Amanda Nickles Fader

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Predicting responses to immunotherapy Colon cancers with loss-of-function mutations in the mismatch repair (MMR) pathway have favorable responses to PD-1 blockade immunotherapy. In a phase 2 clinical trial, Le et al. showed that treatment success is not just limited to colon cancer (see the Perspective by Goswami and Sharma). They found that a wide range of different cancer types with MMR deficiency also responded to PD-1 blockade. The trial included some patients with pancreatic cancer, which is one of the deadliest forms of cancer. The clinical trial is still ongoing, and around 20% of patients have so far achieved a complete response. MMR deficiency appears to be a biomarker for predicting successful treatment outcomes for several solid tumors and indicates a new therapeutic option for patients harboring MMR-deficient cancers. Science, this issue p. 409; see also p. 358 A pan-cancer biomarker is identified that can predict successful response to cancer immunotherapy in human patients. The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair–deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.

Laparoendoscopic single-site surgery (LESS) in gynecologic oncology: Technique and initial report

OBJECTIVES Recent reports suggest that laparoendoscopic single-site surgery (LESS), also known as single-port surgery, is technically feasible in treating a variety of disease processes. The purpose of this study was to assess the feasibility of LESS for the surgical treatment of various gynecologic cancers or precancerous conditions through both laparoscopic and robotic-assisted approaches. METHODS A single institution retrospective review of patients treated with LESS on the gynecologic oncology service in 2009 was performed. Patients underwent surgery through a single 2-3 cm umbilical incision with a multi-channel SILS port for laparoscopic cases or a single-channel Gelport for robotic cases on the daVinci Surgical System. RESULTS Thirteen patients had LESS surgery performed, nine done laparoscopically and four robotically. Procedures included endometrial cancer staging (n=1), ovarian cancer staging (n=1), retroperitoneal pelvic lymph node dissection (n=1), risk-reducing extrafascial hysterectomy/bilateral salpingo-oophorectomy (BSO, n=2) and BSO alone (n=5), and an ovarian cystectomy (n=1) and BSO (n=2) for complex adnexal masses. Median patient age and BMI were 47 years and 28, respectively. Median operating time was 65 min. All procedures were successfully performed via a single incision and no post-operative complications occurred. The majority of patients required no narcotics post-operatively. CONCLUSION We present the first series of laparoendoscopic single-site surgery for the treatment of various gynecologic oncology conditions. LESS is feasible in select patients by laparoscopic or robotic-assisted techniques. Further studies are needed to better define the ideal gynecologic procedures for single-site surgery and to assess the benefits of LESS compared with more conventional minimally invasive approaches.

Endometrial cancer and obesity: Epidemiology, biomarkers, prevention and survivorship

Endometrial cancer is the most common gynecologic malignancy in the Western world and is strongly associated with obesity. Despite the fact that most cases are diagnosed in early, more favorable stages, endometrial cancer incidence and mortality rates are on the rise. Morbidly obese women with endometrial cancer are more likely to die of their co-morbidities and also of their cancers when compared to their leaner cohorts. Given the increasing rates of morbid obesity in the United States, it is essential to develop appropriate screening tools and guidelines to reduce cancer morbidity and death amongst this group. Through an analysis of the existing literature, we present a review of the epidemiologic trends in obesity and endometrial cancer, discuss the promising role of screening biomarker studies, review prevention efforts and modifiable risk factors, and ways in which health outcomes and quality of life for endometrial cancer survivors may be optimized.

Role of Surgery in Ovarian Carcinoma

Surgery plays a critical role in the optimal management of all stages of ovarian carcinoma. In apparent early-stage ovarian cancer, a comprehensive surgical evaluation allows stratification of patients into low- and high-risk categories. Low-risk patients may be candidates for fertility-sparing surgery and can safely avoid chemotherapy and be observed. Treatment of patients with high-risk early- or advanced-stage ovarian cancer usually requires a combined modality approach. Although it is well known that epithelial ovarian cancer is moderately chemosensitive, what distinguishes it most from other metastatic solid tumors is that surgical cytoreduction of tumor volume is highly correlated with prolongation of patient survival. Procedures such as radical pelvic surgery, bowel resection, and aggressive upper abdominal surgery are commonly required to achieve optimal cytoreduction. Women who develop recurrent disease may be eligible for a secondary cytoreductive surgery or may require a surgical intervention to palliate disease-related symptoms. For women at high risk of ovarian cancer, prophylactic bilateral salpingo-oophorectomy significantly reduces the incidence of this disease. The purpose of this article is to provide a comprehensive review of the surgical management of ovarian carcinoma. The roles of primary, interval, and secondary cytoreductive surgeries; second-look procedures; and palliative surgery are reviewed. The indications for fertility-sparing and minimally invasive surgery as well as the current guidelines for prophylactic surgery in high-risk mutation carriers are also discussed.

Management of women with uterine papillary serous cancer: A Society of Gynecologic Oncology (SGO) review☆

OBJECTIVE Uterine papillary serous carcinoma (UPSC) is a clinically and pathologically distinct subtype of endometrial cancer. Although less common than its endometrioid carcinoma (EEC) counterpart, UPSC accounts for a disproportionate number of endometrial cancer related deaths. To date, limited prospective trials exist from which evidence-based management can be developed. This review summarizes the available literature concerning UPSC in an effort to provide the clinician with information pertinent to its management. METHODS MEDLINE was searched for all research articles published in English between January 1, 1966 and May 1, 2009 in which the studied population included women diagnosed with UPSC. Although preference was given to prospective studies, studies were not limited by design or by numbers of subjects given the paucity of available reports. RESULTS UPSC is morphologically and genetically different from EEC. Women often present with postmenopausal vaginal bleeding, but may also present with abnormal cervical cytology, ascites, or a pelvic mass. In some cases, the diagnosis may be made with endometrial biopsy, while in other cases it is not made until the time of definitive surgery. Metastatic disease is common and best identified via comprehensive surgical staging. Local and distant recurrences occur frequently, with extra-pelvic relapses reported most commonly. Optimal cytoreduction and adjuvant platinum/taxane-based chemotherapy appear to improve survival, while adjuvant radiotherapy may contribute to loco-regional disease control. CONCLUSIONS Women diagnosed with UPSC should undergo comprehensive surgical staging and an attempt at optimal cytoreduction. Platinum/taxane-based adjuvant chemotherapy should be considered in the treatment of both early- and advanced-stage patients. Careful long-term surveillance is indicated as many of these women will recur. Prospective clinical trials of women with UPSC are necessary in order to delineate the optimal therapy for women with newly diagnosed and recurrent disease.

Oncologic and Reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 Adenocarcinoma: A systematic review

OBJECTIVE The objective of this review was to analyze published contemporary oncologic and reproductive outcomes in women with endometrial hyperplasia or cancer undergoing medical management with progestin therapy. METHODS A systematic review of oncologic and pregnancy outcomes in women with complex atypical hyperplasia or grade 1 adenocarcinoma was performed using a comprehensive search of the MEDLINE literature. English language studies published from 2004 to 2011 which utilized hormonal therapy were identified using key words endometrial hyperplasia, endometrial cancer, fertility preservation, hormone and progestin therapy. Fishers exact test was used to calculate statistical differences. RESULTS Forty-five studies with 391 study subjects were identified. The median age was 31.7 years. Therapies included medroxyprogesterone (49%), megestrol acetate (25%), levonorgestrel intrauterine device (19%), hydroxyprogesterone caproate (0.8%), and unspecified/miscellaneous progestins (13.5%). Overall, 344 women (77.7%) demonstrated a response to hormonal therapy. After a median follow up period of 39 months, a durable complete response was noted in 53.2%. The complete response rate was significantly higher for those with hyperplasia than for women with carcinoma (65.8% vs. 48.2%, p=.002). The median time to complete response was 6 months (range, 1-18 months). Recurrence after an initial response was noted in 23.2% with hyperplasia and 35.4% with carcinoma during the study periods (p=.03). Persistent disease was observed in 14.4% of women with hyperplasia and 25.4% of women with carcinoma (p=.02). During the respective study periods, 41.2% of those with hyperplasia and 34.8% with a history of carcinoma became pregnant (p=.39), with 117 live births reported. CONCLUSION Based on this systematic review of the contemporary literature, endometrial hyperplasia has a significantly higher likelihood of response (66%) to hormonal therapy than grade 1 endometrial carcinoma (48%). Disease persistence is more common in women with carcinoma (25%) compared to hyperplasia (14%). Reproductive outcomes do not seem to differ between the cohorts.

Robotic-assisted laparoendoscopic single-site surgery in gynecology: initial report and technique.

Robotic surgery has greatly improved surgeon dexterity and ergonomics but has substantially increased the number and size of ports required. The typical robotic surgical procedure will use three 8-mm ports and two 12-mm ports. Single-port laparoscopy, also known as Laparo-Endoscopic Single Site (LESS) surgery, is an attempt to further enhance cosmetic benefits and reduce morbidity of minimally invasive surgery.We present our initial clinical experience and technique with robotic-assisted single-port surgery in gynecology.

Platinum/taxane‐based chemotherapy with or without radiation therapy favorably impacts survival outcomes in stage I uterine papillary serous carcinoma

A study was undertaken to determine recurrence patterns and survival outcomes of stage I uterine papillary serous carcinoma (UPSC) patients.

Laparoendoscopic single-site surgery (LESS) in gynecology: a multi-institutional evaluation

OBJECTIVE The study objectives were to determine the surgical outcomes of a large series of gynecology patients treated with laparoendoscopic single-site surgery (LESS). STUDY DESIGN This was a retrospective, multi-institutional analysis of gynecology patients treated with LESS in 2009. Patients underwent surgery via a single 1.5- to 2.5-cm umbilical incision with a multichannel single port. RESULTS A total of 74 women underwent LESS. Procedures were performed for benign pelvic masses (n = 39), endometrial hyperplasia (n = 9), endometrial (n = 15) and ovarian (n = 6) cancers, and nongynecologic malignancies (n = 5). Median patient age and body mass index were 47 years and 28, respectively. A Pearson product-moment correlation coefficient was computed and demonstrated a significant linear relationship between the operating time and number of cases for cancer staging (r = -0.71; n = 26; P < .001) and nonstaging (r = -0.78; n = 48; P < .002) procedures. Perioperative complications were low (3%). CONCLUSION LESS is feasible, safe, and reproducible in gynecology patients with benign and cancerous conditions. Operative times are reasonable and can be decreased with experience.

Contained power morcellation within an insufflated isolation bag.

OBJECTIVE: To describe a technique for contained power morcellation within an insufflated isolation bag at the time of uterine specimen removal during minimally invasive gynecologic procedures. METHODS: Over the study period of January 2013 to April 2014, 73 patients underwent morcellation of the uterus or myomas within an insufflated isolation bag at the time of minimally invasive hysterectomy or myomectomy. This technique involves placing the specimen into a large plastic bag within the abdomen, exteriorizing the opening of the bag, insufflating the bag within the peritoneal cavity, and then using a power morcellator within the bag to remove the specimen in a contained fashion. Procedures were performed at four institutions and included multiport laparoscopy, single-site laparoscopy, multiport robot-assisted laparoscopy, or single-site robot-assisted laparoscopy. Demographic and perioperative characteristics were collected for the cases. RESULTS: Surgical specimen morcellation within an insufflated isolation bag was successfully used in all cases. The median operative time was 114 minutes (range 32–380 minutes), median estimated blood loss was 50 mL (range 10–500 mL), and the median specimen weight was 257 g (range 53–1,481 g). There were no complications related to the contained morcellation technique nor was there visual evidence of tissue dissemination outside of the isolation bag. CONCLUSION: Morcellation within an insufflated isolation bag is a feasible technique. Methods for morcellating uterine tissue in a contained manner may provide an option to minimize the risks of open power morcellation while preserving the benefits of minimally invasive surgery. LEVEL OF EVIDENCE: II