Weight Loss During Intrauterine Progestin Treatment for Obesity-associated Atypical Hyperplasia and Early-Stage Cancer of The Endometrium.

Intrauterine progestin is a treatment option for women with atypical hyperplasia or low-risk endometrial cancer who wish to preserve their fertility, or whose poor surgical fitness precludes safe hysterectomy. We hypothesized that in such women with obesity, weight loss during progestin treatment may improve oncological outcomes. We conducted a prospective nonrandomized study of women with obesity and atypical hyperplasia or low-grade stage 1a endometrial cancer undergoing progestin treatment. Women with a body mass index (BMI) ≥ 35 kg/m2 were offered bariatric surgery; those who declined and those with a BMI of 30 to 34.9 kg/m2 were encouraged to lose weight by low-calorie diet. We assessed uptake of bariatric surgery; weight lost during progestin treatment; and the impact of more than 10% total body weight loss on progestin treatment response at 12 months. 71 women [median age 58 years (interquartile range; IQR 35-65); mean BMI 48 kg/m2 (SD 9.3)] completed the study. Twenty-three women (32%) had bariatric surgery, on average 5 months (IQR 3-8) after progestin treatment commenced. Weight change during progestin treatment was -33.4 kg [95% confidence interval (CI) -42.1, -24.7] and -4.6 kg (95% CI -7.8, -1.4) in women receiving bariatric surgery and low-calorie diet, respectively (P < 0.001). Forty-three women (61%) responded to progestin, while 23 (32%) showed stabilized and 5 (7%) progressive disease. Response at 12 months was not predicted by age or baseline BMI, but women who lost more than 10% of their total body weight were more likely to respond to progestin than those who did not (adjusted odds ratio 3.95; 95% CI 1.3, 12.5; P = 0.02). Thus weight loss may improve oncological outcomes in women with obesity-associated endometrial neoplastic abnormalities treated with progestin. PREVENTION RELEVANCE: This study found that weight loss improves response rates in women with obesity and atypical hyperplasia or low-risk endometrial cancer undergoing conservative management with intrauterine progestin. Given the additional benefits of weight loss for fertility, cardiovascular health and quality of life, future research should focus on how best to accomplish it.

PRE-surgical Metformin In Uterine Malignancy (PREMIUM): a Multi-Center, Randomized Double-Blind, Placebo-Controlled Phase III Trial.

PURPOSE: Endometrioid endometrial cancer is strongly associated with obesity and insulin resistance. Metformin, an insulin sensitizer, reduces endometrial tumor growth in vitro. Presurgical window studies allow rapid in vivo assessment of antitumor activity. Previous window studies found metformin reduced endometrial cancer proliferation but these lacked methodological rigor. PREMIUM measured the anti-proliferative effect of metformin in vivo using a robust window study design.Patients and Methods: A multicenter, double-blind, placebo-controlled trial randomized women with atypical hyperplasia or endometrioid endometrial cancer to receive metformin (850 mg daily for 3 days, and twice daily thereafter) or placebo for 1 to 5 weeks until surgery. The primary outcome was posttreatment IHC expression of Ki-67. Secondary outcomes investigated the effect of metformin on markers of the PI3K-Akt-mTOR and insulin signaling pathways and obesity. RESULTS: Eighty-eight women received metformin (n = 45) or placebo (n = 43) and completed treatment. There was no overall difference in posttreatment Ki-67 between the metformin and placebo arms, in an ANCOVA analysis adjusting for baseline Ki-67 expression (mean difference -0.57%; 95% CI, -7.57%-6.42%; P = 0.87). Metformin did not affect expression of markers of the PI3K-Akt-mTOR or insulin signaling pathways, and did not result in weight loss. CONCLUSIONS: Short-term treatment with standard diabetic doses of metformin does not reduce tumor proliferation in women with endometrioid endometrial cancer awaiting hysterectomy. This study does not support a biological effect of metformin in endometrial cancer and casts doubt on its potential application in the primary and adjuvant treatment settings.

Prophylactic pre-operative bilateral ureteric catheters for major gynaecological surgery.

PURPOSE: The use of prophylactic pre-operative bilateral ureteric catheters for major gynaecological surgery is controversial. The aim of this study was to investigate the frequency of ureteric catheter-associated morbidity in our Unit, where systematic pre-operative ureteric catheterisation is performed. METHODS: We conducted a retrospective casenote review of 337 gynaecology patients undergoing laparotomy at Salford Royal Hospital between January 2007 and September 2010. RESULTS: The mean age was 56.36 (range 17-89). Procedures included TAH BSO (n = 249, 74 %), BSO (n = 17, 5 %), radical hysterectomy (n = 36, 11 %), and other (n = 35, 10 %), for indications of ovarian (n = 189, 56 %), uterine (n = 88, 26 %) or cervical cancer (n = 18, 5.3 %), massive fibroids (n = 27, 8 %), severe endometriosis (n = 6, 1.78 %), or other (n = 9, 2.67 %). Bilateral ureteric catheters were attempted in most patients and successfully placed in 315/337 (93 %) patients. In 22 patients (7 %), either no ureteric catheters or a single ureteric catheter was placed due to pre-existing ureteric anomaly, technical difficulty, or surgeon choice. Bilateral ureteric catheterisation took an average of 5.4 min (SD 2.0, range 3.2-9.2) for an experienced consultant or 8.4 min (SD 3.9, range 6.4-18.6) for an SpR trainee to complete. There were no intra-operative ureteric complications. Post-operative complications included urinary tract infection (5/337 patients, 1.48 %), acute renal failure (2/337, 0.6 %), and uretero-vaginal fistulae (1/337 patients, 0.3 %). CONCLUSIONS: Prophylactic pre-operative ureteric catheters are quick and easy to insert and associated with low complication rates. Routine use before major gynaecological surgery can expedite intra-operative identification of the ureters and may reduce accidental ureteric injury.

The surgical rectus sheath block for post-operative analgesia: a modern approach to an established technique.

OBJECTIVE: To describe the surgical rectus sheath block for post-operative pain relief following major gynaecological surgery. TECHNIQUE: Local anaesthetic (20 ml 0.25% bupivacaine bilaterally) is administered under direct vision to the rectus sheath space at the time of closure of the anterior abdominal wall. STUDY DESIGN: We conducted a retrospective case note review of 98 consecutive patients undergoing major gynaecological surgery for benign or malignant disease who received either standard subcutaneous infiltration of the wound with local anaesthetic (LA, n=51) or the surgical rectus sheath block (n=47) for post-operative pain relief. MAIN OUTCOME MEASURES: (1) Pain scores on waking, (2) duration of morphine-based patient controlled analgesia (PCA), (3) quantity of morphine used during the first 48 post-operative hours and (4) length of post-operative stay. RESULTS: The groups were similar in age, the range of procedures performed and the type of pathology observed. Patients who received the surgical rectus sheath block had lower pain scores on waking [0 (0-1) vs. 2 (1-3), p<0.001], required less morphine post-operatively [12 mg (9-26) vs. 36 mg (30-48), p<0.001], had their PCAs discontinued earlier [24h (18-34) vs. 37 h (28-48), p<0.001] and went home earlier [4 days (3-4) vs. 5 days post-op (4-8), p<0.001] [median (interquartile range)] than patients receiving standard subcutaneous local anaesthetic into the wound. CONCLUSIONS: The surgical rectus sheath block appears to provide effective post-operative analgesia for patients undergoing major gynaecological surgery. A randomised controlled clinical trial is required to assess its efficacy further.

Apronectomy combined with laparotomy for morbidly obese endometrial cancer patients.

BACKGROUND: The surgical management of morbidly (BMI >40) and super obese (BMI >50) women with endometrial cancer is challenging. The aim of this study was to describe the short and long term outcomes of apronectomy combined with laparotomy for endometrial cancer staging and tumour debulking. METHODS: A retrospective case note review of morbidly obese patients undergoing combined apronectomy and laparotomy for suspected endometrial cancer between 2007 and 2009 was performed. Short term (operating time, estimated blood loss, complication rates, duration of hospital stay) and long term outcomes (weight profile over 24-month follow up period) were evaluated. RESULTS: Twenty-one patients were identified with a median age of 58 years and a median BMI of 49 (range 37-64). Apronectomy combined with laparotomy took 192 min on average to complete, with a mean estimated blood loss of 497 ml. There were no intra-operative complications. Postoperative complications included anaemia (14% required a blood transfusion), urinary tract infection (5%) and wound complications (wound infection in 29% and partial wound dehiscence in 5%). The median post-operative stay was 9 days. At twenty-four months, one-third of patients were heavier (mean 5 kg, range 2-8 kg) but almost two-thirds of patients were considerably lighter than they had been pre-operatively (mean 13 kg lighter, range 9-17 kg). CONCLUSIONS: Apronectomy combined with laparotomy was safe and well tolerated in this group of patients. Sustained weight loss by two-thirds of the patients over the two-year follow up period may reflect lifestyle changes instigated by individual patients following surgery. Combined apronectomy and laparotomy may provide an alternative to standard surgery for this challenging group of patients.

The accuracy of the sentinel node procedure after excision biopsy in squamous cell carcinoma of the vulva.

INTRODUCTION: Restricting inguinofemoral lymphadenectomy to patients with malignant nodes would reduce treatment-related morbidity in vulval cancer patients. A prospective study was conducted to determine the diagnostic accuracy of the Sentinel Lymph Node (SLN) procedure in vulval cancer patients referred following either diagnostic or excision biopsy. METHODS: Patients with clinical stage I and II squamous cell carcinoma of the vulva underwent SLN identification with peri-scar/lesional injection of (99m)Technetium-labelled nanocolloid (pre-operative lymphoscintigraphy and intra-operative use of a hand-held probe) and intra-operative blue dye. Radical excision of the vulval tumour or scar and formal inguinofemoral lymphadenectomy was then performed as necessary. SLN were processed separately and further examined at multiple levels to exclude micrometastases (H&E/cytokeratin staining) if negative on routine analysis. Clinical follow-up was carried out to identify and treat recurrences or treatment-related morbidity. RESULTS: Thirty-two women took part. Fifteen were referred following excision biopsy and seventeen following diagnostic biopsy of their primary vulval tumour. One or more SLN was successfully detected intra-operatively in 31 patients (97%) and 45 groins. An SLN could not be identified intra-operatively in one case (re-excision of scar). On average, more SLN were identified in patients with their primary vulval lesion in situ compared with those whose tumour had previously been excised (2.6 vs. 1.8, p = 0.03). Midline tumours were more likely (15/17) than lateral tumours (1/15) to have bilateral SLN identified pre-operatively. Two patients with midline tumours previously excised had unilateral SLN. Seven patients (23%) and ten groins had inguinofemoral lymph node metastases. The SLN procedure correctly identified inguinofemoral metastases in six patients (nine groins). In one case (midline tumour, re-excision of scar) the sentinel node was positive on one side but false negative on the other. CONCLUSIONS: The SLN procedure may be used to identify malignant groins in selected patients with vulval cancer. The extent to which previous vulval surgery might influence the accuracy of the SLN procedure deserves further investigation.

The management of vulval cancer.

Referral of women with vulval carcinoma to tertiary centres is now established practise in the UK. The centralisation of care for these women promotes the development of specialist teams of gynaecological oncologists, clinical oncologists, pathologists and clinical nurse specialists with expertise in the management of this relatively rare tumour. The primary care physician plays an essential role in the early detection and subsequent urgent referral of women with suspicious vulval lesions. Improved education and awareness campaigns may encourage women to report vulval symptoms early. Where vulval carcinoma is diagnosed at an early stage, surgical excision is likely to be curative. There is, however, a move away from radical surgery for all patients irrespective of stage of disease towards an individualised approach, which takes into account the size and position of the tumour. The challenge is to reduce morbidity associated with treatment without compromising on cure rates. Restricting groin lymphadenectomy to women with lymph node metastases may be possible with the advent of sentinel node technology and it is anticipated that expertise in this area will show significant advances over the coming years. There is still a place for radical surgery, often in combination with other treatment modalities, in the management of advanced or recurrent disease. This article will review the evidence for the current management of vulval carcinoma.

Regulation of fibroblast growth factor-2 activity by human ovarian cancer tumor endothelium.

Fibroblast growth factor-2 (FGF-2) is a potent angiogenic cytokine that is dependent on heparan sulfate for its biological activity. We have investigated the relationship among heparan sulfate, FGF-2, and the signal-transducing receptors in human, advanced-stage, serous ovarian adenocarcinoma. Using a unique molecular probe, FR1c-Ap, which consisted of a soluble FGF receptor 1 isoform IIIc covalently linked to an alkaline phosphatase moiety, the distribution of heparan sulfate that had the ability to support the formation of a heparan sulfate/FGF-2/FGFR1 isoform IIIc alkaline phosphatase heparan sulfate construct complex was determined. This may be taken as a surrogate marker for the distribution of biologically active heparan sulfate and was distributed predominantly in endothelial cells and stroma but was absent from adenocarcinoma cells. In situ hybridization revealed the expression of FGFR1 mRNA in the endothelium and reverse transcription-PCR confirmed the presence of FGFR1 isoform IIIc but not isoform IIIb. The presence of FGF-2 around tumor endothelium was detected through immunohistochemistry. Double-staining techniques showed that heparan sulfate was found predominantly at the basal aspect of the endothelium and suggested that syndecan-3 might function as one of the proteoglycans involved in FGF-2 signaling in the endothelium. The data suggest that the entire extracellular signaling apparatus, consisting of FGF-2, biologically active heparan sulfate, and FGFRs capable of responding to FGF-2, is present in ovarian cancer endothelium, thereby highlighting the cytokine and its cognate receptor as potential targets for the antiangiogenic treatment of this disease.

Distribution and clinical significance of heparan sulfate proteoglycans in ovarian cancer.

PURPOSE: Heparan sulfate proteoglycans have been implicated in cancer cell growth, invasion, metastasis, and angiogenesis. This study was designed to compare their expression in normal ovary and ovarian tumors and then to examine their prognostic significance in ovarian cancer. EXPERIMENTAL DESIGN: The expression of syndecan-1, -2, -3, and -4, glypican-1, and perlecan was assessed by immunohistochemistry in 147 biopsies that included normal ovary and benign, borderline, and malignant ovarian tumors. Clinical data, including tumor stage, performance status, treatment, and survival, were collected. Univariate and multivariate analyses were performed to evaluate prognostic significance. RESULTS: The expression patterns of syndecan-1 and perlecan were altered in ovarian tumors compared with normal ovary. Syndecan-1 was not detected in normal ovary but was present in the epithelial and stromal cells of benign and borderline tumors and in ovarian adenocarcinomas. Perlecan expression was decreased in basement membranes that were disrupted by cancer cells but maintained in the basement membranes of blood vessels. Syndecan-2, -3, and -4, and glypican-1 were expressed in normal ovary and benign and malignant ovarian tumors. Stromal expression of syndecan-1 and glypican-1 were poor prognostic factors for survival in univariate analysis. CONCLUSION: We report for the first time distinct patterns of expression of cell surface and extracellular matrix heparan sulfate proteoglycans in normal ovary compared with ovarian tumors. These data reinforce the role of the tumor stroma in ovarian adenocarcinoma and suggest that stromal induction of syndecan-1 contributes to the pathogenesis of this malignancy.