A phase II trial of bevacizumab and rucaparib in recurrent carcinoma of the cervix or endometrium.

OBJECTIVE: The aim of this study was to examine the tolerability and efficacy of combination bevacizumab rucaparib therapy in patients with recurrent cervical or endometrial cancer. PATIENTS & METHODS: Thirty-three patients with recurrent cervical or endometrial cancer were enrolled. Patients were required to have tumor progression after first line treatment for metastatic, or recurrent disease. Rucaparib was given at 600 mg BID twice daily for each 21-day cycle. Bevacizumab was given at 15 mg/kg on day 1 of each 21-day cycle. The primary endpoint was efficacy as determined by objective response rate or 6-month progression free survival. RESULTS: Of the 33 patients enrolled, 28 were evaluable. Patients with endometrial cancer had a response rate of 17% while patients with cervical cancer had a response rate of 14%. Median progression free survival was 3.8 months (95% C·I 2.5 to 5.7 months), and median overall survival was 10.1 months (95% C·I 7.0 to 15.1 months). Patients with ARID1A mutations displayed a better response rate (33%) and 6-month progression free survival (PFS6) rate (67%) than the entire study population. Observed toxicity was similar to that of previous studies with bevacizumab and rucaparib. CONCLUSIONS: The combination of bevacizumab with rucaparib did not show significantly increased anti-tumor activity in all patients with recurrent cervical or endometrial cancer. However, patients with ARID1A mutations had a higher response rate and PFS6 suggesting this subgroup may benefit from the combination of bevacizumab and rucaparib. Further study is needed to confirm this observation. No new safety signals were seen.

Relighting behaviour among cigarette smokers seeking treatment: implications for tobacco treatment and policy.

AIMS: During the recent economic downturn, trends towards fewer cigarettes smoked per day have emerged along with the practice of extinguishing and relighting cigarettes. Few studies have characterised factors related to relighting cigarettes and none have explored this behaviour in those seeking tobacco treatment. This study describes treatment-seeking patients who relight cigarettes and examines implications on tobacco policy and treatment. METHODS: Data were collected from a cross-sectional sample of 496 patients at a specialty tobacco treatment programme in New Jersey from 2010 to 2012. RESULTS: Forty-six per cent of the sample reported relighting, and those subjects smoked significantly fewer cigarettes per day (CPD), despite similar levels of dependence and exhaled carbon monoxide (CO) values. In unadjusted analyses, significantly higher rates of relighting were found among females, African-Americans, smokers who had a high school diploma or less, and were unemployed, sick or disabled. Relighting was more prevalent among smokers with higher markers of dependence, menthol smoking and night smoking. In multivariate analyses, markers of dependence and economic factors (employment and education) remained significant. CONCLUSIONS: Characteristics linked to economic factors were related to increased relighting. Implications for tobacco treatment include the impact on pharmacotherapy dosing and counselling interventions. The tobacco control community needs to be aware of this phenomenon. Collecting data on 'smoking sessions per day' might be a more accurate depiction of smoking exposure than CPD.

Does elastography reduce the need for thyroid FNAs?

OBJECTIVE: Ultrasound elastography (USE) assesses lesion stiffness by evaluating tissue distortion in response to stress; it is emerging as a potentially useful tool to augment the ultrasound characterisation of thyroid nodules. The aim of this study was to assess the accuracy of USE examination of thyroid nodules compared with pathological outcome, especially to determine whether USE could reliably detect benign nodules and reduce the numbers of ultrasound guided fine needle aspiration cytology (USgFNAC). DESIGN: Over a three-year period, thyroid nodules were initially characterised by B-mode ultrasound (US) findings. Where USgFNAC was indicated by clinical concern and/or the sonographic appearances, the lesion was then subjected to USE by an experienced operator prior to the USgFNAC. PATIENTS: 147 thyroid nodules were examined by USE and USgFNAC in 146 patients. MEASUREMENTS: The elastographic appearance was subjectively categorized at the time of the examination (soft, intermediate or hard) and subsequently compared with the cytological/histological outcome. RESULTS: A total of 122 nodules were non-neoplastic, 5 nodules were benign neoplasms, 10 nodules had indeterminate cytology and 10 were malignant neoplasms. The sensitivity of USE for malignancy was 90.0%, specificity was 79.6%, PPV was 24.3%, NPV was 99.1% and accuracy was 80.3%. CONCLUSION: Thyroid nodules that are soft at USE have a high likelihood of being non-neoplastic and subjective USE assessment of thyroid nodules by an experienced operator can be a useful means of avoiding USgFNAC for benign nodules. In contrast, we suggest that all nodules that are intermediate or hard on USE undergo USgFNAC.

The development and evolution of a tertiary pancreaticobiliary endoscopic ultrasound service: lessons learned.

This article reviews the development of the hepatopancreatobiliary (HPB) endoscopic ultrasound (EUS) service at Freeman Hospital and seeks to identify from our experience learning points for good practice and pitfalls to avoid. The Freeman HPB EUS service has expanded rapidly over the past 10 years in response to the consolidation of cancer care and aligned to the needs of the cancer network. Effective multidisciplinary teamwork and increased subspecialisation by the endosonographers has allowed the efficient use of capacity and development of skills. Mechanisms for monitoring diagnostic performance put in place at the outset of the EUS-fine needle aspiration programme have helped to identify interventions that have led to improved test performance. An excellent working relationship between all stakeholders is critical to the success of such a service as is a preparedness to seek and respond to the views of patients and referrers.

Which factors predict bowel complications in patients with recurrent epithelial ovarian cancer being treated with bevacizumab?

BACKGROUND: Increased rates of bowel perforation in patients with recurrent epithelial ovarian cancer (EOC) treated with bevacizumab have been reported, but the risk factors for this association are uncertain. We sought to identify factors associated with bowel perforation and fistula formation in recurrent EOC patients treated with bevacizumab. METHODS: A chart review of all patients treated with bevacizumab for recurrent EOC at a single institution was performed. Pertinent patient characteristics and treatment information were collected. Univariate logistic regression was performed to analyze multiple variables. RESULTS: One hundred twelve patients who were treated with 160 different bevacizumab regimens were identified. The median age was 60 years (range, 29-78 years). Patients had received a median of 4 prior chemotherapy regimens (range, 1-10). The median number of cycles was 4 (range, 0.5-31). Ten patients (9%) were diagnosed with bowel perforations, and another 2 patients (1.8%) were diagnosed with fistulas. The 30-day mortality following perforation was 50%, with 30% of patients dying within 1 week. Patients with rectovaginal nodularity were more likely to develop a bowel perforation or fistula than those who did not have this finding, OR=3.64 (95% CI=1.1 to 12.1, p=0.04). None of the other variables were significantly associated with bowel perforations or fistula formation. CONCLUSIONS: Rectovaginal nodularity is associated with an increased risk of bowel perforation or fistula formation for patients with recurrent EOC treated with bevacizumab. Careful consideration should be given prior to initiating bevacizumab treatment in EOC patients with rectovaginal nodularity since the mortality rate with bevacizumab associated bowel perforations is 50%.

Sustained progression-free survival with weekly paclitaxel and bevacizumab in recurrent ovarian cancer.

OBJECTIVE: To determine efficacy, toxicity, and survival in patients with recurrent epithelial ovarian cancer (EOC) receiving combination of weekly paclitaxel and biweekly bevacizumab (PB). METHODS: We reviewed chemotherapy logs identifying all patients receiving combination PB. Toxicities were graded using CTCAEv3.0 criteria. Response rates (RR) were measured using RECIST criteria or by CA-125 levels per modified Rustin criteria. RR and progression-free survival (PFS) were determined and plotted using Kaplan-Meier survival analysis. RESULTS: Fifty-one patients receiving at least two cycles of chemotherapy were evaluable for survival and 55 patients receiving one cycle of PB were evaluable in toxicity analysis. The mean number of previous regimens was four. The overall median PFS was 7 months and median OS was 12 months. The overall response rate (ORR) was 60% (CR 25% and PR 35%). Median PFS for complete and partial responders were 14 and 5 months respectively. Stable disease was seen in 26% with median PFS of 6 months. Thirteen experienced treatment delays for a variety of factors. The most G3/4 toxicities were fatigue (16%), hematologic (9%) and neurotoxicity (7%). Three patients (5%) experienced bowel perforations. CONCLUSIONS: Combination of paclitaxel and bevacizumab is feasible and demonstrates an acceptable toxicity profile and a high response rate. These observations should be useful in planning future clinical trials with this combination therapy.

Comparison of multislice computed tomography and endoscopic ultrasonography with operative and histological findings in suspected pancreatic and periampullary malignancy.

BACKGROUND: This study compared multislice computed tomography (MSCT) with endoscopic ultrasonography (EUS) in the diagnosis and staging of pancreatic and periampullary malignancy. METHODS: Data were collected prospectively on patients having MSCT and EUS for suspected pancreatic and periampullary malignancy. RESULTS: Eighty-four patients had MSCT and EUS, of whom 35 underwent operative assessment (29 resections). In assessing malignancy, there was no significant difference between MSCT and EUS, and agreement was good (82 per cent, kappa = 0.49); the sensitivity and specificity of MSCT were 97 and 87 per cent, compared with 95 and 52 per cent respectively for EUS (P = 0.264). For portal vein/superior mesenteric vein invasion, MSCT was superior (P = 0.017) and agreement was moderate (72 per cent, kappa = 0.42); the sensitivity and specificity were 88 and 92 per cent for MSCT, and 50 and 83 per cent for EUS. For resectability, there was no significant difference and agreement was good (78 per cent, kappa = 0.51). EUS had an impact on the management of 14 patients in whom MSCT suggested benign disease or equivocal resectability. CONCLUSION: MSCT is the imaging method of choice for pancreatic and periampullary tumours. Routine EUS should be reserved for those with borderline resectability on MSCT.

Spontaneous rupture of the oesophagus.

BACKGROUND: The aim of this study was to evaluate the diagnosis, management and outcome of patients with spontaneous rupture of the oesophagus in a single centre. METHODS: Between October 1993 and May 2007, 51 consecutive patients with spontaneous oesophageal rupture were evaluated with contrast radiology and flexible endoscopy. Patients with limited contamination who fulfilled specific criteria were managed by a non-operative approach, whereas the remainder underwent thoracotomy. RESULTS: The median time to diagnosis was 24 (range 4-604) h. Initial diagnosis was by contrast swallow in 18 of 24 patients, computed tomography in 15 of 17 and endoscopy in 18 of 18. There were no deaths among 17 patients who were managed non-operatively with targeted drainage, intravenous antimicrobials, nasogastric decompression and enteral nutrition. Of 31 patients who underwent primary thoracotomy and oesophageal repair (over a Ttube in 29), 11 died in hospital. Three patients could not be resuscitated adequately and did not have surgical intervention. CONCLUSION: Spontaneous oesophageal rupture represents a spectrum of disease. Accurate radiological and endoscopic evaluation can identify those suitable for radical non-operative treatment and those who require thoracotomy.

Endoscopic ultrasonography-detected low-volume ascites as a predictor of inoperability for oesophagogastric cancer.

BACKGROUND: Endoscopic ultrasonography (EUS) can detect low-volume ascites (LVA) not apparent on computed tomography. The aim of this study was to assess the importance of LVA for management of patients with oesophagogastric (OG) cancer. METHODS: Patients with LVA were identified from a prospective OG cancer unit database between January 2002 and January 2006. RESULTS: Of 1118 patients staged with OG cancer, 802 had EUS. The incidence of LVA was 8.4 per cent overall but fell to 6.5 per cent when those with metastases on computed tomography were excluded. Only patients with gastric and OG junction carcinoma had LVA. Staging laparoscopy in the 21 patients with LVA revealed that 11 (52 per cent) were inoperable. The remainder had laparotomy and complete (R0) resection was possible in only five (50 per cent). In 106 patients who had staging laparoscopy after EUS without LVA, 37 (34.9 per cent) were inoperable and 56 of the remaining 69 (81 per cent) had R0 resection. CONCLUSION: The presence of LVA on EUS is uncommon in patients with OG cancer but very important, being indicative of incurable disease in 76 per cent. This information will be helpful in counselling patients regarding management options and the low likelihood of potentially curative treatment.

Characteristics and smoking cessation outcomes of patients returning for repeat tobacco dependence treatment.

Previous studies of tobacco dependence treatment have reported very low cessation rates among smokers who relapse and return to make a subsequent formal attempt to quit. This retrospective cohort study examined 1745 patients who attended a tobacco dependence clinic between 2001 and 2005, and the characteristics and outcomes of those who relapsed and returned for repeat treatment. Patients who returned for repeat treatment showed higher markers of nicotine dependence and were more likely to have a history of treatment for mental health problems than patients who attended the clinic for only one treatment episode. Among patients who relapsed and returned for repeat treatment, the 26-week abstinence rates were similar for each consecutive quit attempt (23%, 22% and 20%). Clinicians should encourage smokers who relapse after an initial treatment episode to return for treatment, and repeat treatment should focus on addressing high nicotine dependence and potentially co-occurring mental health problems in order to improve cessation outcomes.

Ultrasound guidance improves the adequacy of our preoperative thyroid cytology but not its accuracy.

AIMS: Our thyroid cytology audit results of 1990-1995 showed an unsatisfactory rate of 43.1% and prediction of neoplasia with a sensitivity of 86.8%. Increasingly, ultrasound scan (USS)-guided core sampling for cytology is proving a valuable tool instead of freehand fine needle aspiration (FNA) or following unsatisfactory freehand FNA. We present the results of freehand FNA and USS-guided core samples for cytology in two separate patient groups in our centre. METHODS: Patients who had a thyroid resection and preoperative thyroid cytology in our institution between 1996 and 2002 were included. The histological diagnoses were correlated with the preceding cytology results. RESULTS: A total of 450 FNAs were performed on 394 patients. Freehand FNAs were performed for 348 (77.3%) samples and USS-guided core for 102 (22.7%) samples; 121 (26.8%) were repeat aspirates performed on 45 patients. Using aspiration cytology (AC) grading, freehand FNA was cytologically inadequate (AC0 or AC1) in 34.8% cases whereas USS-guided core was inadequate in 17.6% cases (P = 0.001). Freehand FNA (AC3, AC4, AC5) predicted neoplasia with a sensitivity of 83.2%, specificity of 46.6%, accuracy of 63.0%, positive predictive value of 56.0% and negative predictive value of 77.1%. USS-guided core sample for cytology (AC3, AC4, AC5) predicted neoplasia with a sensitivity of 93.5%, specificity of 26.0%, accuracy of 51.9%, positive predictive value of 43.9% and negative predictive value of 86.7%. CONCLUSIONS: Although USS-guided core provides more satisfactory specimens than freehand FNA, in our centre it does not provide increased accuracy.

Postpneumonectomy esophageal fistula: a combined radiological-endoscopic technique.

We report a case of a 70-year-old man who presented with a long-standing esophagocutaneous fistula following a pneumonectomy for aspergilloma. Major surgical procedures, including a pectoralis major flap reconstruction, a pedicled omental transposition and a radial forearm flap transposition, failed to obliterate the fistula. Seven years after initial surgery the esophagocutaneous fistula was successfully treated by means of a minimally invasive joint endoscopic and radiological technique. A radiographic catheter was passed through the fistula. The catheter and the guide wire were manipulated into the esophageal defect and into the upper esophagus. Under endoscopic vision, the catheter was then advanced over the guide wire and out of the patient's mouth. A T-tube was sutured to the catheter outside the mouth, pulled down through the esophagus, and into the esophageal defect and out through the chest wall, leaving the T-part of the tube within the esophagus. The patient made a good recovery and was discharged 7 days later. He was able to resume oral intake 3 weeks after the procedure.

Ultrasound scan-guided core sampling for diagnosis versus freehand FNAC of the thyroid gland.

BACKGROUND AND AIM: Freehand fine needle aspiration cytology (FNAC) is an obligatory investigation of the thyroid nodule. Between 5.0-43.1% of FNAC samples are reported as being initially unsatisfactory. In our unit, thyroid freehand FNAs are performed with a small needle (21 or 23G). Non-dominant nodules as part of multinodular goitres, difficult to palpate nodules or nodules with previously unsatisfactory freehand FNACs are sampled under ultrasound scan (USS) guidance with the larger 20G cutting core sampling technique. We aimed to compare the satisfactory sampling rate and safety of the two different methods. PATIENTS AND METHODS: Cytology forms were reviewed for 262 freehand FNACs and USS-guided core samples, performed in our unit over a two-year interval (1 July 1999 to 30 June 2001). RESULTS: Ultrasound-guided core samples for cytology were unsatisfactory (AC0-1) in 19/121 (15.6%) of the cases, compared with 66/141 (46.8%) of freehand FNACs (p value = < 0.0001). Ten out of eleven patients (91%) had a satisfactory USS-guided core after an unsatisfactory freehand FNA; 7/15 patients (46.7%) had satisfactory repeat freehand FNACs following an initial unsatisfactory freehand FNAC (p value = 0.0191). There were no complications as a result of either freehand FNAC or USS-guided core sampling. CONCLUSION: USS-guided cores provided more satisfactory samples for assessment than freehand FNACs. The USS-guided technique is safe despite the use of the larger cuffing needle. The USS-guided core sampling was also a useful tool for repeat thyroid nodule sampling after an unsatisfactory freehand FNAC.

Prospective study of routine contrast radiology after total gastrectomy.

BACKGROUND: The practice of routine contrast radiology before recommencing oral nutrition after total gastrectomy is not evidence based. The aim of this prospective study was to evaluate the clinical role and timing of this investigation. METHODS: Seventy-six consecutive patients underwent total gastrectomy with a stapled oesophagojejunal anastomosis. A contrast swallow using non-ionic contrast and barium was performed routinely 5 and 9 days after surgery. The surgeon was blinded to the result of the first of these examinations. Patients with clinical evidence of a leak underwent contrast radiology and upper gastrointestinal videoendoscopy. RESULTS: Eight patients (11 per cent) developed a clinical leak from the oesophagojejunal anastomosis, seven before the first scheduled contrast swallow. Contrast radiology identified a leak in four of six patients. Endoscopy detected a leak in both patients with a false-negative swallow and in two patients who were not fit to undergo contrast radiology. Routine contrast radiology identified a subclinical leak in a further five patients (7 per cent), none of whom developed clinical signs. Four of seven in-hospital deaths were associated with an anastomotic leak. CONCLUSION: There is no role for routine contrast swallow after total gastrectomy with a stapled oesophagojejunal anastomosis, but patients with clinical suspicion of leakage should undergo urgent contrast radiology, plus endoscopy if the contrast examination is normal.

Combined percutaneous and endoscopic procedures for bile duct obstruction: simultaneous and delayed techniques compared.

BACKGROUND/AIMS: In patients with obstructive jaundice, when the endoscopic approach fails to achieve biliary drainage, percutaneous cannulation and combined endoscopic/percutaneous endoprosthesis insertion can be performed simultaneously or in stages. This study compared these two approaches. METHODOLOGY: Over a three-year period 41 patients were studied. All had obstructive jaundice for which endoscopic drainage had failed. In 22 patients (group 1) percutaneous transhepatic drainage was followed a few days later by combined endoscopic and percutaneous procedure. In 19 patients (group 2) the percutaneous transhepatic drainage and combined drainage were performed at the same session. In the multiple stage group the mean interval between the first endoscopic retrograde cholangiopancreatography and final combined procedure was 9 days (SD 5.2). The groups were similar for sex, underlying pathology and reasons for failure of endoscopic approach. Group 1 patients were older 73 vs. 65 years (p < 0.05). RESULTS: Patients in group 2 had a more rapid recovery and discharge home: mean 6 days, compared to mean 18 days from the initial procedure for group 1 (p < 0.001). Five patients died of their disease without leaving hospital (4 in group 1, 1 in group 2). In each group drainage failed in 1 patient. Complications were more common in group 1: 73% vs. 37% (p < 0.05). Pancreatitis (3 vs. 2) and septicemia (4 in group 1, 3 in group 2) were similar but group 1 had complications from the external drain: cholangitis and pyrexia in 4 patients, 3 bile leaks, and 1 catheter displacement. CONCLUSIONS: When endoscopic drainage alone fails, a combined percutaneous/endoscopic procedure should only be performed if it can be carried out simultaneously.

Diagnosis and management of a mediastinal leak following radical oesophagectomy.

BACKGROUND: The aim of this study was to evaluate the diagnosis, management and outcome of mediastinal leaks following radical oesophagectomy with a stapled intrathoracic anastomosis. METHODS: Some 291 consecutive patients underwent two-phase subtotal oesophagectomy with gastric interposition for malignancy. Patients with clinical suspicion of a leak were investigated with contrast radiology and flexible upper gastrointestinal endoscopy. RESULTS: Nineteen patients (6.5 per cent) developed a proven mediastinal leak at a median of 8 (range 3-30) days following surgery. Contrast radiology and flexible upper gastrointestinal endoscopy identified that 13 patients had an isolated leak from the oesophagogastric anastomosis and two had widespread leakage secondary to gastrotomy-line dehiscence. Endoscopy revealed a further four patients with gastric necrosis in whom contrast radiology was normal. In six patients the diagnosis of leakage followed an apparently normal routine contrast examination on day 5-8. All 13 isolated anastomotic leaks were managed non-operatively with targeted mediastinal drainage, intravenous antibiotics and antifungal therapy, nasogastric decompression and enteral nutrition; the mortality rate was 15 per cent (two of 13). Patients with gastrotomy dehiscence or gastric necrosis had a more severe clinical picture; they were managed with repeat thoracotomy and either revision of the conduit or resection and exclusion. Despite early intervention four of the six patients died. CONCLUSION: Routine postoperative contrast radiology cannot be recommended. On clinical suspicion of a leak patients require both contrast radiology and endoscopic evaluation. Isolated anastomotic leaks can be managed successfully with non-operative treatment, whereas more extensive leaks from the gastric conduit require revisional surgery which carries a high mortality rate.

TIGRFAMs: a protein family resource for the functional identification of proteins.

TIGRFAMs is a collection of protein families featuring curated multiple sequence alignments, hidden Markov models and associated information designed to support the automated functional identification of proteins by sequence homology. We introduce the term 'equivalog' to describe members of a set of homologous proteins that are conserved with respect to function since their last common ancestor. Related proteins are grouped into equivalog families where possible, and otherwise into protein families with other hierarchically defined homology types. TIGRFAMs currently contains over 800 protein families, available for searching or downloading at www.tigr.org/TIGRFAMs. Classification by equivalog family, where achievable, complements classification by orthology, superfamily, domain or motif. It provides the information best suited for automatic assignment of specific functions to proteins from large-scale genome sequencing projects.