A New Hierarchy of Research Evidence for Tumor Pathology: A Delphi Study to Define Levels of Evidence in Tumor Pathology.

The hierarchy of evidence is a fundamental concept in evidence-based medicine, but existing models can be challenging to apply in laboratory-based health care disciplines, such as pathology, where the types of evidence and contexts are significantly different from interventional medicine. This project aimed to define a comprehensive and complementary framework of new levels of evidence for evaluating research in tumor pathology-introducing a novel Hierarchy of Research Evidence for Tumor Pathology collaboratively designed by pathologists with help from epidemiologists, public health professionals, oncologists, and scientists, specifically tailored for use by pathologists-and to aid in the production of the World Health Organization Classification of Tumors (WCT) evidence gap maps. To achieve this, we adopted a modified Delphi approach, encompassing iterative online surveys, expert oversight, and external peer review, to establish the criteria for evidence in tumor pathology, determine the optimal structure for the new hierarchy, and ascertain the levels of confidence for each type of evidence. Over a span of 4 months and 3 survey rounds, we collected 1104 survey responses, culminating in a 3-day hybrid meeting in 2023, where a new hierarchy was unanimously agreed upon. The hierarchy is organized into 5 research theme groupings closely aligned with the subheadings of the WCT, and it consists of 5 levels of evidence-level P1 representing evidence types that merit the greatest level of confidence and level P5 reflecting the greatest risk of bias. For the first time, an international collaboration of pathology experts, supported by the International Agency for Research on Cancer, has successfully united to establish a standardized approach for evaluating evidence in tumor pathology. We intend to implement this novel Hierarchy of Research Evidence for Tumor Pathology to map the available evidence, thereby enriching and informing the WCT effectively.

Moving Forward on Tumor Pathology Research Reporting: A Guide for Pathologists From the World Health Organization Classification of Tumors Living Evidence Gap Map by Tumour Type Group.

Evidence-based medicine (EBM) can be an unfamiliar territory for those working in tumor pathology research, and there is a great deal of uncertainty about how to undertake an EBM approach to planning and reporting histopathology-based studies. In this article, reviewed and endorsed by the Word Health Organization International Agency for Research on Cancer's International Collaboration for Cancer Classification and Research, we aim to help pathologists and researchers understand the basics of planning an evidence-based tumor pathology research study, as well as our recommendations on how to report the findings from these. We introduce some basic EBM concepts, a framework for research questions, and thoughts on study design and emphasize the concept of reporting standards. There are many study-specific reporting guidelines available, and we provide an overview of these. However, existing reporting guidelines perhaps do not always fit tumor pathology research papers, and hence, here, we collate the key reporting data set together into one generic checklist that we think will simplify the task for pathologists. The article aims to complement our recent hierarchy of evidence for tumor pathology and glossary of evidence (study) types in tumor pathology. Together, these articles should help any researcher get to grips with the basics of EBM for planning and publishing research in tumor pathology, as well as encourage an improved standard of the reports available to us all in the literature.

Multi-Institutional Outcomes of Patients Aged 75 years and Older With Pancreatic Ductal Adenocarcinoma Treated With 5-Fraction Ablative Stereotactic Magnetic Resonance Image-Guided Adaptive Radiation Therapy (A-SMART).

PURPOSE: Treatment options for pancreatic ductal adenocarcinoma (PDAC) are commonly limited for patients with advanced age due to medical comorbidities and/or poor performance status. These patients may not be candidates for more aggressive chemotherapy regimens and/or surgical resection leaving few, if any, other effective treatments. Ablative stereotactic MRI-guided adaptive radiation therapy (A-SMART) is both efficacious and safe for PDAC and can achieve excellent long-term local control, however, the appropriateness of A-SMART for elderly patients with inoperable PDAC is not well understood. METHODS: A retrospective analysis was performed of inoperable non-metastatic PDAC patients aged 75 years or older treated on the MRIdian Linac at 2 institutions. Clinical outcomes of interest included overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional (LRC). Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE, v5). RESULTS: A total of 49 patients were evaluated with a median age of 81 years (range, 75-91) and a median follow-up of 14 months from diagnosis. PDAC was classified as locally advanced (46.9%), borderline resectable (36.7%), or medically inoperable (16.3%). Neoadjuvant chemotherapy was delivered to 84% of patients and all received A-SMART to a median 50 Gy (range, 40-50 Gy) in 5 fractions. 1 Year LRC, PFS, and OS were 88.9%, 53.8%, and 78.9%, respectively. Nine patients (18%) had resection after A-SMART and benefited from PFS improvement (26 vs 6 months, P = .01). ECOG PS <2 was the only predictor of improved OS on multivariate analysis. Acute and late grade 3 + toxicity rates were 8.2% and 4.1%, respectively. CONCLUSIONS: A-SMART is associated with encouraging LRC and OS in elderly patients with initially inoperable PDAC. This novel non-invasive treatment strategy appears to be well-tolerated in patients with advanced age and should be considered in this population that has limited treatment options.

Machine learning computational tools to assist the performance of systematic reviews: A mapping review.

BACKGROUND: Within evidence-based practice (EBP), systematic reviews (SR) are considered the highest level of evidence in that they summarize the best available research and describe the progress in a determined field. Due its methodology, SR require significant time and resources to be performed; they also require repetitive steps that may introduce biases and human errors. Machine learning (ML) algorithms therefore present a promising alternative and a potential game changer to speed up and automate the SR process. This review aims to map the current availability of computational tools that use ML techniques to assist in the performance of SR, and to support authors in the selection of the right software for the performance of evidence synthesis. METHODS: The mapping review was based on comprehensive searches in electronic databases and software repositories to obtain relevant literature and records, followed by screening for eligibility based on titles, abstracts, and full text by two reviewers. The data extraction consisted of listing and extracting the name and basic characteristics of the included tools, for example a tool's applicability to the various SR stages, pricing options, open-source availability, and type of software. These tools were classified and graphically represented to facilitate the description of our findings. RESULTS: A total of 9653 studies and 585 records were obtained from the structured searches performed on selected bibliometric databases and software repositories respectively. After screening, a total of 119 descriptions from publications and records allowed us to identify 63 tools that assist the SR process using ML techniques. CONCLUSIONS: This review provides a high-quality map of currently available ML software to assist the performance of SR. ML algorithms are arguably one of the best techniques at present for the automation of SR. The most promising tools were easily accessible and included a high number of user-friendly features permitting the automation of SR and other kinds of evidence synthesis reviews.

The mutational landscape of human olfactory G protein-coupled receptors.

BACKGROUND: Olfactory receptors (ORs) constitute a large family of sensory proteins that enable us to recognize a wide range of chemical volatiles in the environment. By contrast to the extensive information about human olfactory thresholds for thousands of odorants, studies of the genetic influence on olfaction are limited to a few examples. To annotate on a broad scale the impact of mutations at the structural level, here we analyzed a compendium of 119,069 natural variants in human ORs collected from the public domain. RESULTS: OR mutations were categorized depending on their genomic and protein contexts, as well as their frequency of occurrence in several human populations. Functional interpretation of the natural changes was estimated from the increasing knowledge of the structure and function of the G protein-coupled receptor (GPCR) family, to which ORs belong. Our analysis reveals an extraordinary diversity of natural variations in the olfactory gene repertoire between individuals and populations, with a significant number of changes occurring at the structurally conserved regions. A particular attention is paid to mutations in positions linked to the conserved GPCR activation mechanism that could imply phenotypic variation in the olfactory perception. An interactive web application (hORMdb, Human Olfactory Receptor Mutation Database) was developed for the management and visualization of this mutational dataset. CONCLUSION: We performed topological annotations and population analysis of natural variants of human olfactory receptors and provide an interactive application to explore human OR mutation data. We envisage that the utility of this information will increase as the amount of available pharmacological data for these receptors grow. This effort, together with ongoing research in the study of genetic changes in other sensory receptors could shape an emerging sensegenomics field of knowledge, which should be considered by food and cosmetic consumer product manufacturers for the benefit of the general population.

Nursing students' care of and attitudes towards lesbian, gay, bisexual, trans, and intersex people in times of COVID-19 in Spain: A cross-sectional study.

OBJECTIVE: The objective of this work is to measure the knowledge and attitudes of Catalan nursing students regarding lesbian, gay, bisexual, trans, and intersex (LGBTI) patients, as well as their perception of specific training in this area, according to their internship modalities, sociodemographic circumstances, and academic background during the COVID-19 pandemic. BACKGROUND: During the COVID-19 pandemic, the Spanish Government created the "Health-Aid" internship: A paid alternative to curricular internships. There is extensive evidence that paid work environments perpetuate negative attitudes towards LGBTI patients. METHOD: A cross-sectional survey aimed at Catalan nursing students. The "Attitudes Towards and Knowledge About Lesbian, Gay, Bisexual, Trans and Intersex Patients" questionnaire was adapted. A descriptive study and backward regression models were constructed. RESULTS: Three hundred thirty-seven students, mean age 23.80 years (SD: 5.17) participated; 85% women and 54 (16%) completing the Health Aid internship modality. More than 50% did not attend specific training on the care of the lesbian, gay, bisexual, trans, and intersex population. Differences between internship modalities showed higher values in the curricular internship group: Attitudes (U = 6526.50, p = .031) and training perception (U = 5926.50, p = .008). CONCLUSIONS: Nursing students' attitudes towards lesbian, gay, bisexual, trans, and intersex patients and their perception of specific training on care for this population were negatively influenced by the paid Health Aid internship during the pandemic. IMPLICATIONS FOR NURSING MANAGEMENT: Even under dire circumstances, clinical training must be properly managed to address the specific health needs of vulnerable populations, such as lesbian, gay, bisexual, trans, and intersex patients. Paid internships in emergency scenarios may impede these objectives.

Perception of Risk: A Poll of American Association of Hip and Knee Surgeons Members.

BACKGROUND: Providers of total hip and knee replacements are being judged regarding quality/cost by payers using competition-based performance measures with poor medical and no socioeconomic risk adjustment. Providers might assume that other providers shed risk and the perception of added risk can influence practice. A poll was collected to examine such perceptions. METHODS: In 2019 a poll was sent to the 2800 surgeon members of the American Association of Hip and Knee Surgeons using Survey Monkey while protecting respondent anonymity/confidentiality. The questions asked whether the perception of poorly risk-adjusted medical comorbidities and socioeconomic risk factors influence surgeons to selectively offer surgery. RESULTS: There were 474 surgeon responses. Prior to elective total hip arthroplasty/total knee arthroplasty, 95% address modifiable risk factors; 52% require a body mass index <40, 64% smoking cessation, 96% an adequate hemoglobin A1C; 82% check nutrition; and 63% expect control of alcohol 2. Due to lack of socioeconomic risk adjustment, 83% reported feeling pressure to avoid/restrict access to patients with limited social support, specifically the following: Medicaid/underinsured, 81%; African Americans, 29%; Hispanics/ethnicities, 27%; and low socioeconomic status, 73%. Of the respondents, 93% predicted increased access to care with more appropriate risk adjustment. CONCLUSION: Competition-based quality/cost performance measures influence surgeons to focus on medical risk factors in offering lower extremity arthroplasty. The lack of socioeconomic risk adjustment leads to perceptions of added risk from such factors as well. This leads to marginal loss of access for patients within certain medical and socioeconomic classes, contributing to existing healthcare disparities. This represents an unintended consequence of competition-based performance measures.

Periorbital Surgical Anatomy.

This article discusses the periocular anatomy region thoroughly because its knowledge in detail is of paramount importance for any surgeon dedicated to periocular surgery or any practitioner who dedicate their practice to aesthetic medicine. Mastering the anatomical details permits obtaining consistently good results with the minimal amount of complications possible.

Orbital and peri-orbital amyloidosis: a report of four cases.

Our objective was to describe our experience with orbital amyloidosis, and illustrate the different forms of presentation. This was a retrospective case series of four patients with biopsy-proven orbital amyloi- dosis, over the period from 2014 to 2016. We describe its diagnostic and clinical characteristics, management and systemic study. The series comprised three women and one man of mean age 52 ± 9.4 years. Affected sites were the lacrimal gland, tarsal conjunctiva, lacrimal sac and orbit. In three of the four patients, calcifications were observed. Three patients had associated ptosis. The patient with orbital involvement suffered an unusual vascular complication during surgery and systemic disease was detected. Management included debulking and complete resection of the lesion. In conclusion, orbital amyloidosis presents as a wide variety of forms. Its diagnosis is biopsy-based. Calcifications in biopsy specimens or images should raise suspicion of amyloidosis. It is important to always check for systemic amyloidosis.

Transcaruncular rectus tendon fixation to the orbit and frontalis flap for complete third nerve palsy.

PURPOSE: To describe our experience and outcomes managing complete third cranial nerve palsy. METHODS: This was a retrospective analysis of the clinical records of 7 consecutive patients treated at our centre for unilateral third nerve palsy over the period 2010-2016. We describe our surgical approach using a frontalis muscle flap to correct the eyelid ptosis associated with medial fixation of the rectus muscle tendon to the orbit to correct the horizontal deviation. RESULTS: The seven patients, four women and three men, were of mean age of 44 ± 19 years [18-75 years]. Follow up was 29 ± 31 months [5-82 months]. In the preoperative exam, exotropia in prism diopters (PD) was -70 ± -28 PD [-30 to -90 PD]. At the end of follow up, this was reduced to -11 ± -14 PD [0 to -30 PD]. Preoperative marginal reflex distance 1 (MRD1) was -4 ± 1 mm [-3 to -5 mm] and palpebral fissure height (PFH) was 0.5 ± 1 mm [0-2 mm]. Surgical undercorrection was the target in all patients due to the absent or poor Bell's phenomenon. At the end of follow up, MRD1 was 2.5 ± 0.5 mm [2-3 mm] and PFH was 7 ± 1 mm [6-8 mm]. Cosmetic and functional results were good in all patients. CONCLUSIONS: Medial fixation of the rectus muscle tendon to the orbit associated with a frontalis muscle flap is a valid option for the treatment of exotropia and ptosis in patients with third cranial nerve palsy.

Postoperative Care of the Facial Plastic Surgery Patient-Forehead and Blepharoplasty.

In any kind of surgery, postoperative care is essential for a good result, but especially when the matter at stake is facial plastic surgery. Despite having performed a perfect surgery, with the least amount of damage to the soft tissues and osteocartilaginous structures, minimal bleeding, and in terms of the surgical time, without adequate postoperative care our results can be affected considerably in the short and long run. Therefore, we must have very clear guidelines regarding postoperative care and the duties of our patients, which should be emphasized during the informed consent of the intervention. It is also essential to comment on the warning signs of postoperative complications, which need to be detected and treated in time to achieve the expected post-surgery results. Before being discharged from the hospital, the patient again receives the postoperative instructions, as well as receiving a paper copy to avoid any possible misunderstandings. In this article, we will detail the postoperative care and complications of brow lift and upper and lower blepharoplasty.

The Rise and Fall of Accelerated Partial Breast Irradiation via Brachytherapy in a Single Institution.

UNLABELLED: Accelerated partial breast irradiation via brachytherapy (APBI-b) is offered as an alternative to whole breast irradiation (WBI) for selected patients with breast cancer. This study evaluates our clinical experience with APBI-b to identify the reasons for decreased clinical utilization in recent years. We performed an analysis of the prospective database of breast cancer patients treated with APBI-b between 2004 and 2013. During that time, 245 patients received APBI-b, most having stage I (77%) or stage 0 (20%) breast cancer. Since 2004, the number of APBI-b cases per year rose to 49 in 2009, declining thereafter to 14 in 2013 (P < 0.001). The APBI-b case volume dropped in 2010 following the publication of the American Society of Radiation Oncology (ASTRO) consensus guidelines in 2009. After 2009 fewer unsuitable cases received APBI-b (11% vs. 4%,P = 0.1). CONCLUSION: The clinical utilization of APBI-b has decreased after the publication of consensus guidelines. A reduction in unsuitable cases treated after 2009 does not explain the global loss of referrals.

Improving Latino Youths' Environmental Health Literacy and Leadership Skills Through Participatory Research on Chemical Exposures in Cosmetics: The HERMOSA Study.

To increase environmental health literacy (EHL) and leadership skills in Latino youth in Salinas, CA., we worked from 2012-2015 with 15 members of the CHAMACOS Youth Community Council (YCC), an outreach arm of a longitudinal study of impacts of environmental chemicals on children's health. The YCC program provided hands-on research experiences related to Endocrine Disrupting Chemicals (EDCs) in cosmetics and their possible health effects. We use participatory research principles and Bloom's Taxonomy of Educational Objectives to describe the development of EHC and leadership in the youth co-researchers. Using data from multiple qualitative sources, we explore the youths' engagement in a wide range of research and action processes. Promising outcomes, including perceptions of improved youth self-esteem, EHL, leadership, and career orientation are discussed, as are challenges, such as time constraints and high priority youth concerns not addressed by the study. Implications for other youth-engaged participatory science and leadership programs are presented.

Incidence and outcomes of postoperative fluid collections after minimally invasive distal pancreatectomy without placement of surgical drain. A prospective observational cohort study.

BACKGROUND/PURPOSE: There is uncertainty about the role of prophylactic intra-abdominal drains after distal pancreatectomy. In the present study, we aimed to describe the long-term outcomes of postoperative pancreatic collections in patients who underwent a minimally invasive distal pancreatectomy (MIDP) without surgical drain placement. METHODS: From 2018 to 2022, consecutive patients who underwent a MIDP were recorded. Patients were followed at 90 days, 6 months, and in the long term. The use of interventional procedures and antibiotic therapy were documented, and the overall evolution of the collections was assessed. RESULTS: A total of 91 patients underwent MIDP; 11 were excluded; 80 were analyzed. Median age was 63 (51-73) years; 61.3% were women. Most lesions (71.3%) were malignant; 15 patients received neoadjuvant therapy. Procedures were laparoscopic (87.5%) or robotic (12.5%). Incidence of postoperative pancreatic collections was 33%; 10 patients were symptomatic. Interventional endoscopic (n = 3) or percutaneous (n = 3) procedures were required. At a follow-up of 24 (17.5-33.1) months, 18 collections resolved completely, eight partially, and one increased. CONCLUSIONS: Patients who undergo MIDP without surgical drain placement develop well-tolerated pancreatic collections. Although a minority may require endoscopic or percutaneous drainage, the majority can be managed conservatively and resolve spontaneously in the long term.

The American Association of Latino Orthopaedic Surgeons: Our History, Achievements, and Future Goals.

ABSTRACT: The mission of the American Association of Latino Orthopaedic Surgeons (AALOS) is to provide collegiality, advancement, education, and social justice for Latino orthopaedic surgeons and the minority populations they represent. We strive to enhance diversity within the field of orthopaedic surgery by increasing the visibility of AALOS, highlighting its core focus, and emphasizing its mission. The purposes of this article are to discuss the need for this organization and highlight its history and future goals. As AALOS recently celebrated its 15-year anniversary, we are excited to continue advancing the field of orthopaedic surgery and improving our patients' care.

Dose-Escalated Preoperative Proton Therapy for Retroperitoneal Sarcomas: Initial Outcomes of a New Treatment Paradigm.

Purpose: Retroperitoneal sarcomas (RPS) have varied treatment practices with regard to the use of radiation therapy (RT). Preoperative RT ∼50 Gy is commonly used, but the Surgery With or Without Radiation Therapy in Untreated Nonmetastatic Retroperitoneal Sarcoma (STRASS-1) randomized trial demonstrated no improvement in abdominal recurrence-free survival with preoperative RT. Dose escalation has been proposed to improve the efficacy of preoperative RT. We analyzed RPS treated with preoperative intensity modulated proton therapy (IMPT) to an escalated dose of 63 Gy at a single institution. Methods and Materials: Patients who received preoperative RT with IMPT with RPS between January 2015 and October 2021 were reviewed. IMPT 63 Gy in 28 fractions to the clinical target volume high-risk and 50.4 Gy in 28 fractions to clinical target volume low-risk was used. Patient baseline characteristics, RT dose parameters, toxicities, margin status, and recurrence patterns were recorded. Local control was computed by Fine-Gray analysis and overall survival by Kaplan-Meier analysis. Results: Sixteen patients met the study criteria (n = 16): 12 primary and 4 isolated local recurrences. Median age was 62 years (IQR, 43.5-66 years) and 62.5% were male; 10 were liposarcoma. The median maximum tumor diameter was 19.9 cm (IQR, 12-24 cm). With a median follow-up of 18 months (IQR, 11.5-37 months), the estimated 3-year freedom from local failure rate was 68.2% (95% CI, 41.7%-94.7%); 3-year overall survival (OS) rate was 68.8% (95% CI, 41.9%-95.8%). No Radiation Therapy Oncology Group grade ≥3 acute or late toxicities were noted. Conclusions: In our RPS cohort, preoperative dose-escalated RT to 63 Gy demonstrated comparable local control without G3 acute toxicities. Given the high local recurrence rates of RPS, this approach warrants further study to validate these results and identify patients most likely to benefit from therapy.

Further experience with pancreatic stump closure using a reinforced staple line.

BACKGROUND: We previously demonstrated that pancreatic transection with a reinforced staple line results in significantly lower fistula rates than when stapling without reinforcement. (J Gastrointest Surg. 2007;11:345-349). Criticism of this initial study focused on the small size of the treated group (N = 13). We report four more years of experience with this technique with a larger sample size. METHODS: This was a before-after trial. Patients included had distal pancreatectomies with stapled stump closure. The main intervention analyzed was staple-line reinforcement with Seamguard. The experimental group consisted of a consecutive series of stapled pancreatectomies with reinforcement performed from 2005 to 2010. The control group was a consecutive series of stapled pancreatectomies without reinforcement performed between 2003 and 2005 (previously published). The main outcome measure was pancreatic fistula. RESULTS: 54 patients were included; 36 in the experimental group and 18 in the control group. Mean age was 62; 50% were males. The most common diagnoses were adenocarcinoma (31%), cystic neoplasm (24%), and neuroendocrine tumor (22%). There were no mortalities. Postoperative pancreatic leak rate was 39% in the control group, and 8% in the experimental group (P = 0.01). Seven of ten patients with leak required additional drain placement. Development of pancreatic leak resulted in prolonged hospital stays (12 vs eight days, P < 0.007). CONCLUSION: We demonstrate sustained success of reinforced stapling for pancreatic stump closure. Our technique is straightforward and results in reduced morbidity and cost. Our results suggest that surgical drains may not be needed when this technique is applied.

Lymph Node Dissection in Intrahepatic Cholangiocarcinoma: a Critical and Updated Review of the Literature.

BACKGROUND: Lymphatic spread of intrahepatic cholangiocarcinoma (iCCA) is common and negatively impacts survival. However, the precise role of lymph node dissection (LND) in oncologic outcomes for patients with intrahepatic cholangiocarcinoma remains to be established. METHODS: Updated evidence on the preoperative diagnosis and prognostic value of lymph node metastasis is reviewed, as well as the potential benefit of LND in patients with iCCA. RESULTS: The ability to accurately determine nodal status for iCCA with current imaging modalities is equivocal. LND has prognostic value for both survival and disease recurrence. However, execution rates of LND are highly varied in the literature, ranging from 26.9 to 100%. At least 6 lymph nodes should be examined from nodal stations of the hepatoduodenal ligament and hepatic artery as well as based on the location of the primary tumor. Neoadjuvant therapies may be beneficial if lymph node metastases at diagnosis are suspected. Surgeons performing a minimally invasive approach should focus on increasing LND rates and harvesting ≥ 6 lymph nodes. Lymph node negativity is required in patients with iCCA being considered for liver transplantation under investigational protocols. CONCLUSION: Despite an upward trend in the LND rate, the reality is that only 10% of patients with iCCA receive an adequate LND. This review underscores the importance of routinely increasing the rate of adequate LND in these patients in order to achieve accurate staging, appropriately select patients for adjuvant therapy, and improve the prognosis of clinical outcomes. While prospective data is lacking, the therapeutic impact of LND remains unknown.

Causes of Death Among Patients With Initially Inoperable Pancreas Cancer After Induction Chemotherapy and Ablative 5-fraction Stereotactic Magnetic Resonance Image Guided Adaptive Radiation Therapy.

Purpose: Nearly all patients with pancreatic ductal adenocarcinoma (PDAC) eventually die of progressive cancer after exhausting treatment options. Although distant metastases (DMs) are a common cause of death, autopsy studies have shown that locoregional progression may be directly responsible for up to one-third of PDAC-related deaths. Ablative stereotactic magnetic resonance-guided adaptive radiation therapy (A-SMART) is a novel treatment strategy that appears to improve locoregional control compared with nonablative radiation therapy, potentially leading to improved overall survival. Methods and Materials: A single-institution retrospective analysis was performed of patients with nonmetastatic inoperable PDAC treated between 2018 to 2020 using the MRIdian Linac with induction chemotherapy, followed by 5-fraction A-SMART. We identified causes of death that occurred after A-SMART. Results: A total of 62 patients were evaluated, of whom 42 (67.7%) had died. The median follow-up time was 18.6 months from diagnosis and 11.0 months from A-SMART. Patients had locally advanced (72.6%), borderline resectable (22.6%), or resectable but medically inoperable PDAC (4.8%). All patients received induction chemotherapy, typically leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, and oxaliplatin (69.4%) or gemcitabine/nab-paclitaxel (24.2%). The median prescribed dose was 50 Gy (range, 40-50), corresponding to a median biologically effective dose of 100 Gy10. Post-SMART therapy included surgery (22.6%), irreversible electroporation (9.7%), and/or chemotherapy (51.6%). Death was attributed to locoregional progression, DMs, cancer-related cachexia/malnutrition, surgery/irreversible electroporation complications, other reasons not due to cancer progression, or unknown causes in 7.1%, 45.2%, 11.9%, 9.5%, 11.9%, and 14.3% of patients, respectively. Intra-abdominal metastases of the liver and peritoneum were responsible for 84.2% of deaths from DMs. Conclusions: To our knowledge, this is the first contemporary evaluation of causes of death in patients with PDAC receiving dose-escalated radiation therapy. We demonstrated that the predominant cause of PDAC-related death was from liver and peritoneal metastases; therefore novel treatment strategies are indicated to address occult micrometastatic disease at these sites.

Hypoxia Controls the Glycome Signature and Galectin-8-Ligand Axis to Promote Protumorigenic Properties of Metastatic Melanoma.

The prognosis for patients with metastatic melanoma (MM) involving distant organs is grim, and treatment resistance is potentiated by tumor-initiating cells (TICs) that thrive under hypoxia. MM cells, including TICs, express a unique glycome featuring i-linear poly-N-acetyllactosamines through the loss of I-branching enzyme, ß1,6 N-acetylglucosaminyltransferase 2. Whether hypoxia instructs MM TIC development by modulating the glycome signature remains unknown. In this study, we explored hypoxia-dependent alterations in MM glycome‒associated genes and found that ß1,6 N-acetylglucosaminyltransferase 2 was downregulated and a galectin (Gal)-8-ligand axis, involving both extracellular and cell-intrinsic Gal-8, was induced. Low ß1,6 N-acetylglucosaminyltransferase 2 levels correlated with poor patient outcomes, and patient serum samples were elevated for Gal-8. Depressed ß1,6 N-acetylglucosaminyltransferase 2 in MM cells upregulated TIC marker, NGFR/CD271, whereas loss of MM cell‒intrinsic Gal-8 markedly lowered NGFR and reduced TIC activity in vivo. Extracellular Gal-8 bound preferentially to i-linear poly-N-acetyllactosamines on N-glycans of the TIC marker and prometastatic molecule CD44, among other receptors, and activated prosurvival factor protein kinase B. This study reveals the importance of hypoxia governing the MM glycome by enforcing i-linear poly-N-acetyllactosamine and Gal-8 expression. This mechanistic investigation also uncovers glycome-dependent regulation of pro-MM factor, NGFR, implicating i-linear poly-N-acetyllactosamine and Gal-8 as biomarkers and therapeutic targets of MM.