Final report on serial phase II trials of all-intraperitoneal chemotherapy with or without bevacizumab for women with newly diagnosed, optimally cytoreduced carcinoma of Müllerian origin.

BACKGROUND: Intraperitoneal (IP) chemotherapy can improve outcomes for women with optimally cytoreduced epithelial ovarian cancer but toxicities are a concern. We conducted 2 phase 2 trials of an IV/IP regimen using carboplatin and paclitaxel without (Trial A) and with bevacizumab (Trial B). METHODS: Both trials consisted of carboplatin AUC 6 day 1, and paclitaxel 60 mg/m2 on days 1,8, 15 of a 21-day cycle; in Trial B, patients received IV bevacizumab 15 mg/kg every cycle starting cycle 2. Chemotherapy was administered IV for cycle 1 and then IP for all subsequent cycles. Primary objectives included safety and tolerability, pathologic CR rate (Trial A), and the rate of completion of IP cycles of therapy (Trial B). Progression-free (PFS), overall survival (OS), and pharmacokinetic analysis were secondary endpoints. RESULTS: 81 patients were treated on both trials (n = 40 and 41 in trials A and B, respectively). Median age for trials A and B was 59 (range, 36-76) and 55 (range, 19-69) years, respectively. 68% and 85% of patients, respectively for A and B, completed at least 4 cycles of treatment in both trials. Treatment with bevacizumab resulted in higher rates of grade 3 fatigue (37 versus 33%) and grade 3-4 diarrhea (22 versus 8%). Median PFS was 23.5 (95%CI 16.2-35.3) and 25 (95%CI 16.4-42.7) months, respectively; median OS was 68 (95%CI 49.5-NR) and 79.7 (95%CI 59.0-79.7) months, respectively for Trial A and B. CONCLUSIONS: Weekly administered IP carboplatin and IP paclitaxel is tolerable and safe with similar activity with and without concommittant bevacizumab in these 2 trials.

Comparison of testing approaches for Clostridium difficile infection at a large community hospital.

Multiple diagnostic approaches are available for Clostridium difficile infection (CDI); current guidelines support two-step testing (2ST) as the preferred approach. We retrospectively evaluated the impact of switching from toxin enzyme immunoassay (EIA) to 2ST, and then to polymerase chain reaction (PCR), on CDI rates, test utilization and CDI treatment at a 900-bed tertiary care community teaching hospital. All inpatients tested for CDI between December 2008 and February 2011 were included. A positive toxin EIA or PCR was diagnostic of CDI; 2ST was performed using glutamate dehydrogenase EIA, followed by PCR if positive. Repeat tests within 8 weeks on the same patient were considered part of the same testing episode. Data were collected electronically and studied in aggregate from 9725 unique inpatients tested for CDI, representing 20 836 individual tests. PCR detected 41% more patients with CDI than toxin EIA (p <0.0001), and 15% more than 2ST (p 0.02), corresponding to higher hospital-onset and community-onset CDI rates. The number of CDI tests performed per patient decreased by 48% with PCR (p <0.0001) compared with toxin EIA. For patients with CDI, time to the first positive test result was shortest with PCR. For patients without CDI, a negative PCR, but not 2ST, was associated with 22% fewer CDI treatment days, compared with toxin EIA (p <0.0001). Compared with both toxin EIA and 2ST, PCR detected more CDI patients faster and with less frequent testing, and negative PCR results were associated with less empirical CDI treatment.

Safety and acceptability of practice-nurse-managed care of depression in patients with diabetes or heart disease in the Australian TrueBlue study.

OBJECTIVES: To determine the safety and acceptability of the TrueBlue model of nurse-managed care in the primary healthcare setting. DESIGN: A mixed methods study involving clinical record audit, focus groups and nurse interviews as a companion study investigating the processes used in the TrueBlue randomised trial. SETTING: Australian general practices involved in the TrueBlue trial. PARTICIPANTS: Five practice nurses and five general practitioners (GPs) who had experienced nurse-managed care planning following the TrueBlue model of collaborative care. INTERVENTION: The practice nurse acted as case manager, providing screening and protocol-management of depression and diabetes, coronary heart disease or both. PRIMARY OUTCOME MEASURES: Proportion of patients provided with stepped care when needed, identification and response to suicide risk and acceptability of the model to practice nurses and GPs. RESULTS: Almost half the patients received stepped care when indicated. All patients who indicated suicidal ideations were identified and action taken. Practice nurses and GPs acknowledged the advantages of the TrueBlue care-plan template and protocol-driven care, and the importance of peer support for the nurse in their enhanced role. CONCLUSIONS: Practice nurses were able to identify, assess and manage mental-health risk in patients with diabetes or heart disease.

Prognostic implications and molecular associations of NADH dehydrogenase subunit 4 (ND4) mutations in acute myeloid leukemia.

To study the prevalence and prognostic importance of mutations in NADH dehydrogenase subunit 4 (ND4), a mitochondrial encoded transmembrane component of the electron transport chain respiratory Complex I, 452 AML patients were examined for ND4 mutations by direct sequencing. The prognostic impact of ND4 mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors. In all, 29 of 452 patients (6.4%) had either somatic (n=12) or germline (n=17) ND4 mutations predicted to affect translation. Somatic mutations were more likely to be heteroplasmic (P<0.001), to occur in predicted transmembrane domains (P<0.001) and were predicted to have damaging effects upon translation (P<0.001). Patients with somatically acquired ND4 mutations had significantly longer relapse-free survival (P=0.017) and overall survival (OS) (P=0.021) than ND4(wildtype) patients. Multivariate analysis also demonstrated a tendency for increased survival in patients with somatic ND4 mutations (RFS: hazard ratio (HR) 0.25, confidence interval (CI) 0.06-1.01, P=0.052; OS: HR 0.29, CI 0.74-1.20, P=0.089). Somatic ND4(mutated) patients had a higher prevalence of concomitant DNMT3A mutations (P=0.023) and a higher percentage of the NPM1/FLT3-ITD low-risk genotype (P=0.021). Germline affected cases showed higher BAALC (P=0.036) and MLL5 (P=0.051) expression levels. Further studies are warranted to validate the favorable prognostic influence of acquired ND4 mutations in AML.

Stage-for-stage comparison of definitive chemoradiotherapy, surgery alone and neoadjuvant chemotherapy for oesophageal carcinoma.

BACKGROUND: Definitive chemoradiotherapy (dCRT) has been proposed as an alternative therapy for selected patients with oesophageal cancer. The aim of this study was to determine the outcomes of dCRT, surgery alone, and neoadjuvant chemotherapy followed by surgery (CS) in patients with oesophageal cancer. METHODS: Consecutive patients diagnosed with oesophageal cancer and managed by a multidisciplinary team were staged by computed tomography and endoluminal ultrasonography. Those deemed unsuitable for surgery on the grounds of performance status, bulky local disease or personal choice received dCRT. The primary outcome measure was overall survival measured from date of diagnosis. RESULTS: Of 417 patients, 173 received dCRT, 126 underwent surgery alone and 118 received CS. The incidence of grade III/IV toxicity after dCRT and CS was 39.3 and 60.2 per cent respectively. Operative morbidity rates were 42.9 and 44.4 per cent after surgery alone and CS respectively. Thirty-day mortality rates were zero, 7.9 and 0.8 per cent after dCRT, surgery alone and CS respectively. Overall 2-year survival rates were 44.3, 56.2 and 42.4 per cent (P = 0.422). CONCLUSION: These findings support the need for a randomized trial of dCRT versus CS for resectable oesophageal cancer.

Oral health during pregnancy.

OBJECTIVES: To assess how obstetrician-gynecologists address oral health during pregnancy. METHODS: Questionnaires were mailed to obstetrician-gynecologists in March 2008. RESULTS: The response rate was 41%, with 351 respondents included in the final analysis. Most obstetrician-gynecologists agree that routine dental care during pregnancy is important (84%), periodontal disease can have adverse effects on pregnancy outcome (84%), and treating periodontal disease positively affects pregnancy outcome (66%). The majority seldom ask pregnant patients whether they have recently seen a dentist (73%), ask about current oral health (54%), or provide information about oral care (69%). Over a third (38%) do not advise patients to see a dentist for routine prophylaxis, 80% of these saying they had not previously thought about it. Most respondents (77%) reported having patients be declined dental services because of pregnancy. Over half (52%) indicated lack of insurance as a substantial barrier to oral care. CONCLUSION: Obstetrician-gynecologists recognize the importance of good oral health during pregnancy but largely do not address it. Improved training in the importance of oral health, recognizing oral health problems, and knowledge of procedure safety during pregnancy may make doctors more comfortable with assessing oral health and more likely to address it with patients.

Prospective comparison of endosonography, computed tomography, and histopathological stage of junctional oesophagogastric cancer.

AIMS: To assess the strength of agreement between the perceived preoperative stage of Siewert II (oesophagogastric junction) and Siewert III (proximal gastric tumours) as determined by computed tomography (CT) and endoscopic ultrasound (EUS), both alone and in combination, with histopathological stage. METHODS: Forty-four patients with Siewert II (n=18) and III (n=26) adenocarcinomas of the oesophagogastric junction underwent preoperative CT at their local hospitals followed by specialist EUS, and the strengths of the agreement between the radiological stages and the histopathological stages were determined by the weighted Kappa statistic (Kw). RESULTS: Kw for Siewert II T and N stages was 0.491 (p=0.016) and 0.4 (p=0.087) for CT compared with 0.852 (p=0.0001) and 1 (p=0.0001) for EUS. Kw for Siewert III T and N stages was 0.181 (p=0.206) and 0.121 (p=0.376) for CT compared with 0.173 (p=0.195) and 0.263 (p=0.031) for EUS. CONCLUSION: Siewert II tumour T and N stages were more accurately predicted by EUS than CT, but Siewert III tumour T and N stages were more difficult to assess, arguably because of anatomical constraints at the oesophagogastric junction. CT and EUS are complimentary techniques, and these results highlight the importance of multidisciplinary discussion in planning treatment.

Workload and resource implications of upper gastrointestinal cancer surgical centralisation in South East Wales.

INTRODUCTION: The aim of this study was to determine whether one specialist unit could manage all patients diagnosed with oesophagogastric cancer in Gwent and Cardiff and Vale NHS Trusts over a 6-month period with regard to workload, resource and training opportunities. PATIENTS AND METHODS: All patients diagnosed with oesophagogastric (OG) cancer in Gwent and Cardiff and Vale NHS Trusts and referred to the regional South East Wales Upper GI multidisciplinary team over the 6-month period from 1 July to 31 December 2005 were studied prospectively and compared with the previous 6-month caseload at Cardiff and Vale. RESULTS: Out-patient workload increased from 160 new (33 OG cancers) and 533 follow-up patients (161 OG cancers) between 1 January and 30 June 2005, to 290 new (68 OG cancers, 106% increase) and 865 follow-up patients (230 OG cancers, 43% increase) between 1 July, and 31 December 2005. The number of patients undergoing radical surgery increased from 14 to 23 (D2 gastrectomy 8 versus 13; oesophagectomy 6 versus 10). Cancer-related workload in the latter period generated 118 intermediate equivalents (IEs) of operative work for two specialist surgeons and one SpR occupying 38% of the total time available on 104 scheduled operating lists, compared with 64 IEs in the previous 6 months, representing an 84% increase in cancer-related operative training opportunities. CONCLUSIONS: Centralisation of oesophagogastric cancer surgery is feasible and desirable if national guidelines are to be satisfied, and this strategy has significant positive implications for surgical training and audit.

Prognostic significance of failure to cross esophageal tumors by endoluminal ultrasound.

SUMMARY: Failure to intubate and cross esophageal tumors by endosonography is reported in as many as 30% of cases and is thought to be associated with an especially poor prognosis. The aim of this study was to audit the above in a large consecutive case series of Endoscopic Ultrasound (EUS) examinations for esophageal cancer performed in a regional specialist cancer network with particular reference to outcome. A consecutive series of 411 patients underwent EUS examination by a specialist radiologist over a period of 9 years. Forty (10%) of patients required dilation, and there was total failure to cross the tumor in 12 patients (2.9%). Failure to traverse the primary tumor was associated with a diagnosis of squamous cell cancer (8 of 12 patients, 66%, rho = -0.182, P = 0.011). Limited staging information was obtained in 7 of these patients, which altered the computed tomography stage in 5 patients (71%, 3 upstaged, 2 downstaged). Six patients received definitive chemoradiotherapy, two patients surgery and four patients palliative chemotherapy. The median and 5-year survival in patients whose tumors were not crossed was 10 months and 28%, respectively, compared with 24 months and 24%, respectively in patients whose tumors were fully assessed. Failure to cross esophageal tumors in practice was far less common than the literature suggests, and esophageal tumor luminal stenosis should no longer be considered a limitation of endosonography.

Phase II multicenter open-label study of karenitecin in previously treated epithelial ovarian and primary peritoneal cancer: a Gynecologic Oncology Group Study.

The topoisomerase I agents are established as a therapy in recurrent ovarian cancer. Karenitecin, an analog of topotecan with solubility and pharmacologic advantages, was tested in a phase II trial in previously treated patients with recurrent or persistent ovarian cancer. The drug was administered intravenously over 1 h at a dose of 1.0 mg/m(2) daily for 5 days every 21 days. Patients were treated until disease progression, intolerable toxicity, or voluntary withdrawal. Response was evaluated according to modified RECIST criteria. Twenty-seven patients were entered into the study. One patient was inevaluable for not receiving any treatment. Of the 26 evaluable patients, there were two partial responses and one complete response for a total response rate of 12%. This response rate was insufficient to justify accrual to the second stage. The most common grade 3 or 4 toxicities were neutropenia (19%) and gastrointestinal (15%). Karenitecin is a well-tolerated topoisomerase compound but has minimal activity in extensively pretreated ovarian cancer with the dose-schedule employed.

Prospective cohort comparison of neoadjuvant chemoradiotherapy versus chemotherapy in patients with oesophageal cancer.

BACKGROUND: Chemotherapy and chemoradiotherapy are common neoadjuvant treatments for resectable T3 N0-1 M0 oesophageal carcinoma. The aim of this study was to compare the outcomes of these therapies in consecutive cohorts of patients. METHODS: Between January 1998 and December 2001, 88 patients received neoadjuvant chemoradiotherapy (two cycles of cisplatin and 5-fluorouracil (5-FU), prior to 45 Gy in 25 F concurrent radiotherapy with cisplatin and 5-FU). From 2002, 117 patients received neoadjuvant chemotherapy (76 patients had two cycles of cisplatin and 41 had four cycles of epirubicin, cisplatin and 5-FU). The primary outcome measure was survival, and analysis was by intention to treat. RESULTS: Postoperative morbidity and mortality rates were 56 per cent (40 patients) and 10 per cent (seven patients) respectively in the chemoradiotherapy group, compared with 47 per cent (46 patients) and 1 per cent (one patient) in the chemotherapy group (P = 0.008). The cumulative 5-year survival rate by intention to treat was 35 per cent after chemoradiotherapy versus 21 per cent after chemotherapy (P = 0.188). The cumulative corrected 5-year survival rate after completed treatment was 44 per cent for chemoradiotherapy compared with 25 per cent for chemotherapy (P = 0.032). CONCLUSION: Neoadjuvant chemoradiotherapy should remain an option for patients with satisfactory performance status.

Prospective comparison of transthoracic versus transhiatal esophagectomy following neoadjuvant therapy for esophageal cancer.

Transthoracic esophagectomy (TT) has been championed as a better cancer operation than transhiatal esophagectomy (TH) because the approach facilitates meticulous wide tumor excision and lymphadenectomy. However, neoadjuvant chemoradiotherapy (CRTS) and chemotherapy (CS) have been reported to improve outcomes, and we aimed to compare outcomes after multimodal therapy related to the operative approach. One hundred and fifty-one consecutive patients were studied prospectively. All patients were staged with computed tomography and endoluminal ultrasound, and treatment decisions were related to stage and performance status. One hundred and nineteen TT (median age 58 years, 92 male, 54 CRTS, 65 CS) were performed compared to 32 TH (median age 57 year, 27 male, 14 CRTS, 18 CS). Primary outcome measure was survival. Post-operative morbidity and mortality were 54% and 4%, respectively, after TT compared with 59% and 6% after TH (chi2 0.239 df 1, P=0.625). Recurrent cancer was no less frequent after TT (52%) than after TH (37.5%, chi2 2.151 df=1, P=0.142). Cumulative uncorrected 5-year survival was 34% after TT compared with 53% after TH (log rank 1.44, df=1, P=0.2298). Median survival was also similar in lymph node positive patients (TT vs. TH, 23 months vs. 22 months, respectively, log rank 0.25, df=1, P=0.6199). Despite the fact that patients receiving multimodal therapy and a TH esophagectomy were less fit, operative morbidity, mortality and recurrence were similar, and survival did not differ significantly when compared with multimodal TT esophagectomy.

Targeting the RAS signaling pathway in malignant hematologic diseases.

Molecularly targeting signaling pathways that are involved in the pathogenesis of hematopoietic malignancies may lead to more specific and efficacious therapies. Activation of the RAS signal transduction cascade is a common feature in the molecular pathogenesis of hematologic malignancies. A number of novel agents targeting RAS signaling have been developed over the past decade. This review will focus on these agents, which include inhibitors of RAS post-translational modification (farnesyl transferase (FTase)-, geranylgeranyl transferase-I (GGTase-I)-, isoprenylcysteine carboxylmethyltransferase (ICMTase)-inhibitors, statins, bisphosphonates), and inhibitors of RAF and MEK activity. Although some of these inhibitors (e.g. FTase, RAF and MEK inhibitors) were developed to specifically inhibit RAS signaling, it has become clear that RAS may not be the only critical target of these compounds. This review provides a background on RAS signaling in hematologic malignancies and discusses opportunities to exploit aberrant cancer cell signaling in order to develop better treatment options for patients suffering from these diseases.

Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck.

Despite significant advances in the use of surgery, chemotherapy and radiotherapy to treat squamous cell carcinoma of the head and neck (SCCHN), prognosis has improved little over the past 30 years. There is a clear need for novel, more effective therapies to prevent relapse, control metastases and improve overall survival. Improved understanding of SCCHN disease biology has led to the introduction of molecularly targeted treatment strategies in these cancers. The epidermal growth factor receptor (EGFR) is expressed at much higher levels in SCCHN tumours than in normal epithelial tissue, and EGFR expression correlates with poor prognosis. Therefore, much effort is currently directed toward targeting aberrant EGFR activity (e.g. cell signalling) in SCCHN. This review discusses the efficacy of novel therapies targeting the EGFR (e.g. anti-EGFR antibodies and EGFR tyrosine kinase inhibitors) that are currently tested in SCCHN patients.

Prognostic significance of body mass indices for patients undergoing esophagectomy for cancer.

The aim of this study was to determine the role of body mass index (BMI) in a Western population on outcomes after esophagectomy for cancer. Two hundred and fifteen consecutive patients undergoing esophagectomy for esophageal cancer of any cell type were studied prospectively. Patients with BMIs > 25 kg/m were classified as overweight and compared with control patients with BMIs below these reference values. Ninety-seven patients (45%) had low or normal BMIs, 86 patients (40%) were overweight, and a further 32 (15%) were obese. High BMIs were associated with a higher incidence of adenocarcinoma versus squamous cell carcinoma (83%vs. 14%, P = 0.041). Operative morbidity and mortality were 53% and 3% in overweight patients compared with 49% (P = 0.489) and 8% (P = 0.123) in control patients. Cumulative survival at 5 years was 27% for overweight patients compared with 38% for control patients (P = 0.6896). In a multivariate analysis, age (hazard ratio [HR] 1.492, 95% CI 1.143-1.948, P = 0.003), T-stage (HR 1.459, 95% CI 1.028-2.071, P = 0.034), N-stage (HR 1.815, 95% CI 1.039-3.172, P = 0.036) and the number of lymph node metastases (HR 1.008, 95% CI 1.023-1.158, P = 0.008), were significantly and independently associated with durations of survival. High BMIs were not associated with increased operative risk, and long-term outcomes were similar after R0 esophagectomy.

Interactions of doctors with the pharmaceutical industry.

OBJECTIVE: To assess the opinions and practice patterns of obstetrician-gynaecologists on acceptance and use of free drug samples and other incentive items from pharmaceutical representatives. METHODS: A questionnaire was mailed in March 2003 to 397 members of the American College of Obstetricians and Gynecologists who participate in the Collaborative Ambulatory Research Network. RESULTS: The response rate was 55%. Most respondents thought it proper to accept drug samples (92%), an informational lunch (77%), an anatomical model (75%) or a well-paid consultantship (53%) from pharmaceutical representatives. A third (33%) of the respondents thought that their own decision to prescribe a drug would probably be influenced by accepting drug samples. Respondents were more likely to think the average doctor's prescribing would be influenced by acceptance of the items than theirs would be (p<0.002). Respondents who distributed drug samples to patients indicated doing so because of patients' financial need (94%) and for their convenience (76%) and less so as a result of knowledge of the efficacy of the sample product (63%). A third (34%) of respondents agreed that interactions with industry should be more strictly regulated. CONCLUSION: Obstetrician-gynaecologists largely indicated that they would act in accordance with what they think is proper regarding accepting incentive items from pharmaceutical representatives. Although accepting free drug samples was considered to be appropriate more often than any other item, samples were most commonly judged to be influential on prescribing practices. The widely accepted practice of receiving and distributing free drug samples needs to be examined more carefully.

The role of Bcl-X(S) in radiation sensitivity.

Bcl-X(S) is a pro-apoptosis member of the Bcl2 family that has been shown to induce cell death and enhance chemosensitivity. We have investigated the effect of Bcl-X(S) overexpression on radiation sensitivity. Using a tetracycline-repressible system, we found that removal of tetracycline for 16 h induced Bcl-X(S) and reduced the surviving fraction of NIH 3T3 cells to 25%. However, radiation sensitivity was not significantly affected by Bcl-X(S) expression; the mean inactivation doses for Bcl-X(S) repressed and Bcl-X(S) induced cells were 2.7 +/- 0.3 and 2.3 +/- 0.1 Gy, respectively. We conclude that Bcl-X(S) induces cell death without affecting radiation sensitivity. These results suggest that mitochondrial pathways to apoptosis may not have a significant role in survival after irradiation.

Estrogens and non-reproductive behaviors related to activity and fear.

Estrogens affect a variety of behaviors in addition to sexual responses, some of them related to motor activity and emotional reactivity. This is true in experimental animals and in humans. The literatures on these subjects are confusing because not all of the experimental results point in the same direction. Here we propose the following theoretical suggestion, hoping to account for the variety of reports extant: following the generally arousing effects of estrogens, their hormonal actions on motor activity and fear depend on context. In a safe environment, estrogen treatment causes increased activity. But in a novel environment or in contexts otherwise perceived as threatening, activity is reduced by estrogen, due to the hormone's arousing action, which heightens fear. Many hormone-dependent neural circuits involving several neuropeptides could provide mechanisms for this dynamic. We suggest a causal route could involve the activation of corticotropin releasing hormone gene expression in the brain. In sum, estrogenic effects on arousal states, as manifest differently according to details of the environmental context during behavioral test, could account for some of the discrepancies in the literature.

Therapeutic efficacy of prenylation inhibitors in the treatment of myeloid leukemia.

Farnesyltransferase inhibitors (FTIs) represent a new class of anticancer agents that specifically target post-translational farnesylation of various proteins that mediate several cellular processes such as signal transduction, growth, differentiation, angiogenesis and apoptosis. These compounds were originally designed to block oncogenic RAS-induced tumor growth by impeding RAS localization to the membrane, but it is now evident that FTIs also affect processing of several other proteins. The need for novel therapies in myeloid leukemia is underscored by the high rate of treatment failure due to high incidences of relapse- and treatment-related toxicities. As RAS deregulation is important in the pathogenesis of myeloid leukemias, targeting of RAS signaling may provide a new therapeutic strategy. Several FTIs (eg BMS-214662, L-778,123, R-115777 and SCH66336) have entered phase I and phase II clinical trials in myeloid leukemias. This review discusses recent clinical results, potential combination therapies, mechanisms of resistance and the clinical challenges of toxicities associated with prenylation inhibitors.