Abdominal donor-site complications following autologous breast reconstruction: A multi-institutional multisurgeon study.

BACKGROUND: The deep inferior epigastric perforator (DIEP) free flap is the gold standard procedure for autologous breast reconstruction. Although breast-related complications have been well described, donor-site complications and contributing patient risk factors are poorly understood. METHODS: We examined a multi-institutional, prospectively maintained database of patients undergoing DIEP free flap breast reconstruction between 2015 and 2020. We evaluated patient demographics, operative details, and abdominal donor-site complications. Logistic regression modeling was used to predict donor-site outcomes based on patient characteristics. RESULTS: A total of 661 patients were identified who underwent DIEP free flap breast reconstruction across multiple institutions. Using logistic regression modeling, we found that body mass index (BMI) was an independent risk factor for umbilical complications (odds ratio [OR] 1.11, confidence interval [CI] 1.04-1.18, p = 0.001), seroma (OR 1.07, CI 1.01-1.13, p = 0.003), wound dehiscence (OR 1.10, CI 1.06-1.15, p = 0.001), and surgical site infection (OR 1.10, CI 1.05-1.15, p = 0.001) following DIEP free flap breast reconstruction. Further, immediate reconstruction decreases the risk of abdominal bulge formation (OR 0.22, CI 0.108-0.429, p = 0.001). Perforator selection was not associated with abdominal morbidity in our study population. CONCLUSIONS: Higher BMI is associated with increased abdominal donor-site complications following DIEP free flap breast reconstruction. Efforts to lower preoperative BMI may help decrease donor-site complications.

Importance of Incidental Findings in Preoperative Computed Tomography Angiography for Abdominally Based Free Flap Breast Reconstruction: A Multi-Institutional Study.

BACKGROUND: In addition to its intended purpose of perforator mapping, computed tomography angiography can also identify incidental findings that may require further evaluation. In this multi-institutional study, the authors evaluated the frequency of incidental findings and their significance and effects on treatment course and aimed to identify risk factors for detecting such findings. METHODS: A retrospective review of patients who underwent perforator mapping with computed tomography angiography was performed over a 5-year period from three academic institutions. Relevant sociodemographic and clinicopathologic information, computed tomography angiography reports, follow-up visits, and treatment outcomes were reviewed. Univariate and multivariate analyses were performed to assess the relationship between risk factors and incidental findings. RESULTS: From January of 2015 to July of 2020, a total of 656 patients were identified who met inclusion criteria. Overall, 342 incidental findings were found, 76 of which required additional imaging or consultation. Ultimately, 10 patients (1.5 percent) had findings that altered reconstructive management, including five patients (0.8 percent) having severe disease that resulted in the cancellation of their reconstruction. Advanced age and immediate reconstruction timing were independent risk factors for incidental findings. CONCLUSIONS: Incidental findings are commonly identified on preoperative computed tomography angiography for deep inferior epigastric perforator flap breast reconstruction. Suspicious findings should be investigated thoroughly because they can alter the reconstructive course. Understanding of high-risk groups for incidental findings can further advance patient education during initial consultation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Global Health Microsurgery Training With Cell Phones.

BACKGROUND: Lack of surgical care for trauma, burns, congenital anomalies, and other surgical diseases is a growing portion of global disability and death accounting for 30% of the global disease burden. Global surgical and anesthesia care aim to achieve excellence and equality of clinical care through leadership, innovation, teaching, research, and advocacy. Stanford University Division of Plastic Surgery faculty partnered with ReSurge International to teach reconstructive microsurgery in low- and middle-income countries. CHALLENGE: Global surgery teaching and training are challenged by limited resources. Surgical loupes and operating microscopes used to perform complex microsurgery magnify the surgical field are very expensive. Our goal was to identify low-cost alternatives to teach and practice microsurgery suturing. INNOVATION: Use cell phone camera with zoom capacity to teach and practice microsurgery suturing. RESULTS: Cell phones with zoom feature are widely available even in low- and middle-income countries. A cell phone was placed on a stand over a microsurgery practice station. The camera was used to zoom and focus on the suturing station to mimic a surgical field with loupes or microscope magnification. Nine attending surgeons and 7 residents practiced microsurgery with microsurgical instruments and 9-0 nylon suture under the magnification of a cell phone camera. The Stanford Microsurgery and Resident Training Scale was used to track their progress. A feedback survey was given to the participants to identify the usefulness of the cell phone setup for microsurgery suture practice. CONCLUSIONS: Global surgery teaching and training face many challenges especially limited resources. Identifying low-cost alternative is crucial. Cell phone camera with zoom is a low-cost alternative to loupes or operating microscope for microsurgical teaching and training.

Successful treatment of lymphedema in a vasculopath and neuropathic patient.

This is a case report of a 68-year-old male with stage III right lower extremity lymphedema following right inguinal lymph node dissection and adjuvant chemoradiotherapy for Hodgkin's lymphoma. He developed peripheral neuropathy and radiation-induced right femoral artery thrombosis, treated with saphenous vein graft. He underwent three vascularized lymph node transfers (VLNTs) to the upper medial thigh, posterior calf, and ankle with placement of nanofibrillar collagen scaffolds. Three months after surgery, he had volume reduction, less neuropathic pain, and improved ambulation.

The role of adjunct nanofibrillar collagen scaffold implantation in the surgical management of secondary lymphedema: Review of the literature and summary of initial pilot studies.

Secondary lymphedema is a worldwide affliction that exacts a significant public health burden. This review examines the etiology, presentation, and management of secondary lymphedema. In addition, emerging adjunctive strategies are explored, specifically evidence from animal and pilot human studies regarding implantation of a collagen nanofibrillar scaffold (BioBridge™; Fibralign Corporation, Union City, CA) in promoting lymphangiogenesis, preventing and treating lymphedema, and enhancing outcomes with lymphaticovenous anastomosis and vascularized lymph node transfer.

Significance of preoperative radiographic pancreatic density in predicting pancreatic fistula after surgery for pancreatic neuroendocrine tumors.

BACKGROUND: Postoperative pancreatic fistula remains the most severe and worrisome complication after surgery. Predictive preoperative assessment remains challenging. The authors examine the role of pancreatic computed tomography density in predicting postoperative pancreatic fistula after surgery for pancreatic neuroendocrine tumors. METHODS: A single institutional retrospective review of pancreatic surgery for neuroendocrine tumors between 1998 and 2010 was conducted. Preoperative contrast-enhanced computed tomography scans were reviewed, with mean region of interest measurements of pancreatic parenchymal density obtained from 10-mm thick axial computed tomography images. RESULTS: A total of 119 patients were identified: 59 with enucleations and 60 with resections. Decreased preoperative pancreatic density was significantly associated with an increased grade of postoperative pancreatic fistula (P < .01). Subgroup analyses revealed that decreased gland density was associated with increased grade of postoperative pancreatic fistula in the resection (P < .01) but not in the enucleation group (P = .34). CONCLUSIONS: A significant association between postoperative pancreatic fistula grade and preoperative pancreatic computed tomography density is observed in patients undergoing resection for pancreatic neuroendocrine tumors.

Telomerase variant A279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal carcinomas.

BACKGROUND: Although implicated in the pathogenesis of several chronic inflammatory disorders and hematologic malignancies, telomerase mutations have not been thoroughly characterized in human cancers. The present study was performed to examine the frequency and potential clinical relevance of telomerase mutations in esophageal carcinomas. METHODS: Sequencing techniques were used to evaluate mutational status of telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) in neoplastic and adjacent normal mucosa from 143 esophageal cancer (EsC) patients. MTS, flow cytometry, time lapse microscopy, and murine xenograft techniques were used to assess proliferation, apoptosis, chemotaxis, and tumorigenicity of EsC cells expressing either wtTERT or TERT variants. Immunoprecipitation, immunoblot, immunofluorescence, promoter-reporter and qRT-PCR techniques were used to evaluate interactions of TERT and several TERT variants with BRG-1 and ß-catenin, and to assess expression of cytoskeletal proteins, and cell signaling. Fluorescence in-situ hybridization and spectral karyotyping techniques were used to examine telomere length and chromosomal stability. RESULTS: Sequencing analysis revealed one deletion involving TERC (TERC del 341-360), and two non-synonymous TERT variants [A279T (2 homozygous, 9 heterozygous); A1062T (4 heterozygous)]. The minor allele frequency of the A279T variant was five-fold higher in EsC patients compared to healthy blood donors (p<0.01). Relative to wtTERT, A279T decreased telomere length, destabilized TERT-BRG-1-ß-catenin complex, markedly depleted ß-catenin, and down-regulated canonical Wnt signaling in cancer cells; these phenomena coincided with decreased proliferation, depletion of additional cytoskeletal proteins, impaired chemotaxis, increased chemosensitivity, and significantly decreased tumorigenicity of EsC cells. A279T expression significantly increased chromosomal aberrations in mouse embryonic fibroblasts (MEFs) following Zeocin™ exposure, as well as Li Fraumeni fibroblasts in the absence of pharmacologically-induced DNA damage. CONCLUSIONS: A279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal cancer cells. These findings warrant further analysis of A279T expression in esophageal cancers and premalignant esophageal lesions.

The role of surgery in the management of patients with refractory chronic granulomatous disease colitis.

BACKGROUND: Chronic granulomatous disease is a rare immunodeficiency complicated by dysregulated inflammation and granulomatous complications of the GI tract. The management of chronic granulomatous disease colitis presents the dilemma of an immunocompromised host requiring immunosuppressive therapy which can potentiate fatal infections. OBJECTIVE: The aim of this study was to identify the types of GI surgery performed in patients and determine the role of surgery in the management of refractory colitis. DESIGN AND SETTINGS: A retrospective single-institution chart review was performed. PATIENTS: Of 268 patients with chronic granulomatous disease treated at the National Institutes of Health between 1985 and 2011, 98 (37%) were identified as having colitis; 27 (10%) had a history of GI luminal surgery. MAIN OUTCOME MEASURES: Patient characteristics, type of GI surgery, and clinical outcomes were documented. RESULTS: A total of 62 GI luminal surgeries were performed in 27 patients with chronic granulomatous disease and colitis. All 27 had a history of perineal disease requiring intervention. Four (15%) had additional surgery performed for reasons other than colitis. Otherwise, 12 (44%) had surgery limited to the perineum, 2 (7%) had a segmental resection, and 13 (48%) underwent fecal diversion with ileostomy or colostomy. Despite local procedures, 7 (58%) patients in the perineal-only group remained symptomatic. Both patients with a segmental resection had persistent perineal disease, and 1 had a recurrent colovesicular fistula. Of the 13 ostomy patients, 11 initially received a diverting ostomy. Eight (73%) of these ultimately required additional procedures for refractory disease, and 4 (36%) developed peristomal pyoderma gangrenosum. Four patients who underwent proctocolectomy with end ileostomy, either initially (2) or as a definitive procedure (2), experienced resolution of colitis and perineal disease. LIMITATIONS: This study is limited by its retrospective design, small sample size, and highly selected patient population. CONCLUSIONS: Proctocolectomy with end ileostomy may offer a definitive treatment in a patient with refractory chronic granulomatous disease colitis given current therapeutic limitations.

Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis.

MicroRNAs are critical mediators of stem cell pluripotency, differentiation, and malignancy. Limited information exists regarding microRNA alterations that facilitate initiation and progression of human lung cancers. In this study, array techniques were used to evaluate microRNA expression in normal human respiratory epithelia and lung cancer cells cultured in the presence or absence of cigarette smoke condensate (CSC). Under relevant exposure conditions, CSC significantly repressed miR-487b. Subsequent experiments demonstrated that miR-487b directly targeted SUZ12, BMI1, WNT5A, MYC, and KRAS. Repression of miR-487b correlated with overexpression of these targets in primary lung cancers and coincided with DNA methylation, de novo nucleosome occupancy, and decreased H2AZ and TCF1 levels within the miR-487b genomic locus. Deoxy-azacytidine derepressed miR-487b and attenuated CSC-mediated silencing of miR-487b. Constitutive expression of miR-487b abrogated Wnt signaling, inhibited in vitro proliferation and invasion of lung cancer cells mediated by CSC or overexpression of miR-487b targets, and decreased growth and metastatic potential of lung cancer cells in vivo. Collectively, these findings indicate that miR-487b is a tumor suppressor microRNA silenced by epigenetic mechanisms during tobacco-induced pulmonary carcinogenesis and suggest that DNA demethylating agents may be useful for activating miR-487b for lung cancer therapy.

Minimally invasive liver resection to obtain tumor-infiltrating lymphocytes for adoptive cell therapy in patients with metastatic melanoma.

BACKGROUND: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma has been reported to have a 56% overall response rate with 20% complete responders. To increase the availability of this promising therapy in patients with advanced melanoma, a minimally invasive approach to procure tumor for TIL generation is warranted. METHODS: A feasibility study was performed to determine the safety and efficacy of laparoscopic liver resection to generate TIL for ACT. Retrospective review of a prospectively maintained database identified 22 patients with advanced melanoma and visceral metastasis (AJCC Stage M1c) who underwent laparoscopic liver resection between 1 October 2005 and 31 July 2011. The indication for resection in all patients was to receive postoperative ACT with TIL. RESULTS: Twenty patients (91%) underwent resection utilizing a closed laparoscopic technique, one required hand-assistance and another required conversion to open resection. Median intraoperative blood loss was 100 mL with most cases performed without a Pringle maneuver. Median hospital stay was 3 days. Three (14%) patients experienced a complication from resection with no mortality. TIL were generated from 18 of 22 (82%) patients. Twelve of 15 (80%) TIL tested were found to have in vitro tumor reactivity. Eleven patients (50%) received the intended ACT. Two patients were rendered no evidence of disease after surgical resection, with one undergoing delayed ACT with generated TIL after relapse. Objective tumor response was seen in 5 of 11 patients (45%) who received TIL, with one patient experiencing an ongoing complete response (32+ months). CONCLUSIONS: Laparoscopic liver resection can be performed with minimal morbidity and serve as an effective means to procure tumor to generate therapeutic TIL for ACT to patients with metastatic melanoma.

Rate of clinically significant postoperative pancreatic fistula in pancreatic neuroendocrine tumors.

BACKGROUND: In 2005, the International Study Group of Pancreatic Fistula (ISGPF) developed a definition and grading system for postoperative pancreatic fistula (POPF). The authors sought to determine the rate of POPF after enucleation and/or resection of pancreatic neuroendocrine tumors (PNET) and to identify clinical, surgical, or pathologic factors associated with POPF. METHODS: A retrospective analysis of pancreatic enucleations and resections performed from March 1998 to April 2010. We defined a clinically significant POPF as a grade B that required nonoperative intervention and grade C. RESULTS: One hundred twenty-two patients were identified; 62 patients had enucleations and 60 patients had resections of PNET. The rate of clinically significant POPF was 23.7 % (29/122). For pancreatic enucleation, the POPF rate was 27.4 % (17/62, 14 grade B, 3 grade C). The pancreatic resection group had a POPF rate of 20 % (12/60, 10 grade B, 2 grade C). This difference was not significant (p = 0.4). In univariate analyses, patients in the enucleation group with hereditary syndromes (p = 0.02) and non-insulinoma tumors (p = 0.02) had a higher POPF rate. Patients in the resection group with body mass index (BMI) > 25 (p < 0.01), multiple endocrine neoplasia type 1 (MEN-1; p < 0.01) and those who underwent simultaneous multiple procedures (p = 0.02) had a higher POPF rate. Multivariate analyses revealed that hereditary syndromes were able to predict POPF in the enucleation group, while having BMI > 25 and increasing lesion size were also associated with POPF in the group undergoing resection. CONCLUSIONS: We found a clinically significant POPF rate after surgery in PNET to be 23.7 % with no difference by the type of operation. Our POPF rate is comparable to that reported in the literature for pancreatic resection for other types of tumors. Certain inherited genetic diseases-von Hippel-Lindau disease (VHL) and MEN-1-were associated with higher POPF rates.

Polycomb repressor complex-2 is a novel target for mesothelioma therapy.

PURPOSE: Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of human cancers. This study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM). EXPERIMENTAL DESIGN: Microarray, quantitative reverse transcriptase PCR (qRT-PCR), immunoblot, and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral short hairpin RNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity, and tumorigenicity of MPM cells either exhibiting knockdown of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Microarray and qRT-PCR techniques were used to examine gene expression profiles mediated by knockdown of EZH2 or EED, or DZNep. RESULTS: EZH2 and EED, which encode components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM lines relative to normal mesothelial cells. EZH2 was overexpressed in approximately 85% of MPMs compared with normal pleura, correlating with diminished patient survival. Overexpression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knockdown of EZH2 orEED, or DZNep treatment, decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knockdown of PRC-2 members or DZNep treatment. CONCLUSIONS: Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy.

Cigarette smoke induces C/EBP-ß-mediated activation of miR-31 in normal human respiratory epithelia and lung cancer cells.

BACKGROUND: Limited information is available regarding mechanisms by which miRNAs contribute to pulmonary carcinogenesis. The present study was undertaken to examine expression and function of miRNAs induced by cigarette smoke condensate (CSC) in normal human respiratory epithelia and lung cancer cells. METHODOLOGY: Micro-array and quantitative RT-PCR (qRT-PCR) techniques were used to assess miRNA and host gene expression in cultured cells, and surgical specimens. Software-guided analysis, RNA cross-link immunoprecipitation (CLIP), 3' UTR luciferase reporter assays, qRT-PCR, focused super-arrays and western blot techniques were used to identify and confirm targets of miR-31. Chromatin immunoprecipitation (ChIP) techniques were used to evaluate histone marks and transcription factors within the LOC554202 promoter. Cell count and xenograft experiments were used to assess effects of miR-31 on proliferation and tumorigenicity of lung cancer cells. RESULTS: CSC significantly increased miR-31 expression and activated LOC554202 in normal respiratory epithelia and lung cancer cells; miR-31 and LOC554202 expression persisted following discontinuation of CSC exposure. miR-31 and LOC554202 expression levels were significantly elevated in lung cancer specimens relative to adjacent normal lung tissues. CLIP and reporter assays demonstrated direct interaction of miR-31 with Dickkopf-1 (Dkk-1) and DACT-3. Over-expression of miR-31 markedly diminished Dkk-1 and DACT3 expression levels in normal respiratory epithelia and lung cancer cells. Knock-down of miR-31 increased Dkk-1 and DACT3 levels, and abrogated CSC-mediated decreases in Dkk-1 and DACT-3 expression. Furthermore, over-expression of miR-31 diminished SFRP1, SFRP4, and WIF-1, and increased Wnt-5a expression. CSC increased H3K4Me3, H3K9/14Ac and C/EBP-ß levels within the LOC554202 promoter. Knock-down of C/EBP-ß abrogated CSC-mediated activation of LOC554202. Over-expression of miR-31 significantly enhanced proliferation and tumorigenicity of lung cancer cells; knock-down of miR-31 inhibited growth of these cells. CONCLUSIONS: Cigarette smoke induces expression of miR-31 targeting several antagonists of cancer stem cell signaling in normal respiratory epithelia and lung cancer cells. miR-31 functions as an oncomir during human pulmonary carcinogenesis.