KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition.

Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.

The role of CTNNB1 mutations and matrix metalloproteinases (MMPs) in anti-angiogenesis treatment of endometrial carcinoma.

OBJECTIVE: Treatment options and associated biomarkers for advanced and recurrent disease are limited. Endometrial cancers (ECs) with CTNNB1 exon 3 mutations appear to have preferential response to bevacizumab, an anti-angiogenesis treatment, though the mechanism of action is unknown. We aim to identify mediators of bevacizumab-responsive endometrial cancers. METHODS: We analyzed RNA expression from TCGA and protein expression from CPTAC to identify likely targets for ß-catenin overactivity. We then transiently and stably overexpressed ß-catenin in EC cells to confirm the results suggested by our in silico analysis. We performed corroborative experiments by silencing CTNNB1 in mutated cell lines to demonstrate functional specificity. We implanted transduced cells into xenograft models to study microvessel density. RESULTS: CTNNB1-mutated ECs were associated with increased ß-catenin and MMP7 protein abundance (P < 0.001), but not VEGF-A protein abundance. Overexpressing ß-catenin in EC cells did not increase VEGF-A abundance but did increase expression and secretion of MMP7 (P < 0.03). Silencing CTNNB1 in CTNNB1-mutated cells decreased MMP7 gene expression in EC (P < 0.0001). Microvessel density was not increased. CONCLUSIONS: These data provide a mechanistic understanding for bevacizumab-response in CTNNB1-mutated ECs demonstrated in GOG-86P. We hypothesize that overexpressed and secreted MMP7 potentially digests VEGFR-1, releasing VEGF-A, and increasing its availability. These activities may drive the formation of permeable vessels, which contributes to tumor progression, metastasis, and immune suppression. This mechanism is unique to EC and advocates for further clinical trials evaluating this treatment-related biomarker.

Mini-plus percutaneous setting in total laparoscopic hysterectomy.

INTRODUCTION: We aimed to analyze the preliminary experience of a mini-plus percutaneous instrument (MpPc) setting in total laparoscopic hysterectomy (TLH). MATERIAL AND METHODS: Forty-three women who underwent a mini-plus percutaneous total laparoscopic hysterectomy at a tertiary-care university-based teaching hospital and academic affiliated private hospital between May 2017 and 2018 were included. MpPc-TLH was performed through one optical trans-umbilical 5-mm trocar, one 5-mm ancillary port on the right side, either one 2.4-mm percutaneous endoscopic instrument or 3-mm mini-laparoscopic port on the right upper quadrant and if required one 3-mm ancillary port on the left lower quadrant. RESULTS: A total of 43 patients were included, with a median age of 48 years (range, 38-71 years). Indication for surgery included uterine myomas (n = 20), benign adnexal mass (n = 7), endometrial intraepithelial neoplasia (n = 6), endometrial cancer (n = 5), adenomyosis with abnormal bleeding (n = 3), and high-grade cervical dysplasia (n = 2). The median operating time was 100 min (range, 60-180 min), and the median estimated blood loss was 30 ml (range, 20-60ml). The median postoperative abdominal pain Visual Analog Scale score was 3 (range, 0-6). CONCLUSIONS: The preliminary data suggest that MpPc approach is a feasible and safe surgical modality for total laparoscopic hysterectomy.

CCNE1 amplification among metastatic sites in patients with gynecologic high-grade serous carcinoma.

OBJECTIVE: We sought to characterize the variability of CCNE1 amplification among metastatic sites of CCNE1 amplified high grade serous carcinoma (HGSC) cases to investigate the feasibility of targeting this alteration for therapeutic purposes. METHODS: Patients with CCNE1 amplified HGSC who underwent surgical cytoreduction with metastatic sites were identified from institutional molecular profiling reports and a population of HGSC cases screened using digital droplet PCR (ddPCR). Cases with normal CCNE1 copy number were included as controls. Slides from metastatic sites were cut from formalin-fixed paraffin-embedded tissue blocks, dissected for tumor of > 50% purity, and underwent DNA extraction. CCNE1 copy number was determined by ddPCR. Tumor purity was confirmed with mutant TP53 allele fraction from targeted massively parallel sequencing. RESULTS: Four of 15 patients from an institutional database screened by ddPCR were found to have CCNE1 amplification. Three additional patients were identified from a query of institutional commercial clinical reports. Among these 7 CCNE1 amplified cases (2 uterine, 5 ovarian), 5 showed preservation of CCNE1 amplification (copy number > 5) among all metastatic sites. The remaining 2 cases had multiple metastatic sites without preserved CCNE1 amplification. Non-amplified cases had predominantly normal CCNE1 copy number across metastatic sites. CONCLUSIONS: CCNE1 amplification is an early genomic event in HGSC and is preserved in most metastatic sites suggesting a uniform response to pathway targeting therapies.

Vaginal-assisted laparoscopic nerve sparing radical trachelectomy

Fertility-sparing surgery has gained popularity in the last three decades for the management of cervical cancer in women under 40 years of age. Radical trachelectomy is a fertility-sparing surgical technique for women who wish to retain their fertility. Vaginal-assisted laparoscopic radical trachelectomy is feasible in selected patients with early cervical cancer. The aim of this video is to present a nerve-sparing vaginal-assisted laparoscopic radical trachelectomy demonstrating pelvic anatomical structures.

Primary Retroperitoneal Müllerian Adenocarcinoma: Report of Two Cases Treated With Radical Surgery.

BACKGROUND: Primary retroperitoneal Müllerian adenocarcinoma (PRMA) is a very rare type of primary retroperitoneal tumour. CASE 1: A 45-year-old woman presented with left lower extremity swelling and pain. Imaging revealed that the tumour had invaded the left common iliac vein and artery, internal and external iliac arteries, sciatic and obturator nerves, and pelvic wall. CASE 2: A 37-year-old was admitted with pelvic pain. Imaging showed the tumor at the left iliac bifurcation infiltrating the internal iliac artery and left sciatic, obturator, and femoral nerves. Both of these patients were treated with radical surgery that achieved no visible tumour at the end of the operation. CONCLUSION: There is no guideline for the diagnosis and management of this entity due to its rarity. These cases should be managed at highly specialized centres with expertise in radical surgery.

Mini-Laparoscopic Gynecological Surgery Using Smaller Ports Minimizes Incisional Pain and Postoperative Scar Size: A Paired Sample Analysis.

Objective. The aim of this study was to assess postoperative incisional pain and cosmetic scores in mini-laparoscopic gynecological surgeries undertaken with different port sizes. Material and Method. In this prospective study, all women who underwent mini-laparoscopic gynecological surgery with 2.4-, 3-, and 5-mm lateral ports for benign gynecological conditions between March 2017 and April 2019 were included. The primary outcome was postoperative incisional pain at rest, walking, and after a provoked Valsalva maneuver assessed by numeric rating scale scores at 6 hours, 12 hours, 24 hours, and 3 days and 7 days after surgery. Secondary outcome measures included cosmetic scores of each port site (evaluated by using patient-observer scar assessment scale [POSAS]), operation time, and intra- and postoperative complications. Results. A total of 330 lateral port sites in 110 patients who underwent benign gynecological surgery via mini-laparoscopy were assessed for pain and cosmetic appearance. Pain scores at each time point were significantly lower for 2.4- and 3-mm ports than those for 5-mm ports; however, no significant difference was detected between 2.4-mm and 3-mm port sites (P = .6). The difference was more evident at 24 hours when routine analgesic drugs were stopped (P = .004). For POSAS scores, both 2.4-mm and 3-mm ports were superior to 5-mm port sites (P = .002); however, there was no significant difference between 2.4-mm and 3-mm port sites (P = .2). There were 2 port-related complications: one subcutaneous emphysema and one bleeding from a 5-mm trocar site 1 hour after surgery. Conclusion. Mini-laparoscopic gynecologic surgery using smaller ports resulted in decreased postoperative incisional pain and superior cosmetic appearance.

Step-by-step colpotomy in total laparoscopic hysterectomy: a technique to avoid apical support damage to the upper vagina

The purpose of this video article is to demonstrate our colpotomy technique that enables maximal protection of the cervical ring, helps to prevent the ureteral injury by distancing, and avoids shortening of the vagina at total laparoscopic hysterectomy. Step-by-step explanation of the colpotomy technique is presented using educational video setting in university-affiliated private hospital. After the uterine artery transection, a VECTEC surgical uterine manipulator (VECTEC, Hauterive, France) was inserted into the vagina in place of the sharp curette. The plastic rotating blade of uterine manipulator was strongly pushed forward into the anterior vaginal fornix. Colpotomy incision was started from the uppermost middle point of an anterior vagina, and extended to both sides with a monopolar L-hook electrocautery at 40 watts cutting mode. Then the manipulator's blade was maneuvered into the right lateral fornix, and THUNDERBEAT platform (Olympus Medical Systems Corp, Tokyo, Japan) was chosen as the modality of energy for the transection of the rest of the vagina. At the posterior part of colpotomy, the vaginal wall was cut from the uppermost part of uterosacral ligaments, as well. Finally, the left lateral fornix was cut by the same principles, and colpotomy was completed circumferentially. In conclusion, maximal preservation of paracervical ligaments with this technique preserve the apical support of vagina, and avoids shortening of vaginal length. The technique also minimizes the ureteral injury by distancing.

Clermont-Ferrand versus Vectec uterine manipulator for total laparoscopic hysterectomy.

OBJECTIVE: To compare the operation time and performance of two uterine manipulators used for total laparoscopic hysterectomy (TLH). MATERIAL AND METHODS: Design: Retrospective cohort analysis. Design classification: Canadian Task Force Classification II-2. SETTING: Tertiary-care university-based teaching hospital and academic affiliated private hospital. PATIENTS: All consecutive patients who underwent for TLH between January 2014 and June 2017. All operations were performed by two expert endoscopic surgeons using one of the following uterine manipulators depending on surgeon preferences: Clermont-Ferrand (CF) or Vectec (VT) MAUT60. Patients were excluded if additional surgeries such as urogynecological procedures were performed, TLH was converted to laparotomy prior to colpotomy, and when their operation records could not be obtained. A total of 169 patients were added to final analysis. Operation time, colpotomy time and the subjective performance of manipulators such as movement of the uterus, visualization of the vaginal fornices, and maintenance of pneumoperitoneum were evaluated by watching un-edited operation videos. RESULTS: A total of 169 patients (83 patients in CF group; 86 patients in VT group) were included in the final analysis. Patients' baseline characteristics were comparable between groups. Operation time and time required for colpotomy were significantly shorter in the VT group. Lateral movements of the manipulators and elevation of the uterus were better with VT compared to CF (p = .001 for both). Compared to the CF, VT was superior for visualization of the vaginal fornices (p = .004) and maintenance of pneumoperitoneum (p < .001). Both surgeons had perfect agreement on the performance grading of manipulators (p < .001, Kappa values were between 0.86-0.92). There was no difference between groups in estimated blood loss and duration of hospital stay. Reinsertion or the need to change the manipulator was not required in either group. No pelvic or vaginal abscess, cuff cellulitis, dehiscence, or hematoma formations were noted. CONCLUSION: Laparoscopic hysterectomy assisted with the VT uterine manipulator is associated with shorter operation and colpotomy time. Furthermore, the movements of uterus, visualization of the vaginal fornices, and maintenance of pneumoperitoneum were significantly better with VT compared to the CF manipulator.

Contained Power Morcellation Versus Transvaginal Extraction for Retrieval of Laparoscopically Removed Myomas: A Comparison of Perioperative Outcomes.

OBJECTIVE: To evaluate clinical and operative outcomes of transvaginal extraction (TVE) and contained power morcellation (CPM) for myoma retrieval after laparoscopic myomectomy. MATERIALS AND METHODS: Prospective data from 35 consecutive cases using CPM were compared with retrospective data of all cases using TVE from December 2014 to January 2017. Patients were matched 1:1 based on myoma diameter. A total of 62 women were included in the final analysis. Specimen retrieval was performed using the TVE or CPM within an insufflated isolation bag. RESULTS: Age, body mass index, mode of prior obstetric delivery, history of previous abdominal surgery, indication for myomectomy, and the myoma(s) characteristics were similar between groups. Retrieval time was significantly shorter in the TVE group compared with the CPM group: 10 minutes (3-15 minutes) versus 17 minutes (14-42 minutes); P < .001. Time required for placement of the instruments was 9.7 minutes for the isolation bag and 0.5 minutes for the vaginal extractor. Additional analgesic administration for pain relief was necessary in 13 patients (42%) in the TVE group and 23 patients (72%) in the CPM group ( P = .01). Total cost of the hospital stay was significantly higher in the CPM group compared with the TVE group ( P < .001). Estimated blood loss and duration of hospital stay were similar between groups. CONCLUSION: Both CPM and TVE can be used for safe retrieval of large myomas that are removed laparoscopically. Compared with CPM, TVE was associated with a shorter retrieval time, less postoperative pain, and less hospital costs.

Surgical correction of T-shaped uteri in women with reproductive failure: Long term anatomical and reproductive outcomes.

OBJECTIVE: To evaluate the long term anatomical and reproductive outcomes of hysteroscopic treatment for T shaped uterus in patients presenting with reproductive failure. METHODS: This prospective cohort study included 56 patients with a history of long-standing unexplained infertility, recurrent implantation failure (RIF), and/or recurrent pregnancy loss (RPL) who were eligible for metroplasty by office hysteroscopy. Office hysteroscopy under conscious sedation was performed. Anatomical outcomes were assessed with pre- and postoperative measurements of the transostial, isthmic and myometrial diameters and the uterine volume using three-dimensional transvaginal sonography (3D-TVS). Reproductive outcome was assessed after spontaneous or assisted conception. RESULTS: Hysteroscopic treatment significantly increased the volume of the uterus from a mean of 2.5+1mL before surgery to 3.2±1mL by the end of 1 year as measured by 3D-TVS. According to the main indication to perform metroplasty, 20 of 32 (62.5%) patients with long standing unexplained infertility, 9 of 14 (64%) patients with RIF, and 8 of 10 (80%) patients with RPL conceived either spontaneously or with assisted reproduction. CONCLUSIONS: Office hysteroscopic metroplasty results in a significant long-term expansion of the uterine cavity and improved reproductive outcomes in women presenting with a T shaped uterus and poor reproductive history.

Hyperthermic intraperitonal chemotherapy is an independent risk factor for development of acute kidney injury.

PURPOSE: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) or hyperthermic intrapleural chemotherapy (HIC) has been established as the new treatment modality for selected patients with peritoneal and pleural malignancies. The purpose of the study was to compare the development of acute kidney injury (AKI) in patients who received intravenous cisplatin alone, HIPEC and underwent surgery. METHODS: This retrospective study included 104 patients who underwent different therapeutic procedures including systemic cisplatin, surgery and HIPEC or HIC using cisplatin for the treatment of peritoneal carcinomatosis from a variety of primary tumors at Koc University Hospital and American Hospital between January 2015 to December 2017. RESULTS: AKI developed in 18 (17.3%) patients. Baseline creatinine was significantly increased in 3 groups after therapies. The development of AKI was highest in patients treated with HIPEC compared to patients treated with intravenous cisplatin and patients who underwent surgery. AKI developed 31.2% in the HIPEC group (10 of 32 patients), 11.7% in the surgery group (4 of 34 patients) and 10.5% in intravenous cisplatin group (4 of 38 patients), respectively (p 0.04). CONCLUSION: HIPEC may not be so safe with regard to kidney function. Every attempt should be taken to decrease kidney damage during this procedure.

Use of a gelatin-thrombin hemostatic matrix in obstetrics and gynecological surgery.

Gelatin-thrombin matrix (GTM) is a hemostatic sealant consisting of bovine-derived gelatin matrix and human-derived thrombin, combining both mechanical and active mechanisms to achieve hemostasis. It was approved by the Food and Drug Administration in 1999. GTM has been used by several surgical specialties; however, it is a possibly an under-used tool in obstetrics and gynecology. A limited number of studies have been performed on its use during laparoscopic endometrioma excision and myomectomy. It may prove useful in endometrioma excision in reproductive aged women because it is likely to harm ovarian reserve less than electrocautery; however, this conclusion needs to be validated. The only study on GTM use in myomectomy included 50 women randomized into GTM and control groups, and showed decreased blood loss and shorter hospital stays in the GTM group. In gynecologic oncology, it was successfully used to reduce lymphocele cases in a cohort study. GTM has been used successfully in obstetrics in a handful of cases of uncontrolled bleeding from caesarean scar, placental site, ectopic pregnancy, rectovaginal hematoma, and venous plexus over the vaginal vault after emergency postpartum hysterectomy. Risk of viral transmission is a major concern about GTM, yet there are no reports on disease transmission with GTM use to date. Rare but serious adverse effects and complications have been reported such as fatal or near-fatal thromboembolism and small bowel obstruction. Although GTM is mostly a safe product, it is still not free of complications and risks. In conclusion, although routine use of GTM cannot be recommended due to concerns about its safety, cost, and availability, it may prove useful when conventional hemostatic methods such as suturing and electrocauterization fail or are not appropriate.

Unidirectional barbed suture for vaginal cuff closure without backward stitch in total laparoscopic hysterectomy.

AIM: To evaluate the safety and efficacy of unidirectional barbed suture technique for vaginal cuff closure in total laparoscopic hysterectomy (TLH). METHODS: In a retrospective chart review, data were analyzed from 165 patients who underwent a TLH with an unidirectional barbed suture technique for vaginal cuff closure from January 2012 to June 2016 at tertiary-care university-based teaching hospital and academic affiliated hospital. Vaginal cuff was closed by single layer 3/0 V-Loc unidirectional 9″, 180 day Absorbable Wound Closure Device (Covidien Healthcare, Mansfield, MA) and the suture was not stitched backward to secure distal end. RESULTS: A total of 165 patients were included and the median age was 50 years (range, 35-84 years). The median completion time for hysterectomy time was 100 min (range, 40-240 min) and the median vaginal cuff closure time was 7 min (range, 4-15 min). The median estimated blood loss was 87.8 mL (range 30-250 mL) and the median uterine weight was 200 g (range, 40-900 g). Intraoperative complication included bladder perforation (1.2%) and postoperative complications were vaginal cuff dehiscence (1.8%), cuff cellulitis (0.6%), vesicovaginal fistula (0.6%) and unexplained fever (0.6%). CONCLUSION: According to the results of current study, the use of unidirectional barbed suture without backward stitching appears to be safe for the vaginal cuff closure in TLH.

Utilization of the Bologna criteria: a promise unfulfilled? A review of published and unpublished/ongoing trials.

OBJECTIVE: To study the use of the Bologna criteria (BC) for the definition of poor ovarian responders (POR) in clinical practice and research. DESIGN: Systematic review of published and unpublished/ongoing trials between January 2012 and August 2017 on POR. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): The databases were searched using the relevant medical subject headings including all subheadings. The search was limited to humans and English language. The references of the included studies were cross-searched for possibly missed articles. Only clinical trials providing an evidence level ≥ III were included. Case reports, review, letters, and hypothetical articles were excluded. MAIN OUTCOME MEASURE(S): Extracted studies were divided into two groups: studies in which the BC were used or not. RESULT(S): One hundred nine published clinical studies analyzing a total of 30,540 women and 112 unpublished/ongoing trials were identified. The BC were used to define POR in 56 (51%) of the published and 44 (39%) of the unpublished trials. The use of the BC gradually increased from 29% to 53% from 2012 to 2017. Asian researchers were more likely to use the BC compared with European and North American researchers (65%, 49%, and 23%, respectively). Neither the design of the study nor the impact factor of the publishing journal was correlated with the use of the BC. CONCLUSION(S): There is still reluctance to use the BC for the definition of POR, which makes it difficult to combine data from small studies and reach a meaningful conclusion.

Robot-assisted laparoscopic transperitoneal infrarenal lymphadenectomy in patients with locally advanced cervical cancer by single docking: Do we need a backup procedure?

To present our initial experience on the feasibility of robotic transperitoneal para-aortic lymphadenectomy up to left renal vein via single docking approach by high port insertion technique followed by left shoulder docking as a rescue backup procedure in surgically obstructed patients undergoing surgical staging because of locally advanced cervical cancer (LACC). Prospective observational preliminary study. Canadian Task Force classification II-3. Tertiary-care academic affiliated private hospital. Ten patients with LACC who underwent robotic transperitoneal infrarenal para-aortic lymphadenectomy between January 2012 and December 2014. All patients with pathologically proven cervical cancer underwent a PET/CT scanning in a similar fashion at the department of nuclear medicine. PET/CT scans were evaluated by the nuclear medicine specialist. Following pre-operative work-up, robot-assisted transperitoneal infrarenal para-aortic lymphadenectomy was performed up to left renal vein by the same experienced surgeon. Sections of 5 mm were performed and stained with routine hematoxylin and eosin (H&E), and node count was done separately by experienced gynecopathologist. During the study period, 12 consecutive patients with LACC were counseled for pre-therapeutic robot-assisted transperitoneal para-aortic lymphadenectomy. Two patients declined the procedure and underwent standardized chemo-radiation therapy whereas remaining ten patients constituted the study group. In the study group, the median age was 46 years (range 33-59 years), and the median body mass index 28.5 kg/m2 (range 18.5-35.1 kg/m2). Clinical staging was stage IIB in four patients, IIIB in four, and IVA in one. Histopathological diagnosis was squamous cell carcinoma in nine patients, and adenocarcinoma in one. On PET/CT scans, seven out of ten patients were positive for pelvic lymph node metastasis. With respect to para-aortic area, only one of the ten patients had suspected metastasis in PET/CT. For nine patients with LACC, the median docking time was 6.5 min (range 4-15 min), and the median operating time for para-aortic lymphadenectomy was 120 min (range 60-165 min). The median trocar time was 14.5 min (range 5-45 min). In two out of ten patients, the surgical removal of whole lymphatic tissue between inferior mesenteric artery and left renal vein was not completely possible by a single docking of robotic column. Therefore, a new optic trocar was placed in the umbilicus and the robotic column was relocated over the left shoulder of the patient and residual lymphatic tissue measuring approximately 2 cm in the long axis immediately below the left renal vein was removed and the surgery was completed up to the left renal vein. All para-aortic lymphadenectomies have been completed by robotic route. There were no intra-operative complications. No patient received a blood transfusion. Early post-operative grade 2 and 3a complications according to Dindo classification occurred in two patients: one symptomatic lymphocyst and one local infection on assistant port site in one patient. The patient with suspected para-aortic lymph node metastasis in PET/CT showed no metastatic disease on histopathologic exam of para-aortic lymph nodes. The patient with recurrent disease and negative para-aortic lymph nodes on frozen section examination underwent robot-assisted total pelvic exenteration. Five of the residual eight patients had histologically proven metastasis in the para-aortic lymph node(s). Treatment modification occurred in six patients related to pre-treatment staging surgery. According to pathological results, extended field radiation therapy has been added in five patients and it was omitted in one patient. The median time interval between surgery and initiation of radiotherapy was 12 days (range 6-23 days). Robotic transperitoneal infrarenal para-aortic lymphadenectomy up to left renal vein by high port insertion technique is a safe and feasible option for staging and treatment planning. However, technically, it is obstructed in a small group of patients and nodal staging surgery up to left renal vein can be completed by consecutive left shoulder docking approach as a backup rescue plan.