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Trimodality therapy for resectable esophageal and gastroesophageal junction cancers utilizing preoperative radiotherapy with concurrent carboplatin and paclitaxel-based chemotherapy is being increasingly utilized secondary to the results of the phase III CROSS trial. However, there is a paucity of reports of this regimen as a component of chemoradiotherapy in North America. We aim to report on our clinical experience using a modified CROSS regimen with higher radiotherapy doses. Patients with advanced ( cT2- cT4 or node positive) esophageal or gastroesophageal junction carcinoma who received preoperative carboplatin/paclitaxel-based chemoradiotherapy with radiation doses of greater than 41.4 Gray ( Gy) followed by esophagectomy were identified from an institutional database. Patient, imaging, treatment, and tumor response characteristics were analyzed. Twenty-four patients were analyzed. All but one tumor had adenocarcinoma histology. The median radiation dose was 50.4 Gy. Pathologic complete response was achieved in 29% of patients, with all receiving 50.4 Gy. Three early postoperative deaths were seen, due in part to acute respiratory distress syndrome and all three patients received 50-50.4 Gy. With a median follow-up of 9.4 months (23 days-2 years), median survival was 24 months. Trimodality therapy utilizing concurrent carboplatin/paclitaxel with North American radiotherapy doses appeared to have similar pathologic complete response rates compared with the CROSS trial, but may be associated with higher toxicity. Although the sample size is small and further follow-up is necessary, radiation doses greater than 41.4 Gy may not be warranted secondary to a potentially increased risk of severe radiation-induced acute lung injury. [ABSTRACT FROM AUTHOR]

Cancer screening continues to be a major challenge, with reliable tests only being available for very few cancers. Multi-cancer early detection (MCED) genomic tests are being developed that allow for blood-based screening for up to 50 cancers simultaneously. The PATHFINDER study was a multi-institution prospective cohort study in healthy participants over the age of 50 years (no cancer history, or history of treated cancer > 3 years prior), investigating the feasibility of the Galleri (GRAIL, LLC) ctDNA methylation MCED blood test. For participants in which the Galleri MCED test revealed methylation signatures indicative of cancer, predicted cancer signal origins were provided to the clinicians to assist with further diagnostic workup. Our institution was the highest accruing site nationally. Here, we describe our institutional test performance. Under IRB approval, a retrospective chart review of participants enrolled in the PATHFINDER study was performed. Cancer risk factors, outcomes of tests and studies performed due to MCED signal positive, time to diagnostic resolution, and treatment outcomes were obtained. From January 2020 to December 2020, our institution enrolled 1735 participants (26% of total study enrollment), 27 of which returned a signal positive for cancer suspicion (1.6%), and ultimately 12 diagnosed cancers (true positives) for a positive predictive value of 44%. Four of 12 were recurrent cancers in participants > 3 years from cancer therapy. There were 15 signal positives without cancer diagnoses (false positives), with one patient receiving extensive work-up for possible uterus, breast or lung cancer origin. Six of 15 false positive results correlated to monoclonal B-cell lymphocytosis (CLL precursor). During the course of 12-month follow-up for signal negatives, 19 participants were diagnosed with a cancer (sensitivity: 39%, specificity: 99.1%). Our institutional experience demonstrates the feasibility of MCED testing. Additional prospective randomized clinical trials are needed before widespread adoption. [ABSTRACT FROM AUTHOR]

For operative candidates, tri-modal therapy with neoadjuvant chemoradiation (CRT) followed by esophagectomy is standard of care for locally advanced esophageal carcinoma. Radiation doses in North America are heterogeneous, ranging from 41.4 Gy to 50 Gy or more. As randomized data comparing radiation doses are lacking, we hypothesize that when comparing higher (≥50 Gy) to lower (≤45.0 Gy) neoadjuvant RT doses, oncologic outcomes are similar, but with an increased risk of adverse events. Our primary objective is to assess clinical outcomes in patients treated with neoadjuvant CRT to <45.0 Gy compared to higher-dose CRT at a single NCI-designated Comprehensive Cancer Center. In this IRB-approved retrospective review, we collected patient demographics, tumor staging, tumor location within the esophagus, detailed radiation treatment records including dose volume histograms (DVH), and oncologic outcomes. Patients were over the age of 18, diagnosed with advanced (cT2–cT4 or node-positive) esophageal or gastroesophageal junction carcinoma, and underwent neoadjuvant CRT followed by esophagectomy between January 1, 2010 and December 31, 2019. This study included 287 treated with tri-modality therapy, of which 77 were treated to ≤45 Gy and 210 were treated with ≥ 50.0Gy. Most patients were males (84%), with a diagnosis of adenocarcinoma (87.8%), and a median age of 65 years. The median follow-up from time of diagnosis was 69 months. The median OS was significantly worse in patients treated with ≥50.0 Gy as compared to ≤45 Gy (median 43.9 months versus median not reached, P = 0.03). There were no significant differences in acute complications between the two groups. Detailed radiation records were available for 121 patients. There was significant variability in lung V20 (14.4%, IQR 9.5-18%), V5 (median 50.3%, IQR 39.5%-65.8%), VS5 (median 1750cc, IQR 1090-2480cc), and heart V45 (median 6.5%, IQR 4-11%), V30 (median 22.8%, IQR 15-35%), and V5 (median 99.5%, IQR 90-100%) within the evaluable cohort, with no correlation to total radiation dose or differences in OS. For locally advanced esophageal carcinoma, neoadjuvant CRT to ≤45 Gy yields improved OS compared to higher pre-operative RT dosing, with similar peri-operative complication rates. Differences in standard OAR dose constraints do not explain this difference in OS. Further analysis is underway to assess potential mechanisms leading to this survival difference, including tumor location, RT dose to the left anterior descending artery, and RT delivery techniques. [ABSTRACT FROM AUTHOR]

Liver transplantation (LTX) is the definitive treatment for hepatocellular carcinoma (HCC) in eligible patients with cirrhosis. Bridging liver-directed therapies (LDTs) are critical for maintaining Milan transplant eligibility (one HCC ≤ 5 cm or 2-3 HCCs all ≤ 3 cm) during long wait-times. However, due to the fear of further hepatic decompensation, many patients with advanced cirrhosis are excluded from receiving any LDTs. This prospective pilot study evaluated the feasibility, safety, and efficacy of SBRT as a bridging therapy in an HCC population with advanced cirrhosis. In this Radiation Oncology Institute (ROI)-funded prospective pilot study, HCC patients with Child-Pugh (CP) B8 or worse cirrhosis who were within Milan transplant criteria and eligible for LTX without prior history of abdominal radiation or Y90 radioembolization and at least 700cc of uninvolved liver were included. SBRT to 40 Gy in 5 fractions was delivered to a single HCC as a bridging strategy (for patients with multi-focal HCC, SBRT was provided to the largest lesion). Previous transarterial chemoembolization (TACE) to the target or non-target lesions was allowed. The primary endpoint was the proportion of patients that were transplant eligible up to 1-year following SBRT. Secondary endpoints included intra- and extra-hepatic disease control, overall survival, proportion of patients that proceeded to transplant, incidence of non-classical radiation-induced liver disease (RILD) within 1 week to 3 months after SBRT (defined as grade 4 AST or ALT elevation, or a ≥ 2-point increase in CP score) and incidence of liver toxicity per CTCAE v5.0. Between 2019 and 2023, seven men and two women with baseline liver functions of CP-B8 (7 patients) and CP-B9 (2 patients) were enrolled. Mean baseline bilirubin for all patients was 3.1mg/dL. Three patients had previous TACE. Eight patients had a single HCC while 1 patient had 2 HCCs (largest treated with SBRT). Median follow up was 343 days. With no instances of intra- or extra-hepatic disease progression, there were no patients who were removed from the transplant list due to Milan size or number criteria. Six (66.6%) ultimately received a liver transplantation at a median time of 12 months from study enrollment. Three (33.3%) failed to receive a liver transplantation due to factors unrelated to SBRT or tumor progression; progression of concurrent cardiac comorbidities deeming LTX unsafe, hip fracture and resultant respiratory failure, and poor compliance to LTX protocol. No cases of non-classical RILD were identified and no patients were emergently transplanted due to hepatic decompensation from SBRT. Bridging SBRT in patients with HCC and advanced cirrhosis may safely maintain LTX eligibility with no incidence of non-classical RILD. This supports the safety of bridging SBRT in a patient population with limited bridging LDT options. Further research is warranted to validate these findings in larger, multi-center trials. [ABSTRACT FROM AUTHOR]

Purpose: The presence of MYC and BCL2 translocations (ie, double-hit lymphoma, DHL) in large B-cell lymphoma (LBCL) is associated with reduced chemosensitivity, but less is known on its impact on radiotherapy (RT) efficacy., Methods and Materials: Patients with LBCL who received their first course of RT for relapsed/refractory disease between 2008 and 2020 were eligible if there was adequate pathologic evaluation to be categorized as DHL versus non-DHL as per the World Health Organization (fifth edition). Separate analyses were conducted by treatment intent. Predictors for response (complete and partial) and local recurrence (LR) were evaluated using Cox regression analysis. LR analysis was restricted to curative-intent patients to ensure adequate follow-up., Results: Three hundred and eighty-three patients (102 DHL, 281 non-DHL, and 44% curative) were treated at 447 sites. Median time from diagnosis to RT was 11.6 months, with 38.7% of patients having primary chemorefractory disease, 37.4% having received >2 lines of systemic therapy, and 24% status post-stem cell transplant. Median biological equivalent dose (alpha/beta: 10) was 28 Gy (range: 3.2-60.0) for palliative and 46.9 Gy (range: 6.4-84.0) for curative-intent patients. With a median follow-up of 41.1 and 41.5 months among curative and palliative patients, respectively, the response was high (81.1% curative, 60.1% palliative). On univariate analysis, DHL pathology was not associated with RT response in either curative or palliative patients. Among curative patients, 2-year LR rate was 38.8%. On multivariable analysis, DHL pathology was associated with a 2 times higher risk of LR (95% CI: 1.05-3.67, P = .03), with a crude LR rate of 42.9% (DHL) versus 28.9% (non-DHL). RT was well tolerated with low rates of grade 3 or higher acute toxicity (1.8% curative, 2.9% palliative)., Conclusions: Relapsed/refractory LBCL remains radioresponsive with a 60%-80% response rate to RT. Although DHL pathology does not appear to influence RT response, its presence is associated with higher rates of LR, suggesting that it may be more radioresistant., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Numerous genomic-based early detection screening tests are being developed. These tests have the potential to revolutionize current single-organ screening paradigms, especially in gastrointestinal cancers. In this review, we underscore the performance of these genomic-based early detection tests based on prospective clinical trials. Moreover, we discuss a professional advancement for gastroenterologists in the diagnostic assessment of individuals who are cancer signal positive., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: Nima Nabavizadeh declare(s) personal fees from GRAIL. Dr. Nabavizadeh played a role in consulting and advisory. . Nima Nabavizadeh declare(s) personal fees from Freenome. Dr. Nabavizadeh played a role in consulting and advisory. . Nima Nabavizadeh declare(s) personal fees from Pharmacy Times. Dr. Nabavizadeh played a role in consulting and advisory. . Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Tizpa et al.)

Introduction: For liver stereotactic body radiation therapy (SBRT), the placement of fiducial markers or retained ethiodized oil by transarterial chemoembolisation (TACE) provides a landmark for consistent target localisation. TACE and fiducial markers are invasive procedures that harbour additional risks. We hypothesise that liver SBRT can be accurately delivered without the use of these invasive surrogate markers., Methods: We retrospectively identified 50 consecutive patients who underwent liver SBRT with respiratory motion management to a single lesion which exhibited retained ethiodized oil per prior TACE delivery. For each SBRT fraction, two manual rigid image registrations were performed by the treating physician. One using the liver contour as a surrogate for the target and second aligning only to the radio-opaque retained ethiodized oil of the treated lesion. The magnitude of the displacement vector between the two registration methods was used to assess the accuracy of target localisation if ethiodized oil was not present., Results: For the 50 patients, a total of 244 analysable cone-beam CTs (CBCTs) were included (six CBCTs excluded due to poor ethiodized oil visualisation). Respiratory motion management techniques consisted of active breathing control for 13 and abdominal compression for 37 patients. Forty-two patients had peripheral lesions and eight had central lesions (<2 cm from left and right portal veins). The average target localisation offset between the two registration methods (i.e. liver contour vs. retained ethiodized oil alignment) for patients with a single peripheral or central liver lesion was 5.8 and 5.3 mm, respectively., Conclusions: Across all patients, the average change in target position exceeded 5 mm for image registration methods based on the liver contour alone versus the retained ethiodized oil region. This suggests that margins greater than 5 mm may be required for respiratory motion-managed liver SBRT treatments in patients who do not undergo prior TACE or fiducial placement., (© 2023 The Authors. Journal of Medical Radiation Sciences published by John Wiley & Sons Australia, Ltd on behalf of Australian Society of Medical Imaging and Radiation Therapy and New Zealand Institute of Medical Radiation Technology.)

SNURPORTIN-1, encoded by SNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphic SNUPN biallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients' primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establish SNUPN deficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis., (© 2024. The Author(s).)

A multitude of blood-based multicancer early detection (MCED) tests assessing cancer-related alterations in circulating genomic analytes and other associated signatures are currently being developed with the potential to disrupt current single-organ screening paradigms. Pathways for clinical implementation of these novel MCED tests have not been delineated, particularly for the patients with signal positive results requiring additional confirmatory testing. In this overview, we highlight early results from prospective clinical studies testing the efficacy of genomic MCED tests in cohorts of patients without known cancer diagnoses. Additionally, we discuss a proposed professional expansion of the oncology practice relating to the diagnostic workup of individuals found to have an MCED signal positive for cancer. As MCED blood tests have the potential to dramatically upend current cancer screening paradigms and downstream cancer therapy, it is imperative for oncologists to be aware of important clinical studies and the multitude of unanswered questions. The current gaps in the clinical implication of these tests may serve as a meaningful and rewarding expansion of oncology practice.

Purpose: Non-operative management of patients with locally advanced rectal cancer (LARC) is emerging as a popular approach for patients that have no evidence of disease following neoadjuvant therapy. However, high rates of local recurrence or distant metastases have highlighted the urgent need for robust biomarker strategies to aid clinical management of these patients., Methods: This review summarizes recent advances in the utility of cell-free (cf) and circulating tumor (ct) DNA as potential biomarkers to help guide individualized non-operative management strategies for LARC patients receiving neoadjuvant therapy., Results: Liquid biopsies and the detection of cfDNA/ctDNA is an emerging technology with the potential to provide a non-invasive approach to monitor disease response and improve the identification of patients with LARC that would best benefit from non-operative management., Conclusions: Substantial work is still needed before cfDNA/ctDNA monitoring can be widely adopted in the clinical setting. Studies reviewed herein highlight several areas of opportunity for improving the effectiveness and utility of cfDNA/ctDNA for managing patients with LARC., (© 2023. The Author(s).)

Background: Neoadjuvant treatment with nab-paclitaxel and gemcitabine for potentially operable pancreatic adenocarcinoma has not been well studied in a prospective interventional trial and could down-stage tumors to achieve negative surgical margins., Methods: A single-arm, open-label phase 2 trial (NCT02427841) enrolled patients with pancreatic adenocarcinoma deemed to be borderline resectable or clinically node-positive from March 17, 2016 to October 5, 2019. Patients received preoperative gemcitabine 1000 mg/m 2 and nab-paclitaxel 125 mg/m 2 on Days 1, 8, 15, every 28 days for two cycles followed by chemoradiation with 50.4 Gy intensity-modulated radiation over 28 fractions with concurrent fluoropyrimidine chemotherapy. After definitive resection, patients received four additional cycles of gemcitabine and nab-paclitaxel. The primary endpoint was R0 resection rate. Other endpoints included treatment completion rate, resection rate, radiographic response rate, survival, and adverse events., Results: Nineteen patients were enrolled, with the majority having head of pancreas primary tumors, both arterial and venous vasculature involvement, and clinically positive nodes on imaging. Among them, 11 (58%) underwent definitive resection and eight of 19 (42%) achieved R0 resection. Disease progression and functional decline were primary reasons for deferring surgical resection after neoadjuvant treatment. Pathologic near-complete response was observed in two of 11 (18%) resection specimens. Among the 19 patients, the 12-month progression-free survival was 58%, and 12-month overall survival was 79%. Common adverse events were alopecia, nausea, vomiting, fatigue, myalgia, peripheral neuropathy, rash, and neutropenia., Conclusion: Gemcitabine and nab-paclitaxel followed by long-course chemoradiation represents a feasible neoadjuvant treatment strategy for borderline resectable or node-positive pancreatic cancer., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Exome sequencing has introduced a paradigm shift for the identification of germline variations responsible for Mendelian diseases. However, non-coding regions, which make up 98% of the genome, cannot be captured. The lack of functional annotation for intronic and intergenic variants makes RNA-seq a powerful companion diagnostic. Here, we illustrate this point by identifying six patients with a recessive Osteogenesis Imperfecta (OI) and neonatal progeria syndrome. By integrating homozygosity mapping and RNA-seq, we delineated a deep intronic TAPT1 mutation (c.1237-52 G>A) that segregated with the disease. Using SI-NET-seq, we document that TAPT1's nascent transcription was not affected in patients' fibroblasts, indicating instead that this variant leads to an alteration of pre-mRNA processing. Predicted to serve as an alternative splicing branchpoint, this mutation enhances TAPT1 exon 12 skipping, creating a protein-null allele. Additionally, our study reveals dysregulation of pathways involved in collagen and extracellular matrix biology in disease-relevant cells. Overall, our work highlights the power of transcriptomic approaches in deciphering the repercussions of non-coding variants, as well as in illuminating the molecular mechanisms of human diseases., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Cholangiocarcinoma is a lethal malignancy of the biliary epithelium that can arise anywhere along the biliary tract. Surgical resection confers the greatest likelihood of long-term survivability. However, its insidious onset, difficult diagnostics, and resultant advanced presentation render the majority of patients unresectable, highlighting the importance of early detection with novel biomarkers. Developing liver-directed therapies and emerging targeted therapeutics may offer improved survivability for patients with unresectable or advanced disease. In this article, the authors review the current multidisciplinary standards of care in resectable and unresectable cholangiocarcinoma, with an emphasis on novel biomarkers for early detection and nonsurgical locoregional therapy options., (© 2022 American Cancer Society.)

Colorectal cancer is the second leading cause of cancer-related deaths in the United States and accounts for an estimated 1 million deaths annually worldwide. The liver is the most common site of metastatic spread from colorectal cancer, significantly driving both morbidity and mortality. Although remarkable advances have been made in recent years in the management for patients with colorectal cancer liver metastases, significant challenges remain in early detection, prevention of progression and recurrence, and in the development of more effective therapeutics. In 2017, our group held a multidisciplinary state-of-the-science symposium to discuss the rapidly evolving clinical and scientific advances in the field of colorectal liver metastases, including novel early detection and prognostic liquid biomarkers, identification of high-risk cohorts, advances in tumor-immune therapy, and different regional and systemic therapeutic strategies. Since that time, there have been scientific discoveries translating into therapeutic innovations addressing the current management challenges. These innovations are currently reshaping the treatment paradigms and spurring further scientific discovery. Herein, we present an updated discussion of both the scientific and clinical advances and future directions in the management of colorectal liver metastases, including adoptive T-cell therapies, novel blood-based biomarkers, and the role of the tumor microbiome. In addition, we provide a comprehensive overview detailing the role of modern multidisciplinary clinical approaches used in the management of patients with colorectal liver metastases, including considerations toward specific molecular tumor profiles identified on next generation sequencing, as well as quality of life implications for these innovative treatments., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Stereotactic body radiotherapy (SBRT) demonstrates excellent local control in early stage lung cancer, however a quarter of patients develop recurrence or distant metastasis. Transforming growth factor-beta (TGF-β) supports metastasis and treatment resistance, and angiotensin receptor blockade (ARB) indirectly suppresses TGF-β signaling. This study investigates whether patients taking ARBs while undergoing SBRT for early stage lung cancer exhibited improved overall survival (OS) or recurrence free survival (RFS) compared to patients not taking ARBs. This was a single institution retrospective analysis of 272 patients treated with SBRT for early stage lung cancer between 2009 and 2018. Patient health data was abstracted from the electronic medical record. OS and RFS were assessed using Kaplan-Meier method. Log-rank test was used to compare unadjusted survival between groups. Univariable and multivariable Cox proportional hazard regression models were used to estimate hazard ratios (HRs). Of 247 patients analyzed, 24 (10%) patients took ARBs for the duration of radiotherapy. There was no difference in mean age, median tumor diameter, or median biologic effective dose between patients taking ARBs or not. Patients taking ARBs exhibited increased OS (ARB = 96.7 mo.; no ARB = 43.3 mo.; HR = 0.25 [95% CI: 0.10 to 0.62, P = .003]) and increased RFS (median RFS, ARB = 64.3 mo.; No ARB = 35.1 mo.; HR = 0.26 [95% CI: 0.10 to 0.63, P = .003]). These effects were not seen in patients taking angiotensin converting enzyme inhibitors (ACEIs) or statins. ARB use while undergoing SBRT for early stage lung cancer may increase OS and RFS, but ACEI use does not show the same effect.