High Gleason grade carcinoma at a positive surgical margin predicts biochemical failure after radical prostatectomy and may guide adjuvant radiotherapy

Study Type – Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Only 30–35% of patients with positive surgical margins after radical prostatectomy develop recurrent disease. Adjuvant radiotherapy reduces the rate of biochemical relapse or metastasis and improves overall survival after radical prostatectomy. Various pathological factors, such as location and extent of positive margins, have been proposed as possible prognostic factors in men with margin‐positive prostate cancer, however, the recent International Society of Urological Pathology consensus meeting in Boston noted that there is limited data on the significance of Gleason grade of the carcinoma at a positive margin. The present study shows that the presence of high grade prostate cancer, i.e. Gleason pattern 4 or 5, at a positive surgical margin is an independent predictor of biochemical recurrence after radical prostatectomy. Moreover, patients with lower grade carcinoma at the margin have a similar prognosis to men with negative margins. Hence, assessment of Gleason grade at the site of positive margin may aid optimal selection of patients for adjuvant radiotherapy.

OBJECTIVE

• ? To establish predictors of biochemical recurrence by analysing the pathological characteristics of positive surgical margins (PSMs), including Gleason grade of the carcinoma at the involved margin.

PATIENTS AND METHODS

• ? Clinicopathological and outcome data on 940 patients who underwent radical prostatectomy (RP) between 1997 and 2003 were collected.
• ? Of these, 285 (30.3%) patients with PSMs were identified for pathological review, including assessment of location of margin, linear extent, number of PSMs, plane of margin and Gleason grade (3 vs 4 or 5) at the margin.

RESULTS

• ? At a median follow‐up of 82 months, the biochemical recurrence rate of the PSM cohort was 29%.
• ? On univariate analysis, the presence of Gleason grade 4 or 5 at the margin (34.4% of cases) was significantly associated with biochemical recurrence (hazard ratio [HR] 2.80, 95% confidence interval [CI]= 1.82–4.32, P < 0.001) compared with the presence of Gleason grade 3.
• ? Linear extent of margin involvement was also associated with recurrence (P= 0.009).
• ? Single vs multiple margin involvement, location, and plane of the involved margin were not significant predictors of recurrence.
• ? On multivariate analysis, Gleason grade 4 or 5 at the margin remained an independent predictor of recurrence (HR 2.14, 95% CI = 1.29–4.03, P= 0.003).

CONCLUSION

• ? The Gleason grade at the site of a PSM identifies patients at increased risk of biochemical recurrence and should aid stratification of patients for adjuvant radiation therapy.

     

Esophageal Candidiasis after Renal Transplantation: Comparative Study in Patients on Different Immunosuppressive Protocols

Objectives: The incidence of esophageal candidiasis (EC) in renal allograft recipients has not been well documented. The present study was done to determine the incidence of EC in renal allograft recipients receiving different forms of immunosuppressive therapy and to identify patients at a high risk of developing Candida esophagitis. Methods: We conducted a retrospective study of 265 live related renal allograft recipients and compared three groups: patients given azathioprine and prednisolone (group I), those given cyclosporine, azathioprine, and prednisolone (group II), and those given cyclosporine and prednisolone (group III). EC was diagnosed by esophagogastroduodenoscopy. Results: The overall incidence of EC was 10.5%. Group II patients had a significantly higher incidence (28.6%) than those in group I (10.4%) and group III (3.8%). EC was noted earlier in patients in groups II and III, who were on higher doses of steroids than group I patients. Dysphagia (57.1%) was the most common presenting symptom of EC, but 21.4% of patients were asymptomatic. Oral thrush was present in 42.9%. The entire esophageal mucosa was affected in six (46.1%) patients in group II and one (20%) in group III. No correlation was found between fungal serology or daily dose of steroids and extent of esophageal involvement. Treatment included nystatin in seven, nystatin and ketoconazole in 10, ketoconazole alone in eight, amphotericin B in one, and ketoconazole and amphotericin B in two episodes. Treatment failure occurred in seven (25%). Three patients died of disseminated candidiasis. Serology and biopsy were poor predictors of dissemination. Conclusions: In this retrospective study of renal allograft recipients, patients on triple drug immunosuppression, diabetics, and those with myelosuppression had an increased risk of developing EC. This high incidence calls for prophylactic use of antifungal agents in selected renal transplant recipients.     

An agonist-induced switch in G protein coupling of the gonadotropin-releasing hormone receptor regulates pulsatile neuropeptide secretion

The pulsatile secretion of gonadotropin-releasing hormone (GnRH) from normal and immortalized hypothalamic GnRH neurons is highly calcium-dependent and is stimulated by cAMP. It is also influenced by agonist activation of the endogenous GnRH receptor (GnRH-R), which couples to G(q/11) as indicated by release of membrane-bound alpha(q/11) subunits and increased inositol phosphate/Ca(2+) signaling. Conversely, GnRH antagonists increase membrane-associated alpha(q/11) subunits and abolish pulsatile GnRH secretion. GnRH also stimulates cAMP production but at high concentrations has a pertussis toxin-sensitive inhibitory effect, indicative of receptor coupling to G(i). Coupling of the agonist-activated GnRH-R to both G(s) and G(i) proteins was demonstrated by the ability of nanomolar GnRH concentrations to reduce membrane-associated alpha(s) and alpha(i3) levels and of higher concentrations to diminish alpha(i3) levels. Conversely, alpha(i3) was increased during GnRH antagonist and pertussis toxin treatment, with concomitant loss of pulsatile GnRH secretion. In cholera toxin-treated GnRH neurons, decreases in alpha(s) immunoreactivity and increases in cAMP production paralleled the responses to nanomolar GnRH concentrations. Treatment with cholera toxin and 8-bromo-cAMP amplified episodic GnRH pulses but did not affect their frequency. These findings suggest that an agonist concentration-dependent switch in coupling of the GnRH-R between specific G proteins modulates neuronal Ca(2+) signaling via G(s)-cAMP stimulatory and G(i)-cAMP inhibitory mechanisms. Activation of G(i) may also inhibit GnRH neuronal function and episodic secretion by regulating membrane ion currents. This autocrine mechanism could serve as a timer to determine the frequency of pulsatile GnRH release by regulating Ca(2+)- and cAMP-dependent signaling and GnRH neuronal firing.     

Low incidence of bleeding-related morbidity with left ventricular assist device implantation in the current era

Left ventricular assist device (LVAD) implantation is historically associated with high incidence of bleeding‐related complications, very high reexploration rates, and frequently massive blood transfusion. Bleeding predisposes to mortality, sepsis, allosensitization, and right ventricular failure. We present results of an integrated approach to reduce bleeding complications. Analysis of 51 implantable LVADs implanted in 50 patients (mean age 52 years; male, 45; Intragency Registry for Mechanically Assisted Circulatory Support [INTERMACS] 1 or 2, 25) in our center in 2008 and 2009, including 15 reoperations. Preoperative coagulopathy was evident in 10 patients. Our strategy included: early LVAD implantation, preoperative nutritional support and hemodynamic optimization, preferential use of continuous flow LVADs, meticulous surgical hemostasis, liberal application of tricuspid annuloplasty, and blood product utilization based on point‐of‐care testing. Two patients (4%) were reexplored for bleeding. Median transfusion rates intraoperatively were: blood: 2 units (interquartile range [IQR] 0–4); plasma: 0 units (0–2.75); platelets: 0 pools (0–1.75), while postoperative transfusion rates for first 48 h were blood: 1 unit (0–2); plasma: 0 units (0–0.75); and platelets: 0 pools (0,1). Right ventricular assist device was utilized in six patients (11%). Median chest tube drainage in first 24 h was 1230 mL (IQR 862–1687). Median time on ventilator was 2 days, intensive care unit was 6 days, and hospitalization was 18 days. Hospital mortality was 20%. Using an integrated approach, we have experienced bleeding and transfusion rates similar to that seen in non‐LVAD complex cardiac operations. The potential to reduce bleeding reduces invasiveness of LVAD surgery, reduces allosensitization, may improve outcomes, and may increase mainstream acceptability of LVADs as definitive therapy for heart failure.     

Metformin in Peritoneal Dialysis: A Pilot Experience

♦ Objective: In a number of patients, the antidiabetic drug metformin has been associated with lactic acidosis. Despite the fact that diabetes mellitus is the most common cause of end-stage renal disease (ESRD) and that peritoneal dialysis (PD) is an expanding modality of treatment, little is known about optimal treatment strategies in the large group of PD patients with diabetes. In patients with ESRD, the use of metformin has been limited because of the perceived risk of lactic acidosis or severe hypoglycemia. However, metformin use is likely to be beneficial, and PD might itself be a safeguard against the alleged complications.♦ Methods: Our study involved 35 patients with insulin-dependent type 2 diabetes [median age: 54 years; interquartile range (IQR): 47-59 years] on automated PD (APD) therapy. Patients with additional risk factors for lactic acidosis were excluded. Metformin was introduced at a daily dose in the range 0.5 - 1.0 g. All patients were monitored for glycemic control by blood sugar levels and HbA1c. Plasma lactic acid levels were measured weekly for 4 weeks and then monthly to the end of the study. Plasma and effluent metformin and plasma lactate levels were measured simultaneously.♦ Results: In this cohort, the median duration of diabetes was 18 years (IQR: 14 - 21 years), median time on PD was 31 months (IQR: 27 - 36 months), and median HbA1c was 6.8% (IQR: 5.9% - 6.9%). At metformin introduction and at the end of the study, the median anion gap was 11 mmol/L (IQR: 9 - 16 mmol/L) and 12 mmol/L (IQR: 9 - 16 mmol/L; p > 0.05) respectively, median pH was 7.33 (IQR: 7.32 - 7.36) and 7.34 (IQR: 7.32 - 7.36, p > 0.05) respectively, and mean metformin concentration in plasma and peritoneal fluid was 2.57 ± 1.49 mg/L and 2.83 ± 1.7 mg/L respectively. In the group overall, mean lactate was 1.39 ± 0.61 mmol/L, and hyperlactemia (>2 mmol/L to 5 mmol/L) was found in 4 of 525 plasma samples (0.76%), but the patients presented no symptoms. None of the patients registered a plasma lactate level above 5 mmol/L. We observed no correlation between plasma metformin and plasma lactate (r = 0.27).♦ Conclusions: Metformin may be used with caution in APD patients with insulin-dependent type 2 diabetes. Although our study demonstrated the feasibility of metformin use in APD, it was not large enough to demonstrate safety; a large-scale study is needed.     

Systematic Review and Meta-Analysis of Antimicrobial Treatment Effect Estimation in Complicated Urinary Tract Infection

Noninferiority trial design and analyses are commonly used to establish the effectiveness of a new antimicrobial drug for treatment of serious infections such as complicated urinary tract infection (cUTI). A systematic review and meta-analysis were conducted to estimate the treatment effects of three potential active comparator drugs for the design of a noninferiority trial. The systematic review identified no placebo trials of cUTI, four clinical trials of cUTI with uncomplicated urinary tract infection as a proxy for placebo, and nine trials with reports of treatment effect estimates for doripenem, levofloxacin, or imipenem-cilastatin. In the meta-analysis, the primary efficacy endpoint of interest was the microbiological eradication rate at the test-of-cure visit in the microbiological intent-to-treat population. The estimated eradication rates and corresponding 95% confidence intervals (CI) were 31.8% (26.5% to 37.2%) for placebo, 81% (77.7% to 84.2%) for doripenem, 79% (75.9% to 82.2%) for levofloxacin, and 80.5% (71.9% to 89.1%) for imipenem-cilastatin. The treatment effect estimates were 40.5% for doripenem, 38.7% for levofloxacin, 34.7% for imipenem-cilastatin, and 40.8% overall. These treatment effect estimates can be used to inform the design and analysis of future noninferiority trials in cUTI study populations.     

Oral myiasis: A case report

Myiasis is a disease commonly seen in animals, especially sheep and cattle. The condition is rare in man. A patient with a neglected fractured mandible with superimposed myiasis is reported.     

Reactivity of hydroxyl groups in cellulose towards chlorotri(p-tolyl)methane

The reactivity of primary and secondary hydroxyl groups of cellulose towards chlorotri(p-tolyl)methane in pyridine was studied in the temperature range of 60 to 100°C. The rate of reaction with the primary hydroxyl groups was found to be 43 times faster than that with the secondary hydroxyl groups of cellulose. The kinetic data showed that the reactivity of chlorotri(p-tolyl)methane towards primary hydroxyl groups of cellulose is higher than that of chlorotriphenylmethane (trityl chloride). The energies of activation for the reaction of primary and secondary hydroxyl groups of cellulose with chlorotri(p-tolyl)methane were found to be 39,6 and 43,1 kJ · mol^?1, respectively. The reaction was observed to be pseudo first order.