SMARCA4 Mutations in Gastroesophageal Adenocarcinoma: An Observational Study via a Next-Generation Sequencing Panel.

BACKGROUND: The clinical impact of SMARCA4 mutations (SMARCA4ms) in gastroesophageal adenocarcinoma (GEA) remains underexplored. This study aimed to examine the association of SMARCA4ms with clinical outcomes and co-occurrence with other gene mutations identified through a next-generation sequencing (NGS) panel in GEA patients. METHODS: A total of 256 patients with metastatic or recurrent GEA who underwent NGS panel profiling at the MD Anderson Cancer Center between 2016 and 2022 were included. Comparative analyses were performed to assess clinical outcomes related to SMARCA4ms. The frequency and types of SMARCA4ms and their co-occurrence with other gene mutations were also examined. RESULTS: SMARCA4ms were identified in 19 patients (7.4%). These SMARCA4ms were significantly associated with non-signet ring cell subtype (p = 0.044) and PD-L1 positive expression (p = 0.046). No difference in survival between the SMARCA4m and SMARCA4-normal group was observed (p = 0.84). There were significant associations between SMARCA4ms and FANCA, IGF1R, KRAS, FANCL, and PTEN alterations. Notably, 15 of the 19 SMARCA4m cases involved SNV missense mutations, with frequent co-occurrences noted with TP53, KRAS, ARID1A, and ERBB2 mutations. CONCLUSIONS: These results serve as the first comprehensive examination of the relationship between SMARCA4ms and clinical outcomes in GEA.

Chemotherapy Plus Atezolizumab Pre- and Post-Resection in Localized Esophageal or Gastroesophageal Junction Adenocarcinomas: A Phase I/II Single-Arm Study.

Efforts to improve the prognosis for patients with locally advanced esophageal or gastroesophageal junction (GEJ) adenocarcinoma have focused on neoadjuvant approaches to increase the pathological complete response (pathCR) rate, improve surgical resection, and prolong event-free and overall survival (OS). Building on the recent evidence that PD-1 inhibition plus chemotherapy improves the OS of patients with metastatic GEJ adenocarcinoma, we evaluated whether the application of this strategy in the neoadjuvant setting would improve the pathological response. This single-center phase I/II trial evaluated the safety, toxicity, and efficacy of neoadjuvant atezolizumab with oxaliplatin and 5-fluorouracil (modified FOLFOX) followed by esophagectomy followed by atezolizumab. The primary objective goal was to achieve 20% pathCR. From the twenty enrolled patients, eighteen underwent resection and two (10%, 95% CI: 1.24-31.7%) achieved pathCR. After a median follow-up duration of 40.7 months, 11 patients had disease recurrence and 10 had died. The median disease-free and OS were 28.8 (95% CI: 14.7, NA) and 38.6 months (95% CI: 30.5, NA), respectively. No treatment-related adverse events led to death. Although modified FOLFOX plus atezolizumab did not achieve the expected pathCR, an acceptable safety profile was observed. Our results support the continued development of a more refined strategy (neoadjuvant chemotherapy plus perioperative immunotherapy/targeted agents) with molecular/immune profiling in parallel.

How Do Employees in the Disability and Family and Domestic Violence Sectors Respond to Disclosures of Violence From Women With Disability?

Women with disability experience higher rates of family and domestic violence (FDV) compared to the rest of the population. There is limited research into how workers in FDV and disability organizations respond to violence against women with disability. Using a case study vignette of a woman with disability disclosing FDV, this phenomenological study explored how 10 employees across the disability and FDV sectors respond to disclosures of abuse, the barriers that influenced their response, and suggested ways to improve their practices. The study found that responses were often insufficient to meet the needs of women with disability.

Exploring Categories of Family Violence Across the Lifespan: A Scoping Review.

Family violence may be experienced at any stage of the lifespan; however, these experiences are often understood differently based on the age of the victim and who perpetrates the abuse. The significance of age is evident in the three categories of child abuse, domestic and family violence (DFV), and elder abuse. Each of these categories has its own definition which determines who is considered a victim or a perpetrator, and the behaviors counted as violent and abusive. These definitions influence how practitioners view victim-survivors' experiences of violence, and the subsequent available responses. This article reports the findings of a scoping review of international literature published between 2011 and 2021, which explored how family violence is categorized and defined. The review was conducted as part of a larger study exploring how violence against women in intimate and family contexts is conceptualized and experienced, as well as the available responses. Forty-eight articles were included in the final review, and five categories of violence in family and intimate contexts were identified. These were child abuse, DFV, elder abuse, adolescent-to-parent violence, and sibling abuse. Comparison of definitions across categories found similarities in terms of the relationship between victim and perpetrator, behavior, intention, and harm caused to the victim. Review findings suggest that definitions of various forms of family violence do not differ greatly. Further research is needed to determine whether responses to family violence across the lifespan can and should be streamlined.

Small Bowel Neuroendocrine Neoplasms-A Review.

ABSTRACT: Neuroendocrine neoplasms (NENs) are rapidly evolving small bowel tumors, and the patients are asymptomatic at the initial stages. Metastases are commonly observed at the time of presentation and diagnosis. This review addresses the small bowel NEN (SB-NEN) and its molecular, histological, and imaging features, which aid diagnosis and therapy guidance. Somatic cell number alterations and epigenetic mutations are studied to be responsible for sporadic and familial SB-NEN. The review also describes the grading of SB-NEN in addition to rare histological findings such as mixed neuroendocrine-non-NENs. Anatomic and nuclear imaging with conventional computed tomography, magnetic resonance imaging, computed tomographic enterography, and positron emission tomography are adopted in clinical practice for diagnosing, staging, and follow-up of NEN. Along with the characteristic imaging features of SB-NEN, the therapeutic aspects of imaging, such as peptide receptor radionuclide therapy, are discussed in this review.

Human Epidermal Growth Factor Receptor-2 Gastric Adenocarcinoma: Expanding Therapy of a Recognized Target.

Human epidermal growth factor receptor-2 (HER2) is a well-known cancer target. Many HER2-targeted agents are marketed and being investigated. Unfortunately, these therapies lack consistent responses and outcomes amongst different tumors. Questions remain as to why HER2 biology is different in different tumor types. Gastric adenocarcinomas (GACs) demonstrate both intra- and inter-tumor HER2 expression heterogeneity and show discordance amongst primary and metastatic disease sites. This creates barriers in determining HER2 agents' effectiveness and contributes to the failure of some HER2-targeted agents in the treatment of HER2-positive advanced GACs. Trastuzumab deruxtecan, an antibody drug conjugate of trastuzumab with a topoisomerase inhibitor, was recently approved for the treatment of refractory HER2-positive advanced GAC patients. There are exciting and newer therapies under investigation. Examining resistance patterns (both adaptive and acquired) along with establishing a better understanding of the intra- and inter-tumor heterogeneity is necessary to ensure successful progress. Here we review the current status of HER2-targeted therapy in GACs. We additionally review newer therapies under investigation and their potential role in HER2 GACs.

Diagnostic Approaches to Neuroendocrine Neoplasms of Unknown Primary Site.

ABSTRACT: Neuroendocrine tumors (NETs) are relatively uncommon heterogeneous neoplasms arising from endocrine and neuronal origin cells showing highly variable clinical behavior. By the time these tumors are discovered, up to 14% of patients with histologically proven NETs have metastasis, with the liver as the most frequently affected organ. Sometimes, no known primary site can be identified via routine imaging. Neuroendocrine tumors of unknown origin carry a poorer prognosis (compared with metastatic NETs with a known primary site) because of a lack of tailored surgical intervention and appropriate medical therapy (eg, chemotherapy or targeted therapy). A multimethod approach is frequently used in the trial to accurately determine the primary site for NETs of unknown primary sites and may include clinical, laboratory, radiological, histopathological, and surgical data. New molecular techniques using the genomic approach to identify the molecular signature have shown promising results. Various imaging modalities include ultrasound, computed tomography (CT), dual-energy CT, magnetic resonance imaging, and functional and hybrid imaging (positron emission tomography/CT, positron emission tomography/magnetic resonance imaging); somatostatin receptor imaging with new tracers is frequently used in an attempt for localization of the primary site.

Exploring Lived Experience of Family and Domestic Violence Against Women With Disability: A Scoping Review.

This article reports on a scoping review exploring understandings of family and domestic violence (FDV) against women with disability (WWD) within the literature and constitutes the second article in a two-part series, the first critiquing the categorization and measurement of FDV and disability. We report findings from qualitative studies included in the review, predominantly interpretivist and critical in orientation. The scoping review included 43 articles, 15 of which are included here, as they draw upon data directly from the perspectives of WWD. Reflexive thematic analysis was conducted, utilizing both inductive and deductive coding, and consultation between the authors. The analysis highlighted experiences of disability-based abuse, the nexus of ableism and sexism within the everyday, and meanings of justice and resilience for WWD. Disability-based abuse was perpetrated primarily by intimate partners, including financial and physical disability-based abuse, and was used to exploit and perpetuate situations of isolation. Sexist and ableist expectations, assumptions, and attitudes converged in everyday encounters within the community, with workers and systems. However, WWD reported strategies of resistance, healing, coping, and moving on in the aftermath of FDV and indicated what can be done to promote justice, both personally and within systems. The findings were discussed drawing on Axel Honneth's theory of recognition to highlight the mechanisms by which recognition and respect can be enhanced to enable full access to citizenship, in particular, for WWD to live free from violence.

Appendiceal Neuroendocrine Neoplasms: A Comprehensive Review.

ABSTRACT: Appendiceal neuroendocrine neoplasm (NEN) is the most common adult appendiceal malignant tumor, constituting 16% of gastrointestinal NENs. They are versatile tumors with varying morphology, immunohistochemistry, secretory properties, and cancer genomics. They are slow growing and clinically silent, to begin with, or present with features of nonspecific vague abdominal pain. Most acute presentations are attributed clinically to appendicitis, with most cases detected incidentally on pathology after an appendectomy. Approximately 40% of them present clinically with features of hormonal excess, which is likened to the functional secretory nature of their parent cell of origin. The symptoms of carcinoid syndrome render their presence clinically evident. However, slow growing and symptomatically silent in its initial stages, high-grade neuroendocrine tumors and neuroendocrine carcinomas of the appendix are aggressive and usually have hepatic and lymph node metastasis at presentation. This review article focuses on imaging characteristics, World Health Organization histopathological classification and grading, American Joint Committee on Cancer/Union or International Cancer Control, European Neuroendocrine Tumor Society staging, European Neuroendocrine Tumor Society standardized guidelines for reporting, data interpretation, early-stage management protocols, and advanced-stage appendiceal NENs. Guidelines are also set for the follow-up and reassessment. The role of targeted radiotherapy, chemotherapy, and high-dose somatostatin analogs in treating advanced disease are discussed, along with types of ablative therapies and liver transplantation for tumor recurrence. The search for newer location-specific biomarkers in NEN is also summarized. Regarding the varying aggressiveness of the tumor, there is a scope for research in the field, with plenty of data yet to be discovered.

Lobular capillary hemangioma (pyogenic granuloma) of the gastrointestinal tract: Clinicopathologic analysis of 34 cases.

OBJECTIVES: Lobular capillary hemangioma (LCH) rarely involves the gastrointestinal (GI) tract. This study describes clinicopathologic features of LCH in a cohort of GI cases. METHODS: We defined lobular capillary hemangioma as "a proliferation of capillary-sized blood vessels arranged at least focally in a lobular configuration," searched departmental archives for cases, and recorded clinicopathologic findings. RESULTS: We identified 34 GI tract LCHs from 16 men and 10 women; 4 patients had multiple lesions. Mean age was 64 years. Cases arose in the esophagus (n = 7), stomach (n = 3), small bowel (n = 7), and colorectum (n = 17). Twelve patients had anemia or rectal bleeding. No patients had a known genetic syndrome. The lesions manifested as mucosal polyps, with median size of 1.3 cm. Microscopically, 20 lesions were ulcerated, and most involved the mucosa, with 9 extending into the submucosa. Vessel dilation was present in 27 patients, endothelial hobnailing in 13, hemorrhage in 13, and focal reactive stromal atypia in 2. Follow-up information was available for 10 patients, none of whom developed same-site recurrence. Six of the 26 cases (23%) were extradepartmental consultations, including 2 of the multifocal cases. CONCLUSIONS: Gastrointestinal tract LCHs often arise as colorectal polyps. They are typically small but can reach a few centimeters in size and can be multifocal.

Nivolumab combination therapy as first-line treatments for unresectable, advanced or metastatic esophageal squamous cell carcinoma.

INTRODUCTION: Esophageal cancers continue to confer a dismal prognosis. Targeted and immune therapies have skyrocketed in the world of cancer management. Unlike other solid tumors, esophageal squamous cell carcinoma (ESCC) has lacked effective targeted therapy. Promising outcomes with immune checkpoint inhibitors (ICIs) have recently changed ESCC management. AREAS COVERED: Nivolumab has been granted several approvals to treat ESCC patients. Nivolumab is recommended as adjuvant therapy for localized ESCC patients following trimodality therapy who have residual cancer in the surgical specimen (lymph node(s) and or the primary). CheckMate-648 led to dual ICI therapy approval with nivolumab plus ipilimumab or nivolumab plus platinum with fluoropyrimidine as first-line treatment for unresectable ESCC patients. ATTRACTION-3 resulted in nivolumab approval for second-line therapy of unresectable ESCC patients who have not been exposed to ICI. Here we provide a review of nivolumab and how this relates to ESCC management. EXPERT OPINION: Some ESCC patients will not experience a response to ICIs. Determining intrinsic and acquired resistance patterns are needed to further capitalize on ICI therapy for ESCC patients. PD-L1 expression has been explored as a potential biomarker. Data show, however, PD-L1 positive tumor patients benefit but this assessment is not always needed.

The impact of a cognitive impairment support program on patients in an acute care setting: a pre-test post-test intervention study.

BACKGROUND: Patients with cognitive impairment are at greater risk of hospital acquired complications, longer hospital stays, and poor health outcomes compared to patients without cognitive impairment. The Cognitive Impairment Support Program is a multi-disciplinary approach to improve screening rates and awareness of patients with cognitive impairment and guide clinician response and communication during their hospitalisation to improve health outcomes. OBJECTIVE: This study evaluated the impact of implementing the Cognitive Impairment Support Program on patient hospital acquired complications, patient reported quality of life and staff satisfaction in an outer metropolitan hospital. DESIGN: A pre-test post-test design was used to collect data in two 6-month time periods between March 2020 and November 2021. PARTICIPANTS: Patients aged ≥ 65 years, admitted to a participating ward for > 24 h. INTERVENTION: The Cognitive Impairment Support Program consisted of four components: cognitive impairment screening, initiation of a Cognitive Impairment Care Plan, use of a Cognitive Impairment Identifier and associated staff education. MEASURES: The primary outcome was hospital acquired complications experienced by patients with cognitive impairment identified using clinical coding data. Secondary outcomes were patient quality of life and a staff confidence and perceived organisational support to care for patients with cognitive impairment. RESULTS: Hospital acquired complication rates did not vary significantly between the two data collection periods for patients experiencing cognitive impairment with a 0.2% (95% confidence interval: -5.7-6.1%) reduction in admissions with at least one hospital acquired complication. Patients in the post intervention period demonstrated statistically significant improvements in many items in two of the Dementia Quality of Life Measure domains: memory and everyday life. The staff survey indicated statistically significant improvement in clinical staff confidence to care for patients with cognitive impairment (p = 0.003), satisfaction with organisational support for patients (p = 0.004) and job satisfaction (p ≤ 0.001). CONCLUSION: This study provides evidence that a multicomponent Cognitive Impairment Support Program had a positive impact on staff confidence and satisfaction and patient quality of life. Broader implementation with further evaluation of the multicomponent cognitive impairment intervention across a range of settings using varied patient outcomes is recommended.

Therapeutic Advances in the Treatment of Gastroesophageal Cancers.

Gastroesophageal cancers are a group of aggressive malignancies that are inherently heterogeneous with poor prognosis. Esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, and gastric adenocarcinoma all have distinct underlying molecular biology, which can impact available targets and treatment response. Multimodality therapy is needed in the localized setting and treatment decisions require multidisciplinary discussions. Systemic therapies for treatment of advanced/metastatic disease should be biomarker-driven, when appropriate. Current FDA approved treatments include HER2-targeted therapy, immunotherapy, and chemotherapy. However, novel therapeutic targets are under development and future treatments will be personalized based on molecular profiling. Herein, we review the current treatment approaches and discuss promising advances in targeted therapies for gastroesophageal cancers.

Epithelial SOX9 drives progression and metastases of gastric adenocarcinoma by promoting immunosuppressive tumour microenvironment.

OBJECTIVE: Many cancers engage embryonic genes for rapid growth and evading the immune system. SOX9 has been upregulated in many tumours, yet the role of SOX9 in mediating immunosuppressive tumour microenvironment is unclear. Here, we aim to dissect the role of SOX9-mediated cancer stemness attributes and immunosuppressive microenvironment in advanced gastric adenocarcinoma (GAC) for novel therapeutic discoveries. METHODS: Bulk RNAseq/scRNA-seq, patient-derived cells/models and extensive functional studies were used to identify the expression and functions of SOX9 and its target genes in vitro and in vivo. Immune responses were studied in PBMCs or CD45+ immune cells cocultured with tumour cells with SOX9high or knockout and the KP-Luc2 syngeneic models were used for efficacy of combinations. RESULTS: SOX9 is one of the most upregulated SOX genes in GAC and highly expressed in primary and metastatic tissues and associated with poor prognosis. Depletion of SOX9 in patient-derived GAC cells significantly decreased cancer stemness attributes, tumour formation and metastases and consistently increased CD8+ T cell responses when cocultured with PBMCs/CD45+ cells from GAC patients. RNA sequencing identified the leukaemia inhibitory factor (LIF) as the top secreted molecule regulated by SOX9 in tumour cells and was enriched in malignant ascites and mediated SOX9-induced M2 macrophage repolarisation and inhibited T cell function. CONCLUSION: Epithelial SOX9 is critical in suppressing CD8+ T cell responses and modified macrophage function in GAC through the paracrine LIF factor. Cotargeting LIF/LIFR and CSF1R has great potential in targeting SOX9-mediated cancer stemness, T cell immunosuppression and metastases suggesting the novel combination therapy against advanced GAC.

Spirituality and children: Perspectives of occupational therapists working with children.

INTRODUCTION: Spirituality is included as a core part of occupational therapy models, as it can enhance connectedness and belonging and provide meaning to occupations. However, research that has explored occupational therapists' perspectives on spirituality has found that a lack of education and understanding of the concept means that currently many therapists do not address it in their practice. Existing research focusses on adult clients, and there is no known published research that focusses on occupational therapists working with children and their views on spirituality in clinical practice. This study explored the perspectives of occupational therapists working with children on spirituality in their clinical practice with children. METHODS: This study used a qualitative descriptive design. Participants included 20 registered occupational therapists working with children in Australia. Data were collected using focus groups and interviews and analysed using thematic analysis to determine key themes. FINDINGS: Five themes were developed: (1) vagueness and subjectivity of spirituality, (2) overlapping characteristics of spirituality and religion, (3) indirect focus on spirituality, (4) differences in children's spirituality, and (5) outcomes of addressing spirituality. CONCLUSION: Occupational therapists working with children report difficulty conceptualising spirituality and describing its role in clinical practice with children. Despite this, most suggested that spirituality is indirectly applied and has a role in improving the wellbeing of children. There is a need for exploration of how to directly support the use of spirituality in practice with children to further support holistic and family-centred care.

Pancreatic acinar cell carcinoma: A comprehensive review.

Acinar cell carcinoma (ACC) is a rare pancreatic malignancy with distinctive clinical, molecular, and morphological features. The long-term survival of ACC patients is substantially superior to that of pancreatic adenocarcinoma patients. As there are no significant patient series about ACCs, our understanding of this illness is mainly based on case reports and limited patient series. Surgical resection is the treatment of choice for patients with the disease restricted to one organ; however, with recent breakthroughs in precision medicine, medicines targeting the one-of-a-kind molecular profile of ACC are on the horizon. There are no standard treatment protocols available for people in which a total surgical resection to cure the condition is not possible. As a result of shared genetic alterations, ACCs are chemosensitive to agents with activity against pancreatic adenocarcinomas and colorectal carcinomas. The role of neoadjuvant or adjuvant chemoradiotherapy has not been established. This article aims to do a comprehensive literature study and present the most recent information on acinar cell cancer.

Nivolumab with or without chemotherapy for metastatic gastroesophageal cancers and future perspectives.

INTRODUCTION: Gastroesophageal cancers (GEC) are frequently found at the advanced stage. GEC treatment advancements have been limited and prognosis, therefore, remains poor. Through numerous clinical trials, the addition of immune checkpoint inhibitors, including nivolumab, to conventional therapy has demonstrated a survival benefit. AREAS COVERED: Here, we focus on the function of nivolumab in patients with advanced GECs. We discuss the most recent trials that led to nivolumab's incorporation into therapy and pathways forward. EXPERT OPINION: Nivolumab in combination with chemotherapy appears well tolerated, with only a small number of patients reporting severe toxicity; therefore, it may be possible to add additional biological agents to improve outcomes. A number of 'nivolumab plus other agents' is currently being investigated, and we anticipate continued advancement in GEC management in the coming years.

Neuroendocrine Neoplasms of the Female Genitourinary Tract: A Comprehensive Overview.

Primary neuroendocrine neoplasms are a rare heterogeneous group of tumors that include well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinoma, and paraganglioma. An extensive literature search was used to compile the data regarding epidemiology, pathogenesis, imaging features, and management of the urinary system NENs. We also included the updated staging of the NENs at various locations of the urinary system.

Neuroendocrine Neoplasms of the Gynecologic Tract.

Gynecological tract neuroendocrine neoplasms (NEN) are rare, aggressive tumors from endocrine cells derived from the neuroectoderm, neural crest, and endoderm. The primary gynecologic NENs constitute 2% of gynecologic malignancies, and the cervix is the most common site of NEN in the gynecologic tract. The updated WHO classification of gynecologic NEN is based on the Ki-67 index, mitotic index, and tumor characteristics such as necrosis, and brings more uniformity in the terminology of NENs like other disease sites. Imaging plays a crucial role in the staging, triaging, restaging, and surveillance of NENs. The expression of the somatostatin receptors on the surface of neuroendocrine cells forms the basis of increasing evaluation with functional imaging modalities using traditional and new tracers, including 68Ga-DOTA-Somatostatin Analog-PET/CT. Management of NENs involves a multidisciplinary approach. New targeted therapies could improve the paradigm of care for these rare malignancies. This article focuses on the updated staging classifications, clinicopathological characteristics, imaging, and management of gynecologic NENs of the cervix, ovary, endometrium, vagina, and vulva, emphasizing the relatively common cervical neuroendocrine carcinomas among these entities.

Esophageal cancer: emerging therapeutics.

INTRODUCTION: Esophageal cancer (EC) is a worldwide healthcare concern and represents an aggressive malignancy. Squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) are the two primary histological subtypes but have yet to vastly differ in management. Outcomes remain poor with current treatment approaches; however, recent progress is focused on distinguishing separate targets based on thistology. AREAS COVERED: Here we provide an overview of EC management via a historical review and recent discoveries. As noted in this review, targeted therapy has lagged behind other solid tumors. Over the previous decade, for EACs there were only two targeted therapies used in the advanced setting with limited benefits. ESCC progress was rather non-existent. We present current ongoing advancements that have occurred in the realm of immunotherapy and emerging new agents. EXPERT OPINION: It is becoming clearer that segregating these two histological subtypes in trials should be the goal of future trial designs. ESCC appears to be more amenable to immune modulation than EAC; however, we are navigating in exciting times as molecular interrogations of EC has expanded with the hope of making more rapid progress. There is still hard work ahead of us to painfully define subsets representing heterogeneity and then finding appropriate agents.