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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.

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.

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.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.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.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.

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.

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. Citation: Muenyi CS, Leon Carrion S, Jones LA, Kennedy LH, Slominski AT, Sutter CH, Sutter TR. 2014. Effects of in utero exposure of C57BL/6J mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin on epidermal permeability barrier development and function. Environ Health Perspect 122:1052–1058; http://dx.doi.org/10.1289/ehp.1308045

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.

Epithelial Ovarian cancer (EOC) is the leading cause of gynecological cancer death in the USA. Recurrence rates are high after front-line platinum chemotherapy and most patients eventually die from platinum-resistant disease. P53 plays an important role in cellular response to platinum-DNA damage. It transcriptionally activates XPC, a platinum-DNA damage recognition protein in the global genome repair (GGR), sub-pathway of nucleotide excision repair (NER). The goal of this research is to investigate the effect of a novel combination of cisplatin, sodium arsenite (NaAs02) and hyperthermia (CPA 39 DC) on EOC cells with different p53 status. Human EOC cells were treated with cisplatin ± 20 IJM NaAs02 for 1 h at 37 or 39°C. NaAs02 ± hyperthermia selectively sensitized wild-type p53 EOC cells to cisplatin by suppressing XPC and enhancing cellular and DNA platinum accumulation. In contrast, only hyperthermia sensitized p53-mutated and p53-null EOC cells to cisplatin by enhancing cellular and DNA platinum accumulation. Cisplatin ± NaAs02 at 37 or 39°C induced pseudo-G1 associated apoptosis in p53 expressing cells. Co-treatment with HSP90 inhibitor 17-DMAG plus CPA 39°C greatly sensitized EOC cells by enhancing cellular platinum accumulation. In order to translate the in vitro findings in an in vivo model, metastatic ovarian cancer was established in nude mice by intraperitoneal injection of A2780/CP70 human EOC cells. Tumor bearing mice were perfused with 3 mg/kg body weight (BW) cisplatin ± 26 mg/kg BW NaAs02 for 1 h at 37 or 43°C using a murine intraperitoneal chemotherapy system developed in our laboratory. Cisplatin induced NER proteins XPC and XPA and suppressed mismatch repair protein MSH2 that is associated with resistance. However, co-treatment with NaAs02 at 37 or 43°C suppressed XPC, restored higher levels of MSH2 and enhanced tumor platinum uptake. Platinum and arsenic generally accumulated in systemic tissues during intraperitoneal lavage and decreased 24 h after perfusion. In conclusion, CPA 39 °C alone or combined with 17-DMAG has the potential to sensitize EOC to cisplatin by attenuating NER, activating mismatch repair, enhancing tumor platinum accumulation and activating apoptotic cell death.

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.

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.