Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer.

Background: Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer. Patients and methods: To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287-395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots. Results: We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3' partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations. Conclusions: Collectively, these data indicate that N-terminal ESR1 fusions involving exons 6-7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.

Multivisceral and small bowel transplantation at shiraz organ transplant center.

BACKGROUND: Multivisceral transplantations were initially done in animal models to understand the immunological effects. Later on, in human beings, it has been considered a salvage procedure for unresectable complex abdominal malignancies. With advancement in surgical techniques, availability of better immunosuppressive drugs, and development of better post-operative management protocols, outcomes have been improved after these complex surgical procedures. OBJECTIVE: To analyze and report results of multivisceral, modified multivisceral, and small bowel transplantations done at Shiraz Organ Transplant Center, Shiraz, southern Iran. METHODS: Medical records of all patients who underwent multivisceral, modified multivisceral, and small bowel transplants were retrospectively analyzed. RESULTS: There were 18 patients. The most common indications for the procedure in our series were unresectable carcinoma of pancreas followed by short bowel syndrome. 10 patients were alive after a median follow-up of 8.7 (range: 3-32) months. The remaining 8 patients died post-operatively, mostly from septicemia. CONCLUSION: Multivisceral and small bowel transplantations are promising treatments for complex abdominal pathologies.

Ex-vivo Resection and Small-Bowel Auto-transplantation for the Treatment of Tumors at the Root of the Mesentery.

BACKGROUND: Tumors involving the root of the mesentery are generally regarded as "unresectable" with conventional surgical techniques. Resection with conventional surgery may end in life-threatening complications in these patients. Ex-vivo resection and auto-transplantation avoids excessive bleeding and prevents ischemic related damage to the small intestine and other organs. OBJECTIVE: To share our experience of ex-vivo resection of the tumors with involvement of small bowel mesentery followed by small bowel auto-transplantation. METHODS: In this study, medical records of all the patients who underwent ex-vivo resection and auto-transplantation at our center were retrospectively analyzed. RESULTS: The most common indication for the procedure in our series was locally advanced pancreatic carcinoma. Our survival rate was 50% with a mean±SD follow-up of 10.1±9.8 (range: 0-26) months. Causes of early in-hospital mortality were multi-organ failure, sepsis, and cerebrovascular accident. Recurrence of disease was noted in one patient while one patient developed hepatic metastasis after 20 months of surgery. CONCLUSION: Ex-vivo resection of the tumor and auto-transplantation is the surgical treatment of choice for the locally advanced abdominal tumors involving the root of the mesentery.

Multivisceral transplantation for the treatment of intra-abdominal tumors.

BACKGROUND: Some intra-abdominal or retroperitoneal tumors such as low-grade slow-growing malignancies may seem unresectable due to major vessel encasement or presence of intra-abdominal dissemination, but the slow growth rate and to some extent long life expectancy of the patients urge us to find some strategies to cure the patients or at least achieve tumor remission or symptom palliation. En bloc resection, followed by multivisceral or liver-sparing "modified" multivisceral transplantation has recently been used for treatment of these patients. RESULTS: Between May 2010 and October 2012, 3 multivisceral and 3 modified multivisceral transplantations were performed in 6 patients (aged 14 to 55 years; mean, 32 years) with some slow growing intra-abdominal malignancies (2 neuroendocrine tumors, 2 gastrointestinal stromal tumors, 1 desmoid tumor, and 1 low-grade sarcoma). All patients survived the procedure. One patient died of pancytopenia 2 months after transplantation and another died with pulmonary emboli at 4 months. The remaining 4 patients are alive without any evidence of disease recurrence. CONCLUSIONS: Although large intra-abdominal desmoid tumors, well-differentiated neuroendocrine tumors, and gastrointestinal stromal tumors are slow growing, they tend to invade locally, especially to the mesenteric root and/or celiac axis and other abdominal viscera. Complete resection followed by multivisceral transplantation could be a therapeutic option for these advanced tumors.

En-bloc Transplantation: an Eligible Technique for Unilateral Dual Kidney Transplantation.

BACKGROUND: Kidney transplantation is the best available treatment for patients with end-stage renal disease. OBJECTIVE: To evaluate the en bloc anastomosis technique for unilateral dual kidney transplantation (DKT). METHODS: From May to October 2011, 5 patients (4 women and 1 man) with mean age of 31.8 years underwent unilateral DKT with this technique in which distal end of the aorta and proximal end of inferior vena cava (IVC) were closed with running sutures. Then, proximal end of the aorta and distal end of the IVC were anastomosed to internal (or external) iliac artery and external iliac vein, respectively. RESULTS: Post-operative course was uneventful. No vascular and urologic complications developed; all patient had acceptable serum creatinine at discharge time and up of 2-6 months of post-operation follow up. CONCLUSION: Unilateral DKT is a safe method for performing DKT. The proposed en bloc anastomosis can improve the outcome of the graft by reducing the cold ischemia and the operation time.