Synchronous Gallstone Ileus and Bouveret's Syndrome: A Report of Two Rare Concurrent Complications of Gallstone Disease.

Cholecystoenteric fistulas occur as a result of a chronic inflammatory insult involving the gallbladder and the erosion of both its wall and a bowel segment. When the fistula develops, it creates a pathway for gallstones to migrate and cause an intestinal obstruction, known as gallstone ileus. When it obstructs the gastric outlet, a proximal variant of gallstone ileus occurs, known as Bouveret's syndrome. A 65-year-old man presented to the emergency department with a three-day history of epigastric and right upper quadrant pain and persistent vomiting, preceded by unintentional weight loss of 15 kg over three months. Endoscopic and complementary imaging studies identified a concurrent gastric outlet obstruction caused by a lodged gallstone in the duodenal bulb and gallstone ileus. The patient underwent an urgent exploratory laparotomy and was submitted to an enterolithotomy and gastrolithotomy. Due to a sudden deterioration on the fourth postoperative day, he underwent an emergent re-laparotomy that found fecal peritonitis and complete dehiscence of both closures. The patient was then managed with damage control surgery. An atypical gastric resection and enterectomy of the distal ileum were performed and the patient was admitted to the intensive care unit in temporary abdominal closure (laparostomy). The patient failed to improve and died on the same day. Ultimately, the patient's multiple comorbidities, including morbid obesity, malnutrition, and diabetes, contributed to poor tissue healing and the fatal outcome. Gallstone ileus and Bouveret's syndrome are two rare complications of cholecystoduodenal fistulas that have not yet been reported to occur simultaneously. Both intestinal and gastric obstruction makes the surgical approach the first-line treatment.

Selective Inhibition of Bruton's Tyrosine Kinase by a Designed Covalent Ligand Leads to Potent Therapeutic Efficacy in Blood Cancers Relative to Clinically Used Inhibitors.

Bruton's tyrosine kinase (BTK) is a member of the TEC-family kinases and crucial for the proliferation and differentiation of B-cells. We evaluated the therapeutic potential of a covalent inhibitor (JS25) with nanomolar potency against BTK and with a more desirable selectivity and inhibitory profile compared to the FDA-approved BTK inhibitors ibrutinib and acalabrutinib. Structural prediction of the BTK/JS25 complex revealed sequestration of Tyr551 that leads to BTK's inactivation. JS25 also inhibited the proliferation of myeloid and lymphoid B-cell cancer cell lines. Its therapeutic potential was further tested against ibrutinib in preclinical models of B-cell cancers. JS25 treatment induced a more pronounced cell death in a murine xenograft model of Burkitt's lymphoma, causing a 30-40% reduction of the subcutaneous tumor and an overall reduction in the percentage of metastasis and secondary tumor formation. In a patient model of diffuse large B-cell lymphoma, the drug response of JS25 was higher than that of ibrutinib, leading to a 64% "on-target" efficacy. Finally, in zebrafish patient-derived xenografts of chronic lymphocytic leukemia, JS25 was faster and more effective in decreasing tumor burden, producing superior therapeutic effects compared to ibrutinib. We expect JS25 to become therapeutically relevant as a BTK inhibitor and to find applications in the treatment of hematological cancers and other pathologies with unmet clinical treatment.

Low-Grade Dysplastic Intracholecystic Papillary Neoplasia: A Case Report.

BACKGROUND The World Health Organization classification of premalignant gallbladder lesions includes adenomas, intraductal papillary neoplasms, biliary intraepithelial neoplasia, and intracystic papillary neoplasms. Noninvasive neoplastic lesions >1 cm that originate from the pancreatobiliary system are defined as intraductal papillary neoplasia when they occur in the biliary ducts. The clinical and pathological features of preinvasive lesions arising in the gallbladder are not yet well defined. However, the most widely accepted classification is that of intracholecystic papillary neoplasm (ICPN). CASE REPORT We present the case of a 71-year-old woman referred to a General Surgery outpatient clinic for suspicious findings on imaging of the gallbladder, namely irregular infundibular parietal thickening. The patient underwent a laparoscopic cholecystectomy and histological examination revealed a thickened gallbladder with mucosa partially surrounded by ICPN with an intestinal pattern and some foci of low-grade dysplasia but no foci of high-grade dysplasia or invasive neoplasia. At follow-up at 30 months, the patient remains clinically well, with no changes visible on computed tomography scan. CONCLUSIONS ICPN of the gallbladder appears to be part of a spectrum of alterations encompassing bile duct or pancreatic lesions. Although it is uncommon, more than half of the lesions are known to have foci of invasive neoplasia at the time of diagnosis. Despite that, the prognosis for these neoplasms is more favorable than for gallbladder neoplasia that originates from another type of lesion. Pathological study of ICPN is essential to define the main characteristics that impact prognosis and survival in these patients.

Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status.

Poly (ADP-ribose) polymerase (PARP) inhibition in BRCA-mutated cells results in an incapacity to repair DNA damage, leading to cell death caused by synthetic lethality. Within the treatment options for advanced triple negative breast cancer, the PARP inhibitor olaparib is only given to patients with BRCA1/2 mutations. However, these patients may show resistance to this drug and BRCA1/2 wild-type tumors can show a striking sensitivity, making BRCA status a poor biomarker for treatment choice. Aiming to investigate if the zebrafish model can discriminate sensitivities to olaparib, we developed zebrafish xenografts with different BRCA status and measured tumor response to treatment, as well as its impact on angiogenesis and metastasis. When challenged with olaparib, xenografts revealed sensitivity phenotypes independent of BRCA. Moreover, its combination with ionizing radiation increased the cytotoxic effects, showing potential as a combinatorial regimen. In conclusion, we show that the zebrafish xenograft model may be used as a sensitivity profiling platform for olaparib in monotherapy or in combinatorial regimens. Hence, this model presents as a promising option for the future establishment of patient-derived xenografts for personalized medicine approaches beyond BRCA status.

Laparostomy during pregnancy: A case report.

INTRODUCTION: Acute appendicitis is the main indication for surgery during pregnancy. Physiologic changes during pregnancy and fear of using ionising radiation exams are some of the reasons to delayed diagnosis and consequently to higher morbidity and mortality rates for mother and fetus. PRESENTATION OF CASE: We present the case of a 38-year-old woman that resorted to the emergency room on the 13th week of pregnancy with abdominal discomfort, nausea and vomiting that lasted for 7 days. She had been in the Obstetric Emergency Department 6 days prior with the same complaints. She had no fever and she was discharged home following normal obstetric ultrasound. On this second visit, after surgical consultation, septic shock with abdominal source was recognised and patient was taken for emergency exploratory laparotomy. Intraoperatively we found generalised purulent peritonitis secondary to perforated acute appendicitis. Appendectomy, thorough abdominal washing and laparostomy were performed. Patient was admitted on the Intensive Care Unit with septic shock, need for vasopressor therapy and dialysis. Four days after the first intervention the abdominal cavity was closed. She was discharged home on the 14th post-operative day and maintained obstetric follow-up for the remaining uncomplicated pregnancy. DISCUSSION: In the presented clinical case, diagnostic delay evolves to abdominal sepsis that demanded a damage control approach. Laparostomy constitutes a damage control gesture, limiting abdominal contamination, preventing abdominal compartment syndrome and allowing subsequent surgical revisions. CONCLUSION: Acute abdominal approach using laparostomy allowed for a good outcome, maintaining ongoing pregnancy and with incisional hernia as the only observed morbidity.