Development of Peritoneal Carcinoma in women diagnosed with Serous Tubal Intraepithelial Carcinoma (STIC) following Risk-Reducing Salpingo-Oophorectomy (RRSO).

INTRODUCTION: The management of Serous Tubal Intraepithelial Carcinoma (STIC) found at the time of Risk-Reducing Salpingo-Oophorectomy (RRSO) remains unclear. We set out to analyse the incidence of peritoneal carcinomas developed after prophylactic surgery and to formulate further guidance for these patients. METHODS: This is a retrospective study of 300 consecutive RRSO performed at the Royal Marsden Hospital between January 2008 and January 2017. RESULTS: The median age at RRSO was 47.8 years (range 34 to 60 years) and median BMI was 26.2 kg/m2 (range 16 to 51 kg/m2). A total of 273 patients (91%) were tested for BRCA mutations. Of these, 124 (45.4%) had a BRCA 1 mutation, 118 (43.2%) had a BRCA 2 mutation, 2 (0.7%) had both a BRCA 1 and a BRCA 2 mutation and 29 (10.6%) had no BRCA mutation detected. Isolated STIC lesions were identified in 7 cases (2.3%) and p53 signatures in 75 cases (25%). There were five (1.6%) incidental tubal carcinomas and one (0.3%) ovarian carcinoma at the time of surgery. Two (28.6%) of the 7 patients with STIC identified following RRSO had high grade serous peritoneal carcinoma diagnosed at 53 and 75 months. One (0.3%) patient from the other 287 patients from our series with no STIC diagnosis or incidental carcinomas at RRSO developed high grade serous carcinoma of peritoneal origin after 92 months. CONCLUSION: This study demonstrates that when a STIC lesion is identified following RRSO there is a significantly higher risk of a subsequent peritoneal cancer. Although there is no published consensus in literature, we recommend that consideration should be given for long term follow-up if a STIC lesion is identified at RRSO.

Sertoli-Leydig Cell Tumour and DICER1 Mutation: A Case Report and Review of the Literature.

Sertoli-Leydig cell tumours of the ovary (SLCT) are rare tumours predominantly caused by mutations in the DICER1 gene. We present a patient with a unilateral SLCT who had an underlying germline DICER1 gene mutation. We discuss the underlying pathology, risks, and screening opportunities available to those with a mutation in this gene as SLCT is only one of a multitude of other tumours encompassing DICER1 syndrome. The condition is inherited in an autosomal dominant fashion. As such, genetic counselling is a key component of the management of women with SLCT.

nab-Paclitaxel plus carboplatin or gemcitabine versus gemcitabine plus carboplatin as first-line treatment of patients with triple-negative metastatic breast cancer: results from the tnAcity trial.

Background: Metastatic triple-negative breast cancer (mTNBC) has a poor prognosis and aggressive clinical course. tnAcity evaluated the efficacy and safety of first-line nab-paclitaxel plus carboplatin (nab-P/C), nab-paclitaxel plus gemcitabine (nab-P/G), and gemcitabine plus carboplatin (G/C) in patients with mTNBC. Patients and methods: Patients with pathologically confirmed mTNBC and no prior chemotherapy for metastatic BC received (1 : 1 : 1) nab-P 125 mg/m2 plus C AUC 2, nab-P 125 mg/m2 plus G 1000 mg/m2, or G 1000 mg/m2 plus C AUC 2, all on days 1, 8 q3w. Phase II primary end point: investigator-assessed progression-free survival (PFS); secondary end points included overall response rate (ORR), overall survival (OS), percentage of patients initiating cycle 6 with doublet therapy, and safety. Results: In total, 191 patients were enrolled (nab-P/C, n = 64; nab-P/G, n = 61; G/C, n = 66). PFS was significantly longer with nab-P/C versus nab-P/G [median, 8.3 versus 5.5 months; hazard ratio (HR), 0.59 [95% CI, 0.38-0.92]; P = 0.02] or G/C (median, 8.3 versus 6.0 months; HR, 0.58 [95% CI, 0.37-0.90]; P = 0.02). OS was numerically longer with nab-P/C versus nab-P/G (median, 16.8 versus 12.1 months; HR, 0.73 [95% CI, 0.47-1.13]; P = 0.16) or G/C (median, 16.8 versus 12.6 months; HR, 0.80 [95% CI, 0.52-1.22]; P = 0.29). ORR was 73%, 39%, and 44%, respectively. In the nab-P/C, nab-P/G, and G/C groups, 64%, 56%, and 50% of patients initiated cycle 6 with a doublet. Grade ≥3 adverse events were mainly hematologic. Conclusions: First-line nab-P/C was active in mTNBC and resulted in a significantly longer PFS and improved risk/benefit profile versus nab-P/G or G/C.

REpeated AutoLogous Infusions of STem cells In Cirrhosis (REALISTIC): a multicentre, phase II, open-label, randomised controlled trial of repeated autologous infusions of granulocyte colony-stimulating factor (GCSF) mobilised CD133+ bone marrow stem cells in patients with cirrhosis. A study protocol for a randomised controlled trial.

INTRODUCTION: Liver disease mortality and morbidity are rapidly rising and liver transplantation is limited by organ availability. Small scale human studies have shown that stem cell therapy is safe and feasible and has suggested clinical benefit. No published studies have yet examined the effect of stem cell therapy in a randomised controlled trial and evaluated the effect of repeated therapy. METHODS AND ANALYSIS: Patients with liver cirrhosis will be randomised to one of three trial groups: group 1: Control group, Standard conservative management; group 2 treatment: granulocyte colony-stimulating factor (G-CSF; lenograstim) 15 µg/kg body weight daily on days 1-5; group 3 treatment: G-CSF 15 µg/kg body weight daily on days 1-5 followed by leukapheresis, isolation and aliquoting of CD133+ cells. Patients will receive an infusion of freshly isolated CD133+ cells immediately and frozen doses at days 30 and 60 via peripheral vein (0.2×10(6) cells/kg for each of the three doses). Primary objective is to demonstrate an improvement in the severity of liver disease over 3 months using either G-CSF alone or G-CSF followed by repeated infusions of haematopoietic stem cells compared with standard conservative management. The trial is powered to answer two hypotheses of each treatment compared to control but not powered to detect smaller expected differences between the two treatment groups. As such, the overall α=0.05 for the trial is split equally between the two hypotheses. Conventionally, to detect a relevant standardised effect size of 0.8 point reduction in Model for End-stage Liver Disease score using two-sided α=0.05(overall α=0.1 split equally between the two hypotheses) and 80% power requires 27 participants to be randomised per group (81 participants in total). ETHICS AND DISSEMINATION: The trial is registered at Current Controlled Trials on 18 November 2009 (ISRCTN number 91288089, EuDRACT number 2009-010335-41). The findings of this trial will be disseminated to patients and through peer-reviewed publications and international presentations.

CT scan does not predict optimal debulking in stage III-IV epithelial ovarian cancer: a multicentre validation study.

Our aim was to design and validate a model of CT findings that predict suboptimal cytoreduction in primary surgery (PS) for Stage III-IV epithelial ovarian cancer (EOC). We performed a retrospective review of preoperative CT scans of patients undergoing PS for EOC in a cancer centre in London, UK, between November 1995 and October 2003 (n = 91). Radiological features predictive of suboptimal cytoreduction were identified and the model tested in a second cohort undergoing PS in Manchester, June 2005 - March 2007 (n = 35). In the London cohort, liver surface disease and infrarenal para-aortic lymph node involvement predicted suboptimal cytoreduction with 80% accuracy. Accuracy of these predictors dropped to 63% when applied to the Manchester cohort. We concluded that CT prediction of suboptimal cytoreduction is unreliable and may not be reproducible. In the absence of favourable data from larger, prospective trials, it should not be used to guide management.

Surgical practice of UK gynaecological oncologists in the treatment of primary advanced epithelial ovarian cancer (PAEOC): a questionnaire survey.

OBJECTIVE: To assess the routine surgical practices of consultant gynaecological oncologists (CGOs) in the United Kingdom in their management of primary advanced (FIGO stages III and IV) epithelial ovarian cancer (PAEOC). METHODS: The same anonymised questionnaire was sent twice to all consultant gynaecological oncologists (CGOs) working in the UK. The questions enquired about surgical practice of the previous calendar year and the respondents were asked to describe their usual or typical management of patients with PAEOC. RESULTS: 45 of 85 CGOs responded (53%). The mean number of ovarian cancer cases operated on by an individual surgeon was 47 (range 6-100). 6% of the surgeons never perform pelvic lymphadenectomy, and 22% of the surgeons never perform para-aortic lymphadenectomy in the primary surgery (PS) group, compared to 8% and 30% in the neoadjuvant chemotherapy (NAC) group. In the PS group 17% of the respondents perform pelvic lymphadenectomy routinely (80% or more of patients) compared to 11% of the respondents in the NAC group. The rates of bowel surgery and surgery for upper abdominal disease were highly variable. The average operating time per case was less than 3h in 78% of the respondents. CONCLUSIONS: The mean operating times, caseload, and types of procedure undertaken in the management of advanced ovarian cancer provide compelling evidence that in many UK cancer centres the surgical goal has not been complete cytoreduction. These data have implications for the centralisation of surgical services, subspecialty training, and the lower survival of UK patients compared to other comparable countries.

Laparoscopic staging for apparent early stage ovarian or fallopian tube cancer. First case series from a UK cancer centre and systematic literature review.

OBJECTIVE: To describe the experience of laparoscopic staging of apparent early stage adnexal cancers. METHODS: Prospectively collected data on women who had laparoscopic staging for apparent early stage adnexal cancers from May 2008 to September 2012 was reviewed. All women had had a prior surgical procedure at which the diagnosis was made, without comprehensive staging. A systematic MEDLINE search from 1980 to 2012 for publications on laparoscopic staging was performed. RESULTS: Thirty-five women had laparoscopic staging. Median age was 45 years (range 21-73). Median operative time was 210 min (range 90-210). Four intra-operative and one post-operative complication occurred; overall complication rate 5/35 (14%). One vena cava and one transverse colon injury underwent laparotomies for repair. Laparotomy conversion rate 2/35 (6%). Following laparoscopic staging, the cancer was upstaged for eight (23%) women; microscopic omental involvement (four women), pelvic lymph node involvement (two women), para-aortic lymph node involvement (one woman) and contra-lateral ovarian involvement (one woman). After follow up for a median of 18 months (range 3-59) the disease free survival was 94% and overall survival was 100%. Nine studies were identified on laparoscopic staging of adnexal cancer, of which this is the largest single institution series. CONCLUSIONS: This study adds to the evidence that laparoscopic staging is at least as safe as staging by laparotomy with appropriate and similar oncological outcomes, but with the advantages of minimal access surgery. We therefore advocate the use of laparoscopy to achieve surgical staging for women with presumed early stage adnexal cancer.

Surgical management and follow-up of patients with cervical cancer: survey of gynaecological oncologists in the UK.

We investigated current surgical management and follow-up of women with cervical cancer focusing on treatment of recurrent disease and the use of routine imaging during follow-up among gynaecological oncologists in the UK. A questionnaire including questions regarding perioperative management of primary disease in cervical cancer, follow-up post-treatment, assessment and management of recurrent cervical cancer, was sent to 84 gynaecological oncologists. Some 87% responded. Considerable variations in surgical management and follow-up were identified. With central recurrence of cervical cancer without prior radiotherapy, 90% would recommend radiotherapy instead of an exenteration. For central recurrence in irradiated women, only three (4%) would not recommend an exenteration. In women with pelvic sidewall relapse without prior radiotherapy, 65 responders (96%) would offer radiotherapy, while in pelvic sidewall relapse post-radiation 25 (37%) would recommend pelvic sidewall resection in a specialised centre. A total of 21% used routine imaging during follow-up. The wide variation in clinical practice indicates that there is a need to establish national guidelines for surgical management and follow-up of primary and recurrent cervical cancer.

A study of split-dose cisplatin-based neo-adjuvant chemotherapy in muscle-invasive bladder cancer.

The aim of this study was to investigate the outcome of patients with muscle-invasive bladder cancer (MIBC) receiving neo-adjuvant chemotherapy (neo-CT) using a cisplatin-based regimen fractionated on days 1 and 8 of a 21-day cycle prior to organ-preservation (chemoradiation) or cystectomy. Patients with stage T2-T4, N0, M0, transitional cell carcinoma (TCC) of the bladder with a calculated glomerular filtration rate (GFR) ≥40 ml/min were eligible for inclusion in the study. Neo-CT comprised of gemcitabine (1,000 mg/m(2) d1, d8, q21) plus cisplatin (35 mg/m(2) d1, d8, q21) for four cycles. Following the administration of neo-CT, patients underwent surgery or radiotherapy (RT) with or without concurrent chemotherapy (CRT), based on the response to neo-CT and clinician and patient preference. A total of 23 patients were recruited: 21 males and 2 females; median age, 69 years (range, 49-85); stage T2=11, T3A=7, T3B=5, grade 2=1, grade 3=22. One patient progressed prior to neo-CT. In total, 75 cycles of neo-CT were administered. Treatment was well-tolerated with only one episode of neutropenic sepsis. Three of 22 patients developed early progression and did not receive radical treatment. For the remaining 19 patients, choice of definitive treatment (surgery vs. RT/CRT) was based on response to neo-CT. Eight patients had residual disease at cystoscopy following the completion of neo-CT; six patients underwent surgery and two underwent RT/CRT. A total of 11 patients had a complete response (CR) to neo-CT, nine of whom were treated by RT/CRT, with the remaining two declining radical treatment. Median follow-up for alive patients was 57 months (range, 4.4-68.5). Three-year survival was 37% (95% CI 17-58%) and 5-year survival was 31% (95% CI 15-52%). Neo-CT is effective and well-tolerated in MIBC. This split-dose cisplatin regimen facilitates treatment in an outpatient setting and allows inclusion of patients with compromised GFR.

The role of surgery in patients with advanced gynaecological cancers participating in phase I clinical trials.

OBJECTIVE: While gynaecological cancer patients who participate in Phase I clinical trials are not routinely considered for elective surgery because of a short life expectancy, this should not be overlooked in carefully selected responding patients. METHODS/RESULTS: We describe two cases of patients with different gynaecological cancers, who received treatment within separate phase I trials, and who then proceeded to surgical resection of their cancers, resulting in complete remission. CONCLUSION: Surgery, when feasible, should be taken into consideration as a potential management option, even when patients are receiving treatment within a phase I trial.

Outcomes of surgical management of bowel obstruction in relapsed epithelial ovarian cancer (EOC).

OBJECTIVE: To describe the outcomes of surgical management of bowel obstruction in relapsed epithelial ovarian cancer (EOC) so as to define the criteria for patient selection for palliative surgery. METHODS: 90 women with relapsed EOC underwent palliative surgery for bowel obstruction between 1992 and 2008. RESULTS: Median age at time of surgery for bowel obstruction was 57 years (range, 26 to 85 years). All patients had received at least one line of platinum-based chemotherapy. Median time from diagnosis of primary disease to documented bowel obstruction requiring surgery was 19.5 months (range, 29 days-14 years). Median interval from date of completed course of chemotherapy preceding surgery for bowel obstruction was 3.8 months (range, 5 days-14 years). Ascites was present in 38/90(42%). 49/90(54%) underwent emergency surgery for bowel obstruction. The operative mortality and morbidity rates were 18% and 27%, respectively. Successful palliation, defined as adequate oral intake at least 60 days postoperative, was achieved in 59/90(66%). Only the absence of ascites was identified as a predictor for successful palliation (p=0.049). The median overall survival (OS) was 90.5 days (range, <1 day-6 years). Optimal debulking, treatment-free interval (TFI) and elective versus emergency surgery did not predict survival or successful palliation from surgery for bowel obstruction (p>0.05). CONCLUSION: Surgery for bowel obstruction in relapsed EOC is associated with a high morbidity and mortality rate especially in emergency cases when compared to other gynaecological oncological procedures. Palliation can be achieved in almost two thirds of cases, is equally likely in elective and emergency cases but is less likely in those with ascites.

Chemotherapy-induced peripheral neuropathy: prevention and treatment.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting side effect of many chemotherapeutic agents. Although many therapies have been investigated for the prevention and/or treatment of CIPN, there is no well-accepted proven therapy. In addition, there is no universally accepted, well-validated measure for the assessment of CIPN. The agents for which there are the strongest preliminary data regarding their potential efficacy in preventing CIPN are intravenous calcium and magnesium (Ca/Mg) infusions and glutathione. Agents with the strongest supporting evidence for efficacy in the treatment of CIPN include topical pain relievers, such as baclofen/amitriptyline/ketamine gel, and serotonin and norepinephrine reuptake inhibitors, such as venlafaxine and duloxetine. Other promising therapies are also reviewed in this paper. Cutaneous electrostimulation is a nonpharmacological therapy that appears, from an early pilot trial, to be potentially effective in the treatment of CIPN. Finally, there is a lack of evidence of effective treatments for the paclitaxel acute pain syndrome (P-APS), which appears to be caused by neurologic injury.

Drug-induced sensorineural deafness caused by antithyroid drugs: a rare side effect.

Acute ototoxicity is a rare but important complication of antithyroid drugs. Although previous cases have been reported in the medical literature, these cases occurred in younger patients with serological evidence of lupus-like syndrome with positive antidouble-stranded deoxyribonucleic acid and antineutrophil cytoplasmic antibodies. We describe the case of a 68-year-old Caucasian male who developed deafness and tinnitus one week after being prescribed carbimazole. The management options include stopping the culprit drug, treatment with immunosuppressive drugs and referring the patient for urgent thyroidectomy. Healthcare professionals who prescribe antithyroid drugs should be aware of this rare but potentially serious complication, so that early drug withdrawal and referral for surgery can be considered.

Isolated groin recurrence in vulval squamous cell cancer (VSCC). The importance of node count.

OBJECTIVE: To determine whether there is a node count which can define an adequate inguinofemoral lymphadenectomy (IFL) in primary VSCC. METHODS: A retrospective and prospective review of patients with node negative VSCC who had a full staging IFL. Detection of isolated groin recurrences (IGR) would allow groins with higher risk of groin recurrence to be identified. RESULTS: The median node count of 228 IFLs in 139 patients was eight (0-24). There were six IGR (4.3%). Increased rate of IGR was present in patients with increased age, tumour diameter and depth of invasion, lymphovascular space invasion, unilateral IFL, and moderate/poor tumour grade. In the 138 groins with node counts of eight or greater there were no IGRs compared to six in the patients with either undissected groins or groin node counts less than eight (p = 0.030) Interval to IGR was significantly shorter than other sites of recurrence. Both disease-specific and overall survival were significantly reduced in IGR. CONCLUSIONS: An inadequate IFL is a nodal count of less than eight per groin; both these groins and undissected groins are at increased risk of IGR and should have close surveillance.

Correlative fluorescence and transmission electron microscopy: an elegant tool to study the actin cytoskeleton of whole-mount (breast) cancer cells.

Elucidating the structure and dynamics of lamellipodia and filopodia in response to different stimuli is a topic of continuing interest in cancer cells as these structures may be attractive targets for therapeutic purposes. Interestingly, a close functional relationship between these actin-rich protrusions and specialized membrane domains has been recently demonstrated. The aim of this study was therefore to investigate the fine organization of these actin-rich structures and examine how they structurally may relate to detergent-resistant membrane (DRM) domains in the MTLn3 EGF/serum starvation model. For this reason, we designed a straightforward and alternative method to study cytoskeleton arrays and their associated structures by means of correlative fluorescence (/laser)- and electron microscopy (CFEM). CFEM on whole mounted breast cancer cells revealed that a lamellipodium is composed of an intricate filamentous actin web organized in various patterns after different treatments. Both actin dots and DRM's were resolved, and were closely interconnected with the surrounding cytoskeleton. Long actin filaments were repeatedly observed extending beyond the leading edge and their density and length varied after different treatments. Furthermore, CFEM also allowed us to demonstrate the close structural association of DRMs with the cytoskeleton in general and the filamentous/dot-like structural complexes in particular, suggesting that they are all functionally linked and consequently may regulate the cell's fingertip dynamics. Finally, electron tomographic modelling on the same CFEM samples confirmed that these extensions are clearly embedded within the cytoskeletal matrix of the lamellipodium.

A phase III randomized, double-blind, placebo-controlled trial of gabapentin in the management of hot flashes in men (N00CB).

INTRODUCTION: Hot flashes represent a significant problem in men undergoing androgen deprivation therapy. MATERIALS AND METHODS: Via a prospective, double-blind, placebo-controlled clinical trial, men with hot flashes, on a stable androgen deprivation therapy program for prostate cancer, received a placebo or gabapentin at target doses of 300, 600, or 900 mg/day. Hot flash frequencies and severities were recorded daily during a baseline week and for 4 weeks while the patients took the study medication. RESULTS: In the 214 eligible patients who began the study drug on this trial, comparing the fourth treatment week to the baseline week, mean hot flash scores decreased in the placebo group by 4.1 units and in the three increasing dose gabapentin groups by, 3.2, 4.6, and 7.0 units. Comparing the three combined gabapentin arms to the placebo arm did not result in significant hot flash differences. Wilcoxon rank-sum P values for change in hot flash scores and frequencies after 4 weeks of treatment were 0.10 and 0.02, comparing the highest dose gabapentin arm to the placebo arm, respectively. The gabapentin was well tolerated in this trial. CONCLUSION: These results support that gabapentin decreases hot flashes, to a moderate degree, in men with androgen ablation-related vasomotor dysfunction.

An unusual cause of collapse and neck pain.

Following a collapse at home, a previously well 24-year-old Ukrainian man living in Ireland was brought to the emergency department. He complained of neck pain and cervical spine radiographs revealed loss of lordosis, scalloping of the posterior vertebral bodies and widening of the neural exit foramina at C7. In view of these unusual radiological findings, further examination of the patient demonstrated multiple flat uniformly hyperpigmented brown macules with multiple subcutaneous well-circumscribed lesions along the distribution of the peripheral nerves. An MRI scan of the neck revealed multiple neurofibromas in the vertebral canal with cord compression at C7-T1. A diagnosis of neurofibromatosis type 1 was made. Other investigations to determine the aetiology of the collapse were normal and the patient was discharged with follow-up at specialist neurology and neurosurgical clinics. In recent years there have been increased numbers of economic migrants presenting to the emergency department in the UK and Ireland from European Union accession states. This case highlights the need for increased awareness among emergency physicians to previously undiagnosed genetic and congenital conditions.