturing 3,434 PTEN mutations. We identify specific patterns of PTEN mutation associated with microsatellite stability/instability (MSS/MSI), tumor mutational burden (TMB), patient age, and tumor location. Within groups separated by MSS/MSI status, this identifies distinct profiles of nucleotide hotspots, and suggests differing profiles of protein-damaging effects of mutations. Moreover, discrete categories of PTEN mutations display non-identical patterns of co-occurrence with mutations in other genes important in CRC pathogenesis, including KRAS, APC, TP53, and PIK3CA. These data provide context for clinical targeting of proteins upstream and downstream of PTEN in distinct CRC cohorts.