To determine factors associated with outcomes following pelvic exenteration for advanced nonrectal pelvic malignancy.
The PelvEx Collaborative provides large volume data from specialist centers to ...ascertain factors associated with improved outcomes.
Consecutive patients who underwent pelvic exenteration for nonrectal pelvic malignancy between 2006 and 2017 were identified from 22 tertiary centers. Patient demographics, neoadjuvant therapy, histopathological assessment, length of stay, 30-day major complication/mortality rate were recorded.The primary endpoints were factors associated with survival. The secondary endpoints included the difference in margin rates across the cohorts, impact of neoadjuvant treatment on survival, associated morbidity, and mortality.
One thousand two hundred ninety-three patients were identified. 40.4% (n = 523) had gynecological malignancies (endometrial, ovarian, cervical, and vaginal), 35.7% (n = 462) urological (bladder), 18.1% (n = 234) anal, and 5.7% had sarcoma (n = 74).The median age across the cohort was 63 years (range, 23-85). The median 30-day mortality rate was 1.7%, with the highest rates occurring following exenteration for recurrent sarcoma or locally advanced cervical cancer (3.3% each). The median length of hospital stay was 17.5 days. 34.5% of patients experienced a major complication, with highest rate occurring in those having salvage surgery for anal cancer.Multivariable analysis showed R0 resection was the main factor associated with long-term survival. The 3-year overall-survival rate for R0 resection was 48% for endometrial malignancy, 40.6% for ovarian, 49.4% for cervical, 43.8% for vaginal, 59% for bladder, 48.3% for anal, and 48.1% for sarcoma.
Pelvic exenteration remains an important treatment in selected patients with advanced or recurrent nonrectal pelvic malignancy. The range in 3-year overall survival following R0 resection (40%-59%) reflects the diversity of tumor types.
Background: The p53 gene is frequently mutated in non-small-cell lung cancer (NSCLC); however, the effect of p53 gene mutations on patient prognosis remains unclear. Therefore, we initiated a ...prospective study to determine the association of p53 gene mutations with survival in patients with stage I NSCLC. Methods: Tumor samples were collected prospectively from 188 patients with operable NSCLC (stages I, II, and IIIA). p53 mutations were detected by direct dideoxynucleotide sequencing and p53 GeneChip analysis. Association of clinical and pathologic variables (e.g., alcohol consumption, sex, age, pathologic stage) with mutation of the p53 gene was determined by logistic regression. Associations between p53 mutation status, clinical and pathologic variables, and survival were assessed using a Cox proportional hazards regression model. All statistical tests were two-sided. Results: p53 mutations were detected in 55% (104/188) of tumors. These mutations were associated with non-bronchoalveolar tumors, a history of alcohol consumption, and younger patient age. The risk of death was statistically significantly higher in patients with p53 mutations in their tumors (hazard ratio HR = 1.6, 95% confidence interval CI = 1.0 to 2.4; P = .049) than in patients with wild-type p53 in their tumors. Tumor stage, the presence of a p53 mutation, and increasing patient age were statistically significant predictors of patient death in the entire patient group; however, the statistically significant prognostic effect of p53 mutation was limited to patients with stage I NSCLC (stage I HR = 2.8, 95% CI = 1.4 to 5.6; stage II HR = 1.8, 95% CI = 0.74 to 4.4; and stage III HR = 0.70, 95% CI = 0.32 to 1.5). Among patients with stage I NSCLC, actuarial 4-year survival was statistically significantly higher in those with wild-type p53 than in those with mutant p53 (78% versus 52%, respectively; difference in 4-year survival = 26%, 95% CI = 6% to 46%; P = .009, log-rank test). Conclusion: Tumor p53 mutations are a statistically significant predictor of poor outcome in patients with stage I NSCLC.
Validated targeted therapy is currently unavailable for patients with invasive breast cancer negative for oestrogen receptors, progesterone receptors and HER2 i.e., those with triple-negative (TN) ...disease. ADAM-17 is a protease involved in the activations of several ligands that bind to and promotes intracellular signalling from the EGFR/HER family of receptors.
Expression of ADAM-17 was measured in 86 triple-negative and 96 non-triple-negative breast cancers. The ADAM-17 specific inhibitor, PF-5480090 (TMI-002, Pfizer) was tested in a panel of breast cancer cell lines for effects on functional outputs.
In this study we show using both Western blotting and immunohistochemistry that ADAM-17 is expressed at significantly higher levels in TN than non-TN breast cancers. Using a panel of breast cancer cell lines in culture, PF-5480090 was found to decrease release of the EGFR ligand, TGF-alpha, decrease levels of phosphorylated EGFR and block cell proliferation in a cell-type-dependent manner. Potentially important was the finding of a significant and moderately strong correlation between ADAM-17 activity and extent of proliferation inhibition by PF-5480090 (r = 0.809; p = 0.003; n = 11). Pretreatment of cell lines with PF-5480090 enhanced response to several different cytotoxic and anti-EGFR/HER agents.
It is concluded that inhibition of ADAM-17, especially in combination with chemotherapy or anti-EGFR/HER inhibitors, may be a new approach for treating breast cancer, including patients with TN disease.
Tourette syndrome (TS) and related tic disorders are commonly associated with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD). It has been argued, however, ...that any observed association between TS and these and other psychopathologies may be due to ascertainment bias in that individuals with multiple problems are more likely to be referred for medical evaluation.
In order to overcome the potential confounding by ascertainment bias, the authors conducted a community-based study of school children using direct interviews to determine the prevalence of tic disorders and any comorbid psychopathology. A standard psychiatric interview and standardized rating scales were utilized to diagnose childhood behavioral disorders.
Of the 1,596 children interviewed, 339 were identified as having tics. The following psychopathologies were found more commonly (p < 0.05) in the children with tics: OCD, ADHD, separation anxiety, overanxious disorder, simple phobia, social phobia, agoraphobia, mania, major depression, and oppositional defiant behavior.
The behavioral spectrum of tic disorders includes OCD, other anxiety disorders, a mood disorder, and attention-deficit and disruptive behavior disorders.
Cell-permeable phosphorescent probes enable the study of cell and tissue oxygenation, bioenergetics, metabolism, and pathological states such as stroke and hypoxia. A number of such probes have been ...described in recent years, the majority consisting of cationic small molecule and nanoparticle structures. While these probes continue to advance, adequate staining for the study of certain cell types using live imaging techniques remains elusive; this is particularly true for neural cells. Here we introduce novel probes for the analysis of neural cells and tissues: negatively charged poly(methyl methacrylate-co-methacrylic acid)-based nanoparticles impregnated with a phosphorescent Pt(II)-tetrakis(pentafluorophenyl)porphyrin (PtPFPP) dye (this form is referred to as PA1), and with an additional reference/antennae dye poly(9,9-diheptylfluorene-alt-9,9-di-p-tolyl-9H-fluorene) (this form is referred to as PA2). PA1 and PA2 are internalised by endocytosis, result in efficient staining in primary neurons, astrocytes, and PC12 cells and multi-cellular aggregates, and allow for the monitoring of local O₂levels on a time-resolved fluorescence plate reader and PLIM microscope. PA2 also efficiently stains rat brain slices and permits detailed O₂imaging experiments using both one and two-photon intensity-based modes and PLIM modes. Multiplexed analysis of embryonic rat brain slices reveals age-dependent staining patterns for PA2 and a highly heterogeneous distribution of O₂in tissues, which we relate to the localisation of specific progenitor cell populations. Overall, these anionic probes are useful for sensing O₂levels in various cells and tissues, particularly in neural cells, and facilitate high-resolution imaging of O₂in 3D tissue models.
To assess the incidence of and risk factors for distal sensory polyneuropathy (DSP) in a cohort of HIV-infected subjects.
We followed 272 subjects semiannually for up to 30 months. DSP was diagnosed ...if subjects had decreased or absent ankle jerks, decreased or absent vibratory perception at the toes, or decreased pinprick or temperature in a stocking distribution. Subjects were further classified at each visit as having asymptomatic DSP (ADSP) (signs only) or symptomatic DSP (SDSP) if, in addition to the neurologic signs, paresthesias or pain was reported.
At baseline, 45% of the subjects did not meet criteria for DSP, 20% met criteria for ADSP, and 35% met criteria for SDSP. Dideoxynucleoside therapy was used by 23% of the patients, and this treatment was independent of their neuropathy status. In longitudinal univariate analyses, history of AIDS diagnoses (hazard ratio HR = 1.89; p = 0.02) and lower CD4 cell count (HR = 0.69; p = 0.0006) were risk factors for incident DSP (ADSP or SDSP). However, for incident SDSP only, in addition to history of AIDS diagnoses, mood and neurologic (other than DSP) and functional abnormalities were significant risk factors. Functional abnormalities remained a significant risk factor in a multiple regression analysis. The presence of ADSP and the use of dideoxynucleosides at baseline were not significant risk factors for incident SDSP. The Kaplan-Meier estimate of the 1-year incidence of SDSP was 36%.
Subjects with moderate-to-severe immunosuppression from HIV infection commonly have SDSP. However, sex, use of dideoxynucleosides, and presence of ADSP were not significant risk factors for SDSP.
Abstract Introduction Vitamin A and its metabolites (called retinoids) have been thought to play a role in the development of idiopathic intracranial hypertension (IIH). The IIH Treatment Trial ...(IIHTT) showed the efficacy of acetazolamide (ACZ) in improving visual field function, papilledema grade, quality of life and cerebrospinal fluid (CSF) pressure. We postulated that IIH patients would demonstrate elevated measures of vitamin A metabolites in the serum and CSF. Methods Comprehensive measures of serum vitamin A and its metabolites were obtained from 96 IIHTT subjects, randomly assigned to treatment with ACZ or placebo, and 25 controls with similar gender, age and body mass index (BMI). These included retinol, retinol binding protein, all- trans retinoic acid (ATRA), alpha- and beta-carotenes, and beta-cryptoxanthin. The IIHTT subjects also had CSF and serum vitamin A and metabolite measurements obtained at study entry and at six months. Results At study entry, of the vitamin A metabolites only serum ATRA was significantly different in IIHTT subjects (median 4.33 nM) and controls (median 5.04 nM, p = 0.02). The BMI of IIHTT subjects showed mild significant negative correlations with serum ATRA, alpha- and beta-carotene, and beta-cryptoxanthin. In contrast, the control subject BMI correlated only with serum ATRA. At six months, the serum retinol, alpha-carotene, beta-carotene, and CSF retinol were increased from baseline in the ACZ treated group, but only increases in alpha-carotene (p = 0.02) and CSF ATRA (p = 0.04) were significantly greater in the ACZ group compared with the placebo group.
No other vitamin A measures were significantly altered over the six months in either treatment group. Weight loss correlated with only with the change in serum beta-carotene (r = − 0.44, p = 0.006) and the change in CSF retinol (r = − 0.61, p = 0.02). Conclusion Vitamin A toxicity is unlikely a contributory factor in the causation of IIH. Our findings differ from those of prior reports in part because of our use of more accurate quantitative methods and measuring vitamin A metabolites in both serum and CSF. ACZ may alter retinoid metabolism in IIH patients.
VRC 012 was a Phase I study of a prototype recombinant adenoviral-vector serotype-35 (rAd35) HIV vaccine, the precursor to two recently published clinical trials, HVTN 077 and 083. On the basis of ...prior evaluation of multiclade rAd5 HIV vaccines, Envelope A (EnvA) was selected as the standard antigen for a series of prototype HIV vaccines to compare various vaccine platforms. In addition, prior studies of rAd5-vectored vaccines suggested pre-existing human immunity may be a confounding factor in vaccine efficacy. rAd35 is less seroprevalent across human populations and was chosen for testing alone and in combination with a rAd5-EnvA vaccine in the present two-part phase I study.
First, five subjects each received a single injection of 109, 1010, or 1011 particle units (PU) of rAd35-EnvA in an open-label, dose-escalation study. Next, 20 Ad5/Ad35-seronegative subjects were randomized to blinded, heterologous prime-boost schedules combining rAd5-EnvA and rAd35-EnvA with a three month interval. rAd35-EnvA was given at 1010 or 1011 PU to ten subjects each; all rAd5-EnvA injections were 1010 PU. EnvA-specific immunogenicity was assessed four weeks post-injection. Solicited reactogenicity and clinical safety were followed after each injection.
Vaccinations were well tolerated at all dosages. Antibody responses measured by ELISA were detected at 4 weeks in 30% and 50% of subjects after single doses of 1010 or 1011 PU rAd35, respectively, and in 89% after a single rAd5-EnvA 1010 PU injection. EnvA-specific IFN-γ ELISpot responses were detected at four weeks in 0%, 70%, and 50% of subjects after the respective rAd35-EnvA dosages compared to 89% of subjects after rAd5. T cell responses were higher after a single rAd5-EnvA 1010 PU injection than after a single rAd35-EnvA 1010 PU injection, and humoral responses were low after a single dose of either vector. Of those completing the vaccine schedule, 100% of rAd5-EnvA recipients and 90% of rAd35-EnvA recipients had both T cell and humoral responses after boosting with the heterologous vector. ELISpot response magnitude was similar in both regimens and comparable to a single dose of rAd5. A trend toward more robust CD8 T cell responses using rAd5-EnvA prime and rAd35-EnvA boost was observed. Humoral response magnitude was also similar after either heterologous regimen, but was several fold higher than after a single dose of rAd5. Adverse events (AEs) related to study vaccines were in general mild and limited to one episode of hematuria, Grade two. Activated partial thromboplastin time (aPTT) AEs were consistent with an in vitro effect on the laboratory assay for aPTT due to a transient induction of anti-phospholipid antibody, a phenomenon that has been reported in other adenoviral vector vaccine trials.
Limitations of the rAd vaccine vectors, including the complex interactions among pre-existing adenoviral immunity and vaccine-induced immune responses, have prompted investigators to include less seroprevalent vectors such as rAd35-EnvA in prime-boost regimens. The rAd35-EnvA vaccine described here was well tolerated and immunogenic. While it effectively primed and boosted antibody responses when given in a reciprocal prime-boost regimen with rAd5-EnvA using a three-month interval, it did not significantly improve the frequency or magnitude of T cell responses above a single dose of rAd5. The humoral and cellular immunogenicity data reported here may inform future vaccine and study design.
ClinicalTrials.gov NCT00479999.
Palliative pelvic exenteration (PPE) is a technically complex operation with high morbidity and mortality rates, considered in patients with limited life expectancy. There is little evidence to guide ...practice. We performed a systematic review to evaluate the impact of PPE on symptom relief and quality of life (QoL).
A systematic review was conducted according to the PRISMA guidelines using Ovid MEDLINE, EMBASe, and PubMed databases for studies reporting on outcomes of PPE for symptom relief or QoL. Descriptive statistics were used on pooled patient cohorts.
Twenty-three historical cohorts and case series were included, comprising 509 patients. No comparative studies were found. Most malignancies were of colorectal, gynaecological and urological origin. Common indications for PPE were pain, symptomatic fistula, bleeding, malodour, obstruction and pelvic sepsis. The pooled median postoperative morbidity rate was 53.6% (13–100%), the median in-hospital mortality was 6.3% (0–66.7%), and median OS was 14 months (4–40 months). Some symptom relief was reported in a median of 79% (50–100%) of the patients, although the magnitude of effect was poorly measured. Data for QoL measures were inconclusive. Five studies discouraged performing PPE in any patient, while 18 studies concluded that the procedure can be considered in highly selected patients.
Available evidence on PPE is of low-quality. Morbidity and mortality rates are high with a short median OS interval. While some symptom relief may be afforded by this procedure, evidence for improvement in QoL is limited. A highly selective individualised approach is required to optimise the risk:benefit equation.
To investigate predictors of survival in Parkinson disease (PD).
Vital status was determined in 800 subjects enrolled in a clinical trial of deprenyl (selegiline) and tocopherol 13 years earlier.
Two ...hundred ninety-six deaths were recorded. There was no difference in the standardized mortality ratios across gender or age group. In univariate analyses, PD-specific variables associated with mortality were increased symmetry of parkinsonism, gait dysfunction as an initial symptom, severity of parkinsonism, and rate of worsening of parkinsonism prior to study enrollment. Cumulative exposure to deprenyl was not associated with mortality. In multivariable analysis, severity of parkinsonism and rate of worsening of parkinsonism remained associated with mortality. A poorer response to levodopa was associated with increased mortality independent of disease severity or dosage of levodopa. Results were unchanged when the analysis was restricted to 747 subjects maintaining a most likely diagnosis of PD throughout 6 years of active follow-up.
Parkinson disease did not affect survival differently across gender or age groups in this selected group of otherwise healthy clinical trial participants. Severity and rate of worsening of parkinsonism and response to levodopa are strongly related to survival.
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