Mid-urethral sling revision for mesh exposure-long-term outcomes of two surgical techniques from a comparative clinical retrospective cohort study.

OBJECTIVE: To compare vaginal closure with versus without sling excision in the management of vaginal sling exposure following mid-urethral sling (MUS). DESIGN: Clinical retrospective cohort study. SETTING: Tertiary urogynaecological centre in Australia. POPULATION: Women with urodynamic stress urinary incontinence (SUI) who had a MUS (n = 2823) during 1999-2017 with a follow-up period up to December 2018. Thirty-three women (1%) had sling exposure and 31 required surgical intervention (1%). METHODS: Clinical review with analysis of surgical database and patient records. MAIN OUTCOME MEASURES: The primary outcome was successful closure and resolution of exposure-related symptoms without the need for re-surgery. Secondary outcomes were repeat procedure and recurrent incontinence following revision. RESULTS: Mean follow up was 103 months. Of the 20 women with a primary excision and closure approach, 19 had successful closure. Seven of 11 women with simple vaginal closure without excision needed another surgery for recurrent mesh exposure. Recurrence of stress incontinence did not occur in any of the four who had 'successful' closure without excision. Of those who had sling division/removal without a concomitant stress continence procedure, 32% (7/22) required further surgery. CONCLUSION: Sling excision and repair have better outcomes with less recurrence of sling exposure compared with simple closure. Following sling removal, one of three women will develop SUI recurrence and require surgery. TWEETABLE ABSTRACT: #Slingexcision &repair leads to less recurrence of exposure versus #simpleclosure for #slingmeshexposure.

Video and review of the surgical management of recurrent urethral diverticulum.

INTRODUCTION: Recurrent urethral diverticulum has been reported in 23% of cases after primary repair and can be difficult to manage. The aim of this video is to demonstrate a surgical technique of repairing a recurrent diverticulum in a woman who had two previous procedures, one with a Martius labial fat pad graft. METHODS: A 40-year-old woman presented with a symptomatic recurrent urethral diverticulum after two previous repairs. She underwent surgery with excision of the diverticular mucosa and multilayer urethral closure using the diverticulum wall after mobilization and then repositioning of the Martius labial fat pad interposition. RESULTS: There were no surgical complications intra- or postoperatively, and the patient had improvement of her symptoms postoperatively with resolution of the diverticulum on ultrasound. CONCLUSIONS: Mobilizing and repositioning a Martius labial fat pad is a feasible technique for complex recurrent urethral diverticulum repairs. The graft alone without meticulous urethral repair will not prevent diverticulum recurrence, fistula formation or stress urinary incontinence. This procedure requires experienced surgeons to minimize surgical complications and optimize outcome.

Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q.

BACKGROUND: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors. METHODS: Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed. RESULTS: Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0-9; unknown in one patient). Median HER2 CN was 17 (range 7-139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay. CONCLUSION: T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials.

Extraperitoneal uterosacral suspension technique for post hysterectomy apical prolapse in 472 women: results from a longitudinal clinical study.

OBJECTIVES: The study aims to evaluate the long-term results of the extraperitoneal uterosacral ligament suspension (bilateral) technique in women with apical prolapse following hysterectomy. DESIGN: Longitudinal clinical follow up conducted between June 2002 and December 2017. SETTING: Tertiary urogynaecology centre in Melbourne, Australia. POPULATION: A total of 472 women with symptomatic vault prolapse who underwent bilateral extraperitoneal uterosacral ligament suspension (EPUSLS). Of these patients, 61% (287/472) had previously had a procedure for pelvic organ prolapse (POP). METHODS: Follow up using structured, standardised questionnaires and examination by POP-Q and Baden-Walker system pre- and postoperatively. MAIN OUTCOME MEASURES: Functional and anatomical results and surgical complications. RESULTS: Mean follow-up duration was approximately 5 years. The objective success rate at vaginal cuff support was 89% (420/472). Only 4% needed revision surgery for vault recurrence. There was improvement in bladder, bowel, and sexual symptoms after the procedure. Mesh exposure rate was 17% (of the 138 having mesh augmentation), with the majority of cases managed conservatively or with minor interventions. The ureteric injury rate was 1% and mainly occurred in patients operated early on in the series. No women had buttock pain. CONCLUSION: EPUSLS is an effective, suture-based procedure for vault prolapse with few complications even on long-term follow up. This technique avoids the need to open the peritoneum vaginally and has a low risk of ureteric injury and gluteal pain. TWEETABLE ABSTRACT: Bilateral extraperitoneal USL suspension of vault is effective with low morbidity and a high success rate.

Phase 2 placebo-controlled, double-blind trial of dasatinib added to gemcitabine for patients with locally-advanced pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate with limited treatment options. Gemcitabine provides a marginal survival benefit for patients with advanced PDAC. Dasatinib is a competitive inhibitor of Src kinase, which is overexpressed in PDAC tumors. Dasatinib and gemcitabine were combined in a phase 1 clinical trial where stable disease was achieved in two of eight patients with gemcitabine-refractory PDAC. Patients and methods: This placebo-controlled, randomized, double-blind, phase II study compared the combination of gemcitabine plus dasatinib to gemcitabine plus placebo in patients with locally advanced, non-metastatic PDAC. Patients received gemcitabine 1000 mg/m2 (30-min IV infusion) on days 1, 8, 15 of a 28-day cycle combined with either 100 mg oral dasatinib or placebo tablets daily. The primary objective was overall survival (OS), with safety and progression-free survival (PFS) as secondary objectives. Exploratory endpoints included overall response rate, freedom from distant metastasis, pain and fatigue progression and response rate, and CA19-9 response rate. Results: There was no statistically significant difference in OS between the two treatment groups (HR = 1.16; 95% confidence interval [CI]: 0.81-1.65; P = 0.5656). Secondary and exploratory endpoint analyses also showed no statistically significant differences. The burden of toxicity was higher in the dasatinib arm. Conclusions: Dasatinib failed to show increased OS or PFS in patients with locally advanced PDAC. Alternative combinations or trial designs may show a role for src inhibition in PDAC treatment.

The effects of mode delivery on postpartum sexual function: a prospective study.

OBJECTIVE: To determine the effect of mode of delivery and perineal injury on sexual function at 6 and 12 months postpartum. DESIGN: Prospective cohort study. SETTING: Tertiary women's hospital in Melbourne, Australia. POPULATION: A cohort of 440 primigravid women. METHODS: The Female Sexual Function Index (FSFI) was completed at first visit (7-19 weeks of gestation), and at 6 and 12 months postpartum. MAIN OUTCOME MEASURES: A statistically significant difference in total FSFI or domain scores over time according to mode of delivery or perineal injury. RESULTS: In this cohort 54% of women had a normal vaginal delivery, 21% had an instrumental delivery, and 25% gave birth by caesarean section. No difference was found in total FSFI or domain scores according to mode of delivery over time between antenatal assessment and 12 months postpartum. Pain was decreased in the caesarean group only at 6 months postpartum. All groups showed pain scores at 12 months that were comparable with antenatal levels. For those who gave birth vaginally, 27% had an intact perineum, 50% had an episiotomy, and 6%, 14%, and 3% had first, second, and third-degree tears, respectively. The only differences between groups were found over time according to perineal injury at 6 months in the arousal domain. At 12 months, total FSFI and domain scores were no different to initial scores. CONCLUSIONS: At 12 months postpartum sexual function has returned to early pregnancy levels, irrespective of mode of delivery or perineal injury.

'Treatment of the sportsman's groin': British Hernia Society's 2014 position statement based on the Manchester Consensus Conference.

INTRODUCTION: The aim was to produce a multidisciplinary consensus to determine the current position on the nomenclature, definition, diagnosis, imaging modalities and management of Sportsman's groin (SG). METHODS: Experts in the diagnosis and management of SG were invited to participate in a consensus conference held by the British Hernia Society in Manchester, U.K. on 11-12 October 2012. Experts included a physiotherapist, a musculoskeletal radiologist and surgeons with a proven track record of expertise in this field. Presentations detailing scientific as well as outcome data from their own experiences were given. Records were made of the presentations with specific areas debated openly. RESULTS: The term 'inguinal disruption' (ID) was agreed as the preferred nomenclature with the term 'Sportsman's hernia' or 'groin' rejected, as no true hernia exists. There was an overwhelming agreement of opinion that there was abnormal tension in the groin, particularly around the inguinal ligament attachment. Other common findings included the possibility of external oblique disruption with consequent small tears noted as well as some oedema of the tissues. A multidisciplinary approach with tailored physiotherapy as the initial treatment was recommended with any surgery involving releasing the tension in the inguinal canal by various techniques and reinforcing it with a mesh or suture repair. A national registry should be developed for all athletes undergoing surgery. CONCLUSIONS: ID is a common condition where no true hernia exists. It should be managed through a multidisciplinary approach to ensure consistent standards and outcomes are achieved.

A phase II trial of gemcitabine, irinotecan and panitumumab in advanced cholangiocarcinoma.

BACKGROUND: Current data suggest that chemotherapy combinations may be superior to single agents in biliary tract cancer. The epidermal growth factor receptor (EGFR) pathway appears to be associated with tumor stage, prognosis and response to therapy. This trial was designed to evaluate the tolerability and efficacy of the combination of panitumumab, a monoclonal anti-EGFR antibody, with gemcitabine and irinotecan. PATIENTS AND METHODS: Patients with advanced (unresectable or metastatic) cholangiocarcinoma, ECOG PS 0-2, and adequate organ function were treated with panitumumab (9 mg/kg) on day 1, and gemcitabine (1000 mg/m(2)) and irinotecan (100 mg/m(2)) on days 1 and 8 of a 21-day cycle. The primary objective was to evaluate the 5-month progression-free survival (PFS). Secondary objectives included overall response rate (ORR) and overall survival (OS). Mutational analyses of EGFR, KRAS and BRAF were carried out when feasible. RESULTS: Thirty-five patients received a median of 7 (0-30) cycles. The most common grade 3/4 toxic effects were neutropenia (10 patients, 29%), thrombocytopenia (10 patients, 29%), skin rash (13 patients, 37%) and dehydration (9 patients, 26%). Two patients had CR, 9 had partial response (PR), and 15 had SD for a disease-control rate of 74% (by RECIST) in 28 assessable patients. Two patients went on to have surgical resection. The 5-month PFS was 69%. The median PFS was 9.7 months and the median OS was 12.9 months. In 17 testable samples, no EGFR or BRAF mutations were identified; there were 7 KRAS mutations, with no difference in OS by KRAS status. CONCLUSIONS: This study showed encouraging efficacy of this regimen with good tolerability. Further study in this area is warranted. Clinical Trials Number: The trial was registered with the National Cancer Institute (www.clinicaltrials.gov identifier NCT00948935).

Health service cost associated with percutaneous vertebroplasty in patients with spinal metastases.

AIMS: To ascertain prospectively the health service cost of vertebroplasty in a cohort of consecutive patients with spinal metastases. MATERIALS AND METHODS: Percutaneous vertebroplasty was performed under conscious sedation and local anaesthetic in the Interventional Suite with fluoroscopic guidance. Data were collected prospectively on standard forms. Quality of life questionnaires (EQ-5D) were filled out pre-, 6 weeks, and at 6 months post-vertebroplasty. RESULTS: The majority of the procedures were performed on an outpatient basis (8/11). The median duration of the procedure was 60 min (range 40-80 min) with a further 60 min spent in the recovery room (range 10-230 min). Personnel involved included a consultant radiologist, a radiology registrar, four nurses, and two radiographers. The average cost of vertebroplasty per patient, including consumables, capital equipment, hotel/clinic costs, and staffing, was £2213.25 (95% CI £729.95). The mean EQ-5D utility scores increased from 0.421 pre-treatment to 0.5979 post-treatment (p = 0.047). The visual analogue scale (VAS) of perceived health improved from a mean of 41.88 to 63.75 (p = 0.00537). CONCLUSION: Health service costs for percutaneous vertebroplasty in patients with spinal metastases is significantly lower than previously estimated and is in keeping with that of other palliative radiological procedures.

Where to for pelvic organ prolapse treatment after the FDA pronouncements? A systematic review of the recent literature.

INTRODUCTION: With the publication of the updated US Food and Drug Administration (FDA) communication in 2011 on the use of transvaginal placement of mesh for pelvic organ prolapse (POP) it is appropriate to now review recent studies of good quality on POP to assess the safety and effectiveness of treatment options and determine their place in management. METHODS: A systematic search for studies on the conservative and surgical management of POP published in the English literature between January 2002 and October 2012 was performed. Studies included were review articles, randomized controlled trials, prospective and relevant retrospective studies as well as conference abstracts. Selected articles were appraised by the authors regarding clinical relevance. RESULTS: Prospective comparative studies show that vaginal pessaries constitute an effective and safe treatment for POP and should be offered as first treatment of choice in women with symptomatic POP. However, a pessary will have to be used for the patient's lifetime. Abdominal sacral colpopexy is effective in treating apical prolapse with an acceptable benefit-risk ratio. This procedure should be balanced against the low but non-negligible risk of serious complications. The results of native tissue vaginal POP repair are better than previously thought with high patient satisfaction and acceptable reoperation rates. The insertion of mesh at the time of anterior vaginal wall repair reduces the awareness of prolapse as well as the risk of recurrent anterior prolapse. There is no difference in anatomic and subjective outcome when native tissue vaginal repairs are compared with multicompartment vaginal mesh. Mesh exposure is still a significant problem requiring surgical excision in approximately ≥ 10 % of cases. The ideal mesh has not yet been found necessitating more basic research into mesh properties and host response. Several studies indicate that greater surgical experience is correlated with fewer mesh complications. In women with uterovaginal prolapse uterine preservation is a feasible option which women should be offered. Randomized studies with long-term follow-up are advisable to establish the place of uterine preservation in POP surgery. CONCLUSION: Over the last decade treatment of POP has been dominated by the use of mesh. Conservative treatment is the first option in women with POP. Surgical repair with or without mesh generally results in good short-term objective and functional outcomes. However, basic research into mesh properties with host response and comparative studies with long-term follow-up are urgently needed.

Complications in pelvic floor surgery.

Pelvic floor disorders affect the quality of life of millions of women worldwide. Many options exist for the treatment of pelvic organ prolapse and urinary incontinence, surgery being one of the main strategies in the management of these conditions. Even though uncommon, all surgery has complications which can cause morbidity and rarely mortality. These complications can impair quality of life in the long-term and be a financial burden on both the patient and the health care system. Pelvic floor reconstructive surgery includes perioperative complications such as injury to neighboring organs, hemorrhage and infection. Recently the International Urogynecology Association and the International Continence Society have proposed a terminology and classification of complications related to female pelvic floor surgery, both using native tissue and synthetic implants to improve surgical audit and aid comparison between studies on pelvic floor procedures. Long-term complications such as pelvic pain and dyspareunia may be as high as 25%. Prolapse surgery associated with mesh may result in better anatomical outcomes but this is offset by the high complication rate, particularly that of mesh exposure which has been reported to be between 3-15%. Minimally invasive anti-incontinence procedures are associated with less morbidity than their abdominal predecessors but they are not free of complications. Complications of mid-urethral slings include those of mesh exposure (0.3%), voiding dysfunction (7%) and de novo urgency (25%). The risk and severity of complications varies depending on the procedure performed and on patient characteristics and, therefore, patients need to be informed of these risks or clinicians will be held responsible. This has never been more true than now with the debate regarding the value of transvaginal mesh and laparoscopic procedures for prolapse, their risks and potential benefits, and the associated medico-legal sequelae.

Resection of focally progressive gastrointestinal stromal tumours resistant to imatinib therapy.

AIMS: To analyse the outcome of patients with gastrointestinal stromal tumour (GIST) who receive imatinib therapy and undergo subsequent resection of focally progressive disease. METHODS: We reviewed the records of all cases of GIST discussed at the West of Scotland Sarcoma regional multi-disciplinary team meeting between January 2002 and December 2009 inclusive. We analysed all patients who had undergone surgery for progressive disease on imatinib therapy. Focally progressive disease was diagnosed on computated tomography (CT) and positron-emission tomography-CT and was defined by a GIST lesion initially responsive to imatinib therapy but then underwent growth with evidence of metabolic activity. All procedures were undertaken in a university teaching hospital by a single surgeon. RESULTS: Nine patients were identified who underwent ten resections of focally progressive GIST. Six had previously undergone resection of their primary tumour while three had presented with un-resectable disease. Nine operations were for resection of a solitary progression while one operation was for three foci of progression. Five patients underwent liver resection which was confined to the segments were there was focal progression of GIST; of these one patient had multiple liver metastases and portal hypertension with a mass at the porta hepatis. The absolute survival for patients after resection was 18.4±13.7 months (mean±standard deviation), with progression free survival of 14.1±13.5 months equating to 56% at 1-year. Four patients had been switched from imatinib to sunitinib, for further multi-focal progression. CONCLUSIONS: Surgical resection of focally progressive GIST may prolong survival and a second or third resection is a feasible option in selected patients.

Long term outcome and elasticity of a polyester mesh used for laparoscopic ventral hernia repair.

BACKGROUND: Repair of a ventral hernia is increasingly being performed by a laparoscopic approach despite lack of good long term follow up data on outcomes. The aim of this study was to examine the long term performance of a polyester mesh and to assess its elastic properties in patients undergoing laparoscopic ventral hernia repair. METHODS: All patients being assessed for a ventral hernia repair between August 2011 and November 2013 were placed on a prospective database. Those undergoing laparoscopic repair with a polyester mesh were seen at clinic at one month and one year, while their electronic records were assessed at 34 months (range 24-48 months) and 104 months (range 92-116 months). In addition, CT scans of the abdomen and pelvis performed for any reason on these patients during the follow up period were reviewed by a consultant gastrointestinal radiologist. Mechanical failure testing of the mesh was also performed. RESULTS: Thirty-two of the 100 patients assessed for ventral hernia repair had a laparoscopic repair with a polyester mesh. Nineteen (59%) had CT scans performed during the follow-up period. No recurrence was recorded at 34 months, while three (9.4%) had a recurrence at 104 months. Two had central breakdown of the mesh at 81 and 90 months, while 1 presented acutely at 116 months after operation. Mesh had stretched across the defect by an average of 21% (range 5.7-40%) in nine patients. Mechanical testing showed that this mesh lost its elasticity at low forces ranging between 1.8 and 3.2 N/cm. CONCLUSION: This study shows that late recurrence is a problem following laparoscopic ventral hernia repair with polyester mesh. The mesh loses it elasticity at a low force. This combined with degradation of mesh seems the most likely cause of failure. This is unlikely to be a unique problem of polyester mesh and further long-term studies are required to better assess this operative approach to ventral hernia repair.

Subcutaneous and visceral adipose tissue in patients with primary and recurrent incisional hernia.

PURPOSE: Visceral obesity rather than body mass index has been reported to be associated with a higher incidence of incisional hernias. The aim of this study was to examine the relationship between CT measured adipose tissue and muscle in primary and recurrent incisional hernia. METHODS: Patients with a 'Primary' or 'Recurrent incisional hernia' were obtained from a prospective cohort of patients who were being assessed for incisional hernia repair over a 2-year period. Computerised tomography (CT)-images were analysed using NIH Image-J software to quantify adipose tissue and skeletal muscle cross-sectional areas at the level of lumber vertebra 3/4 using standard Hounsfield units. To test inter-observer 'absolute agreement', each parameter was measured independently by two investigators and reliability analysis performed. RESULTS: Thirty-six patients were included in the study: 15 had a Primary while 21 had a Recurrent incisional hernia. Both groups had similar baseline characteristics. Reliability analysis for CT-measured areas showed very high interclass correlation coefficient (ICC) between observers. Patients in the recurrent group had significantly greater subcutaneous adipose tissue (SAT) [median = 321.9cm2 vs 230.9cm2, p = 0.04] and visceral adipose tissue (VAT) [median = 221.1cm2 vs 146.8cm2, p = 0.03] than those in the primary group. There was no difference in skeletal muscle areas for right [median = 2.8cm2 vs 2.9cm2] and left [median = 3.7cm2 vs 4.1cm2] rectus muscles between groups. CONCLUSION: Our study shows that patients with a recurrent incisional hernia have significantly more subcutaneous and visceral adipose tissue than those with a primary incisional hernia. Further studies in this area are required if we are to reduce the burden of recurrent hernia following repair of a primary incisional hernia.

MODUL cohort 2: an adaptable, randomized, signal-seeking trial of fluoropyrimidine plus bevacizumab with or without atezolizumab maintenance therapy for BRAFwt metastatic colorectal cancer.

BACKGROUND: MODUL is an adaptable, signal-seeking trial designed to test novel agents in predefined patient subgroups in first-line metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with measurable, unresectable, previously untreated mCRC received induction with ≤8 cycles of FOLFOX + bevacizumab followed by randomization to maintenance treatment comprising control [fluoropyrimidine (FP)/bevacizumab: 5-fluorouracil 1600-2400 mg/m2 46-h intravenous (i.v.) infusion day 1 q2 weeks plus leucovorin 400 mg/m2 2-h infusion i.v. day 1 q2 weeks or capecitabine 1000 mg/m2 b.i.d. orally days 1-14 every 21 days; bevacizumab 5 mg/kg 15-30-min i.v. infusion q2 weeks] or experimental treatment in one of four biomarker-driven cohorts. In patients with BRAF wild-type (BRAFwt) tumors (cohort 2), experimental treatment was FP/bevacizumab + atezolizumab (800 mg 60-min i.v. infusion q2 weeks). Primary efficacy endpoint was progression-free survival (PFS; intent-to-treat population). Enrollment is complete; efficacy and safety findings from cohort 2 are presented. RESULTS: Four hundred and forty-five patients with BRAFwt mCRC were randomized (2 : 1) to maintenance in cohort 2. At a median follow-up of 10.5 months, PFS outcome hypothesis was not met [hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.72-1.17; P = 0.48]; overall survival (OS) was immature. At a median follow-up of 20.3 months (2-year survival follow-up), PFS benefit was also not met (HR 0.95; 95% CI 0.77-1.18; P = 0.666); OS HR with nearly two-thirds of patients with events was 0.83 (95% CI 0.65-1.05; P = 0.117). No new safety signals were identified. The most common grade ≥3 treatment-emergent adverse events (TEAEs) for experimental versus control arms were hypertension (6.1% versus 4.2%), diarrhea (3.1% versus 2.1%), and palmar-plantar erythrodysesthesia syndrome (1.0% versus 2.5%). Four patients experienced TEAEs with fatal outcome, two were study treatment-related: hepatic failure (experimental arm) and large intestine perforation (control arm; bevacizumab-related). CONCLUSIONS: Adding atezolizumab to FP/bevacizumab as first-line maintenance treatment after FOLFOX + bevacizumab induction for BRAFwt mCRC did not improve efficacy outcomes.

Crizotinib in patients with tumors harboring ALK or ROS1 rearrangements in the NCI-MATCH trial.

The NCI-MATCH was designed to characterize the efficacy of targeted therapies in histology-agnostic driver mutation-positive malignancies. Sub-protocols F and G were developed to evaluate the role of crizotinib in rare tumors that harbored either ALK or ROS1 rearrangements. Patients with malignancies that progressed following at least one prior systemic therapy were accrued to the NCI-MATCH for molecular profiling, and those with actionable ALK or ROS1 rearrangements were offered participation in sub-protocols F or G, respectively. There were five patients who enrolled on Arm F (ALK) and four patients on Arm G (ROS1). Few grade 3 or 4 toxicities were noted, including liver test abnormalities, and acute kidney injury. For sub-protocol F (ALK), the response rate was 50% (90% CI 9.8-90.2%) with one complete response among the 4 eligible patients. The median PFS was 3.8 months, and median OS was 4.3 months. For sub-protocol G (ROS1) the response rate was 25% (90% CI 1.3-75.1%). The median PFS was 4.3 months, and median OS 6.2 months. Data from 3 commercial vendors showed that the prevalence of ALK and ROS1 rearrangements in histologies other than non-small cell lung cancer and lymphoma was rare (0.1% and 0.4% respectively). We observed responses to crizotinib which met the primary endpoint for ALK fusions, albeit in a small number of patients. Despite the limited accrual, some of the patients with these oncogenic fusions can respond to crizotinib which may have a therapeutic role in this setting.

Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1).

BACKGROUND: This phase I, open-label, first-in-human study determined dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PD 0332991, an oral cyclin-dependent kinase 4/6 inhibitor with potent anti-proliferative activity in vitro/vivo. METHODS: A total of 33 patients with retinoblastoma protein-positive advanced solid tumours or non-Hodgkin's lymphoma refractory to standard therapy or for which no therapy was available received PD 0332991 once daily (QD) for 14 days followed by 7 days off treatment (21-day cycles; Schedule 2/1). RESULTS: Six patients had DLTs (18%; four receiving 200 mg QD; two receiving 225 mg QD); the MTD was 200 mg QD. Treatment-related, non-haematological adverse events occurred in 29 patients (88%) during cycle 1 and 27 patients (82%) thereafter. Adverse events were generally mild-moderate. Of 31 evaluable patients, one with testicular cancer achieved a partial response; nine had stable disease (≥10 cycles in three cases). PD 0332991 was slowly absorbed (mean T(max) 4.2 h) and eliminated (mean half-life 26.7 h). Volume of distribution was large (mean 3241 l) with dose-proportional exposure. Using a maximum effective concentration model, neutropenia was proportional to exposure. CONCLUSION: PD 0332991 was generally well tolerated, with DLTs related mainly to myelosuppression. The MTD, 200 mg QD, is recommended for phase II study.

Long-term follow-up of patients with a painless inguinal hernia from a randomized clinical trial.

BACKGROUND: Up to one-third of patients with an inguinal hernia have no symptoms from the hernia. The aim of this study was to determine the long-term outcome of patients with a painless inguinal hernia randomized to observation or operation. METHODS: Some 160 men aged 55 years or more with a painless inguinal hernia were randomized to observation or operation between 2001 and 2003. All were invited to attend a research clinic at 6 and 12 months, and 5 years after randomization. Those unable to attend for clinical review were sent a questionnaire based on the clinical review pro forma. RESULTS: After a median follow-up of 7.5 (range 6.2-8.2) years, 42 men had died (19 in the observation and 23 in the operation group); 46 of the 80 men randomized to observation had conversion to operation. The estimated conversion rate (using the Kaplan-Meier method) for the observation group was 16 (95 per cent confidence interval 9 to 26) per cent at 1 year, 54 (42 to 66) per cent 5 years and 72 (59 to 84) per cent at 7.5 years. The main reason for conversion was pain in 33 men, and two presented with an acute hernia. Sixteen men developed a new primary contralateral inguinal hernia and three had recurrent hernias. There have been 90 inguinal hernia repairs in the 80 patients randomized to surgery compared with 56 in those randomized to observation. CONCLUSION: Most patients with a painless inguinal hernia develop symptoms over time. Surgical repair is recommended for medically fit patients with a painless inguinal hernia.