Chemotherapy-associated pneumoperitoneum in cancer patients: a scoping review.

Background: The presence of air in the peritoneal cavity (pneumoperitoneum) is often secondary to perforated viscus. Emergent operative intervention is typically warranted in non-cancer patients. Cancer patients present a unique challenge as they have an increased risk of pneumoperitoneum due to local tumour invasion, radiation therapy, and frequent endoscopic procedures. There is a paucity of literature on the management of patients undergoing chemotherapy who present with pneumoperitoneum. The authors conducted a scoping review to identify and synthesize preliminary evidence on the presentation, management, and outcomes of this patient population. Materials and methods: A scoping review of cases of pneumoperitoneum in cancer patients from 1990 to 2022 was conducted using the Arksey and O'Malley five-stage approach. Inclusion criteria were a known diagnosis of cancer, chemotherapy within 6 months of presentation, and imaging confirmation of pneumoperitoneum. The authors' exclusion criteria were cancer diagnosis at the time of presentation, perforation secondary to local cancer invasion, and last chemotherapy session greater than 6 months prior to presentation. Results: Thirty-four cases (8 paediatric, 26 adults) were identified. The median time from the last chemotherapy treatment to presentation with pneumoperitoneum was 14 days. Twenty-one patients were managed operatively, and 13 were managed non-operatively. The most common source of perforation was multiple sites along the bowel. Thirty-day mortality was 33.3% for the operative cohort and 23.1% for the non-operative group. Conclusions: Pneumoperitoneum in cancer patients remains a highly morbid condition with a mortality rate of approximately 30%, regardless of the treatment approach. Non-operative management should be pursued whenever possible.

Interests and Barriers to Medical Students Participation in a Dedicated Global Surgery Curriculum.

INTRODUCTION: Despite many institutions establishing global surgery (GS) programs to support clinical care and education in resource-limited settings, few have established a specific curriculum in GS. This study's objective was to assess medical student interest in such a curriculum and prospects for future careers in GS/global health (GH), and to define the barriers to pursuing an international rotation. METHODS: We conducted an anonymous online survey of all 495 medical students at a major academic medical center in the mid-South that collected demographic data, country of origin, interest in a GS/GH elective, and barriers to pursuing a GS/GH rotation abroad. The data were analyzed using SPSS software. RESULTS: Prior international experience increased the likelihood of a student's involvement in GS/GH and more preclinical (years 1 & 2) students (90%) than clinical students. (years 3 & 4) (70%) felt strongly about the value of a GS/GH experience. Of the 163 students who completed the survey, 80% expressed interest in a GS/GH elective, with preclinical students expressing more interest (90%) than clinical students (71%). This interest strongly correlated with an interest in pursuing a career in GH (94%) and/or GS (100%). Identified barriers to engagement in a GS/GH experience abroad included financing (74%), scheduling (58%), family obligations (23%), and personal safety (19%). CONCLUSIONS: The students we surveyed were very interested in a GS/GH curriculum that included a rotation abroad, especially if they were to receive financial support. Preclinical students expressed more willingness to self-fund such experiences. The findings of this survey further strengthen the need to incorporate GS/GH in medical school curricula.

Barriers and Motivations for Health Insurance Subscription Among Health-Care Users in Cameroon.

INTRODUCTION: Surgical care is a significant component of the overall health expenditure in low- and middle-income countries. In Cameroon, out-of-pocket payments for surgical service are very high with many patients declining potentially curative surgical procedures. Less than 2% of the population is enrolled in a health insurance scheme leading to a propensity for catastrophic health expenses when accessing care. To assess the perceived barriers and motivations for health insurance subscription among health-care users in Cameroon. METHODS: This was a cross-sectional community-based qualitative study conducted in the Center Region of Cameroon. A total of 37 health-care users (health insurance subscribers and nonsubscribers) were purposively identified. Four focused group discussions and thirteen in-depth interviews were conducted. All anonymized transcripts were analyzed using a thematic analysis approach. RESULTS: The six major themes identified as barriers to health insurance subscription were lack of trust in the existing health insurance schemes, inadequate knowledge on how health insurance works, premiums believed to be too expensive, the complexity of the claims processing system, minimal usage of health-care services and practice of self-medication. Motivational factors included the knowledge of having access to quality health services even without money in the event of an unforeseen illness and having a large family/household size. The importance of mass sensitization on the benefits of health insurance was noted. CONCLUSION: Health insurance is still very underutilized in Cameroon. This results in significant out-of-pocket payment for health services by Cameroonians with catastrophic consequences to households. With most Cameroonians in the informal sector and underemployed, it is imperative to put in place a national strategic plan to overcome existing barriers and increase health insurance coverage especially among the poor. This has the potential to significantly increase access to safe, quality, timely and affordable surgical care.

Management and outcomes of chemotherapy-associated pneumoperitoneum in cancer patients: a scoping review protocol.

Introduction: Pneumoperitoneum - free air within the peritoneal cavity - is often the result of bowel perforation, though other causes include residual postprocedural or postoperative air and barotrauma. In non-cancer patients, operative intervention is often required. Cancer patients, on the other hand, present a unique set of challenges as they usually have elevated risk of pneumoperitoneum from local radiation therapy, frequent endoscopic procedures, and tumor invasion. Factors such as malnutrition, neutropenia, chemotherapy, and steroid use make emergent surgery tenuous in cancer patients. There is a paucity of published literature on the management of pneumoperitoneum in patients actively undergoing chemotherapy. The main objective of this scoping review is to assess the presentation, management, and subsequent outcomes of this unique patient population. Materials and Methods: The authors will utilize the framework for performing scoping reviews as outlined by Arksey and O'Malley. They will perform the search for articles in three electronic databases (i.e. SCOPUS, PubMed, Embase) and relevant gray literature. Only articles available in English and published between 1999 and 2022 will be included. Inclusion criteria will be a known diagnosis of cancer, chemotherapy within 6 months of presentation, and imaging confirmation of pneumoperitoneum. Exclusion criteria will be cancer diagnosis at the time of presentation, perforation secondary to cancer itself, and chemotherapy greater than 6 months prior to presentation. A tailored extraction frame to extract relevant information from published articles that meet our inclusion criteria. The data using both descriptive statistics and thematic analysis of the main study questions. Ethics and Dissemination: Since the authors will not be collecting primary data, formal ethical approval is not required. They study findings will be disseminated through abstracts, conference presentations, and peer-reviewed publications.

Hospital Detention for the Inability to Pay: A Qualitative Study of Patient Experiences in Cameroon.

INTRODUCTION: Equitable access to quality surgical care and low-cost healthcare services for all segments of the population remains a big problem in many African health systems. In Cameroon, it is very common to find medically discharged patients who have received surgical treatment and are unable to pay the resulting bills. These patients can be held in detention in hospitals until payments are complete. Even the corpses of patients who die with unpaid medical bills can be withheld until their family members pay off the debt. While this practice has been ongoing for many y, there remains very little scholarship on the issue reported in the literature. The main objective of this study was to uncover the lived experiences of discharged patients residing in hospital detention for being unable to pay their medical bills. METHODS: In-depth interviews, focus group discussions, and observations were conducted with purposefully selected patients living in detention in 2 rural private hospitals in the Fundong Health District in Cameroon. A thematic framework technique was used to analyze the transcribed data. The study was ethically approved by the Cameroon Bioethics Initiative, and informed consent was obtained from all participants. RESULTS: Living in hospital detention after receiving treatment constitutes an economic, social, and psychological burden for patients. Economically, it exacerbated poverty for the patients unable to purchase food, medications, and clothing due to lack of jobs and financial support. Socially, many of these individuals suffered from isolation, loneliness, shame, stigma, risk of contracting other diseases, and precarious sleeping conditions. The psychological burden was comprised of stress, depression, trauma, nightmares, and suicidal thoughts. CONCLUSIONS: The experiences of discharged patients in hospital detention suggest that they live in very deplorable conditions. There is a need for a functional healthcare protection mechanism, such as universal health coverage, to reduce the cost of healthcare services and surgical operations. Alternative payment mechanisms should also be considered.

Cholecystoappendiceal Fistula From Appendiceal Adenocarcinoma Requiring a Right Hemicolectomy With Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy.

Bilioenteric fistulae are rare and difficult to manage complications of chronic cholecystitis. While cholecystoduodenal and cholecystocolic fistulae are more common, a cholecystoappendiceal fistula is an extremely rare finding. We report the presentation and operative management of a 59-year-old male with cholecystoappendiceal fistula and associated abscess in the gallbladder fossa. The patient was appropriately resuscitated, the abscess drained by interventional radiology, and after a complete workup, underwent a laparoscopic appendectomy and cholecystectomy. Pathology revealed moderately differentiated appendiceal adenocarcinoma requiring a right hemicolectomy with cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). He has recovered well postoperatively with no complications. This case highlights the importance of having a very high index of suspicion for underlying malignancy when managing a fistula of any kind. To the best of our understanding, this is only the second reported case of a cholecystoappendiceal fistula.

Alectinib-associated pneumoperitoneum in stage IV non-small cell lung cancer - A case report.

Introduction and importance: Alectinib, a highly potent, highly selective, brain-penetrant anaplastic lymphoma kinase (ALK) inhibitor is now the first line therapy for patients with metastatic ALK-positive non small cell lung cancer (NSCLC). Case presentation: We report a rare case of pneumoperitoneum following alectinib initiation for metastatic non small cell lung cancer in a 74-year-old African American female. Patient developed abdominal pain approximately 2 weeks after starting alectinib. She was hemodynamically stable, and imaging revealed pneumoperitoneum. Patient was successfully managed non-operatively. Clinical discussion: Gastrointestinal perforation presenting as pneumoperitoneum is a very rare complication of alectinib. To our knowledge our patient is only the second case to be reported in the literature since its approval. The complication is likely attributable to the rapid tumor regression in the gastrointestinal tract. Non-operative management should be attempted if possible. Conclusion: Oncologists should be aware of the risk of gastrointestinal perforation when initiating cytotoxic chemotherapy on patients with metastatic NSCLC. A multidisciplinary approach is critical in appropriately individualizing care in this patient population.

Gallbladder volvulus with gangrenous cholecystitis - A case report.

INTRODUCTION AND IMPORTANCE: Gallbladder torsion (volvulus) is a very rare pathology that occurs when the gallbladder rotates on the cystic duct/cystic artery axis, resulting in blockage of bile drainage and blood flow. CASE PRESENTATION: We present the case of an elderly 87-year-old female who experienced acute gallbladder torsion. The patient presented with acute left chest pain that radiated to the patient's back and nausea but no emesis. A thorough physical examination, serologic studies, abdominal ultrasound, and computed tomography scan revealed gallbladder dilation, a thickened wall, enlarged common bile duct (approximately 1 cm), and the presence of pericholecystic fluid, all of which were consistent with acute cholecystitis. Laparoscopic cholecystectomy led to an intraoperative diagnosis of completely gangrenous gallbladder volvulus (GBV) with a 360-degree counter clockwise rotation. The pathology led to a final diagnosis of acute necrotizing cholecystitis without evidence of malignancy. CLINICAL DISCUSSION: GBV (gallbladder torsion) is typically observed in elderly patients at a female-to-male ratio of 4:1 and a median age at presentation of 77 years. Few advancements have been made in accurate diagnosis of GBV using clinical findings or the results of radiographic imaging, leading to accurate preoperative diagnoses in only 25 % of patients. CONCLUSION: Though GBV usually presents with right upper quadrant pain, our patient had the rare presentation of left sided chest pain mimicking acute coronary syndrome. GBV is an uncommon condition that occurs frequently in the elderly, particularly in women. Accurate preoperative diagnosis remains daunting, since clinical, laboratory, and radiographic findings often lead to an incorrect diagnosis of acute cholecystitis. Prompt diagnosis necessitates a high level of suspicion, and laparoscopic cholecystectomy is the recommended treatment/management.

Characterization of Epigenomic Alterations in HPV16+ Head and Neck Squamous Cell Carcinomas.

BACKGROUND: Epigenetic changes associated with human papillomavirus (HPV)-driven tumors have been described; however, HPV type-specific alterations are less well understood. We sought to compare HPV16-specific methylation changes with those in virus-unassociated head and neck squamous cell carcinomas (HNSCC). METHODS: Within The Cancer Genome Atlas, 59 HPV16+ HNSCC, 238 nonviral HNSCC (no detectable HPV or other viruses), and 50 normal head and neck tissues were evaluated. Significant differentially methylated regions (DMR) were selected, and key associated genes were identified. Partial least squares models were generated to predict HPV16 status in additional independent samples. RESULTS: HPV infection in HNSCC is associated with type-specific methylomic profiles. Multiple significant DMRs were identified between HPV16+, nonviral, and normal samples. The most significant differentially methylated genes, SYCP2, MSX2, HLTF, PITX2, and GRAMD4, demonstrated HPV16-associated methylation patterns with corresponding alterations in gene expression. Phylogenetically related HPV types (alpha-9 species; HPV31, HPV33, and HPV35) demonstrated a similar methylation profile to that of HPV16 but differed from those seen in other types, such as HPV18 and 45 (alpha-7). CONCLUSIONS: HNSCC linked to HPV16 and types from the same alpha species are associated with a distinct methylation profile. This HPV16-associated methylation pattern is also detected in cervical cancer and testicular germ cell tumors. We present insights into both shared and unique methylation alterations associated with HPV16+ tumors and may have implications for understanding the clinical behavior of HPV-associated HNSCC. IMPACT: HPV type-specific methylomic changes may contribute to understanding biologic mechanisms underlying differences in clinical behavior among different HPV+ and HPV- HNSCC.

Cutaneous Effects of In Utero and Lactational Exposure of C57BL/6J Mice to 2,3,7,8-Tetrachlorodibenzo-p-dioxin.

To determine the cutaneous effects of in utero and lactational exposure to the AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), pregnant C57BL/6J mice were exposed by gavage to a vehicle or 5 µg TCDD/kg body weight at embryonic day 12 and epidermal barrier formation and function were studied in their offspring from postnatal day 1 (P1) through adulthood. TCDD-exposed pups were born with acanthosis. This effect was AHR-dependent and subsided by P6 with no evidence of subsequent inflammatory dermatitis. The challenge of adult mice with MC903 showed similar inflammatory responses in control and treated animals, indicating no long-term immunosuppression to this chemical. Chloracne-like sebaceous gland hypoplasia and cyst formation were observed in TCDD-exposed P21 mice, with concomitant microbiome dysbiosis. These effects were reversed by P35. CYP1A1 and CYP1B1 expression in the skin was increased in the exposed mice until P21, then declined. Both CYP proteins co-localized with LRIG1-expressing progenitor cells at the infundibulum. CYP1B1 protein also co-localized with a second stem cell niche in the isthmus. These results indicate that this exposure to TCDD causes a chloracne-like effect without inflammation. Transient activation of the AhR, due to the shorter half-life of TCDD in mice, likely contributes to the reversibility of these effects.

Arsenic Disruption of DNA Damage Responses-Potential Role in Carcinogenesis and Chemotherapy.

Arsenic is a Class I human carcinogen and is widespread in the environment. Chronic arsenic exposure causes cancer in skin, lung and bladder, as well as in other organs. Paradoxically, arsenic also is a potent chemotherapeutic against acute promyelocytic leukemia and can potentiate the cytotoxic effects of DNA damaging chemotherapeutics, such as cisplatin, in vitro. Arsenic has long been implicated in DNA repair inhibition, cell cycle disruption, and ubiquitination dysregulation, all negatively impacting the DNA damage response and potentially contributing to both the carcinogenic and chemotherapeutic potential of arsenic. Recent studies have provided mechanistic insights into how arsenic interferes with these processes including disruption of zinc fingers and suppression of gene expression. This review discusses these effects of arsenic with a view toward understanding the impact on the DNA damage response.

Effects of in utero exposure of C57BL/6J mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin on epidermal permeability barrier development and function.

BACKGROUND: Development of the epidermal permeability barrier (EPB) is essential for neonatal life. Defects in this barrier are found in many skin diseases such as atopic dermatitis. OBJECTIVE: We investigated the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the development and function of the EPB. METHODS: Timed-pregnant C57BL/6J mice were gavaged with corn oil or TCDD (10 µg/kg body weight) on gestation day 12. Embryos were harvested on embryonic day (E) 15, E16, E17, and postnatal day (PND) 1. RESULTS: A skin permeability assay showed that TCDD accelerated the development of the EPB, beginning at E15. This was accompanied by a significant decrease in transepidermal water loss (TEWL), enhanced stratification, and formation of the stratum corneum (SC). The levels of several ceramides were significantly increased at E15 and E16. PND1 histology revealed TCDD-induced acanthosis and epidermal hyperkeratosis. This was accompanied by disrupted epidermal tight junction (TJ) function, with increased dye leakage at the terminal claudin-1-staining TJs of the stratum granulosum. Because the animals did not have enhanced rates of TEWL, a commonly observed phenotype in animals with TJ defects, we performed tape-stripping. Removal of most of the SC resulted in a significant increase in TEWL in TCDD-exposed PND1 pups compared with their control group. CONCLUSIONS: These findings demonstrate that in utero exposure to TCDD accelerates the formation of an abnormal EPB with leaky TJs, warranting further study of environmental exposures, epithelial TJ integrity, and atopic disease.

Cisplatin plus sodium arsenite and hyperthermia induces pseudo-G1 associated apoptotic cell death in ovarian cancer cells.

Cisplatin is effective against solid tumors including ovarian cancer. However, inherent or acquired cisplatin resistance limits clinical success. We recently demonstrated that a combination of sodium arsenite (NaAsO2) and hyperthermia sensitizes p53-expressing ovarian cancer cells to cisplatin by modulating DNA repair pathway and enhancing platinum accumulation. However, it is not understood how this combination therapy modulates cell cycle following platinum-DNA damage. The goal of the present study was to determine if NaAsO2 and hyperthermia alter cisplatin-induced G2 arrest and cause mitotic arrest and mitotic catastrophe. Human epithelial ovarian cancer cells (A2780 and A2780/CP70) were treated with cisplatin ± 20 µM NaAsO2 at 37 or 39°C for 1 h. Cisplatin ± NaAsO2 at 37 or 39°C caused cells to accumulate in G2/M compartment at 36 h after treatment. Western blot analysis of cyclin A and cyclin B suggested that combined NaAsO2, hyperthermia, and cisplatin induced mitotic arrest. However, we observed < 3% mitotic index and phosphorylation of histone H3 on serine 10 was undetectable. These results did not confirm mitotic arrest. BUBR1 (BUB1B) also was not phosphorylated, suggesting disrupted mitotic checkpoint. Postmitotic cells accumulated in pseudo-G1 as demonstrated by cyclin E stabilization, CDKN1A induction, and hypophosphorylation of retinoblastoma protein. These cells also were positive for Annexin V binding indicating they were apoptotic. In summary, cisplatin plus NaAsO2 and hyperthermia induced pseudo-G1 associated apoptosis in ovarian cancer cells.

Sodium arsenite ± hyperthermia sensitizes p53-expressing human ovarian cancer cells to cisplatin by modulating platinum-DNA damage responses.

Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death in the United States. Cisplatin is a DNA damaging agent initially effective against EOC but limited by resistance. P53 plays a critical role in cellular response to DNA damage and has been implicated in EOC response to platinum chemotherapy. In this study, we examined the role of p53 status in EOC response to a novel combination of cisplatin, sodium arsenite, and hyperthermia. Human EOC cells were treated with cisplatin ± 20µM sodium arsenite at 37°C or 39°C for 1 h. Sodium arsenite ± hyperthermia sensitized wild-type p53-expressing (A2780, A2780/CP70, OVCA 420, OVCA 429, and OVCA 433) EOC cells to cisplatin. Hyperthermia sensitized p53-null SKOV-3 and p53-mutant (OVCA 432 and OVCAR-3) cells to cisplatin. P53 small interfering RNA (siRNA) transfection abrogated sodium arsenite sensitization effect. XPC, a critical DNA damage recognition protein in global genome repair pathway, was induced by cisplatin only in wild-type p53-expressing cells. Cotreatment with sodium arsenite ± hyperthermia attenuated cisplatin-induced XPC in wild-type p53-expressing cells. XPC siRNA transfection sensitized wild-type p53-expressing cells to cisplatin, suggesting that sodium arsenite ± hyperthermia attenuation of XPC is a mechanism by which wild-type p53-expressing cells are sensitized to cisplatin. Hyperthermia ± sodium arsenite enhanced cellular and DNA accumulation of platinum in wild-type p53-expressing cells. Only hyperthermia enhanced platinum accumulation in p53-null cells. In conclusion, sodium arsenite ± hyperthermia sensitizes wild-type p53-expressing EOC cells to cisplatin by suppressing DNA repair protein XPC and increasing cellular and DNA platinum accumulation.

Sodium arsenite and hyperthermia modulate cisplatin-DNA damage responses and enhance platinum accumulation in murine metastatic ovarian cancer xenograft after hyperthermic intraperitoneal chemotherapy (HIPEC).

BACKGROUND: Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the USA. Recurrence rates are high after front-line therapy and most patients eventually die from platinum (Pt) - resistant disease. Cisplatin resistance is associated with increased nucleotide excision repair (NER), decreased mismatch repair (MMR) and decreased platinum uptake. The objective of this study is to investigate how a novel combination of sodium arsenite (NaAsO2) and hyperthermia (43°C) affect mechanisms of cisplatin resistance in ovarian cancer. METHODS: We established a murine model of metastatic EOC by intraperitoneal injection of A2780/CP70 human ovarian cancer cells into nude mice. We developed a murine hyperthermic intraperitoneal chemotherapy model to treat the mice. Mice with peritoneal metastasis were perfused for 1 h with 3 mg/kg cisplatin ± 26 mg/kg NaAsO2 at 37 or 43°C. Tumors and tissues were collected at 0 and 24 h after treatment. RESULTS: Western blot analysis of p53 and key NER proteins (ERCC1, XPC and XPA) and MMR protein (MSH2) suggested that cisplatin induced p53, XPC and XPA and suppressed MSH2 consistent with resistant phenotype. Hyperthermia suppressed cisplatin-induced XPC and prevented the induction of XPA by cisplatin, but it had no effect on Pt uptake or retention in tumors. NaAsO2 prevented XPC induction by cisplatin; it maintained higher levels of MSH2 in tumors and enhanced initial accumulation of Pt in tumors. Combined NaAsO2 and hyperthermia decreased cisplatin-induced XPC 24 h after perfusion, maintained higher levels of MSH2 in tumors and significantly increased initial accumulation of Pt in tumors. ERCC1 levels were generally low except for NaAsO2 co-treatment with cisplatin. Systemic Pt and arsenic accumulation for all treatment conditions were in the order: kidney > liver = spleen > heart > brain and liver > kidney = spleen > heart > brain respectively. Metal levels generally decreased in systemic tissues within 24 h after treatment. CONCLUSION: NaAsO2 and/or hyperthermia have the potential to sensitize tumors to cisplatin by inhibiting NER, maintaining functional MMR and enhancing tumor platinum uptake.