A two‐drug combination simulation study for metastatic castrate resistant prostate cancer

Background

Prostate cancer often evolves resistance to androgen deprivation therapy leading to a lethal metastatic castrate‐resistant form. Besides androgen independence, subpopulations of the tumor are genetically heterogeneous. With the advent of tumor genome sequencing we asked which has the greater influence on reducing tumor size: genetic background, heterogeneity, or drug potency?

Methods

A previously developed theoretical evolutionary dynamics model of stochastic branching processes is applied to compute the probability of tumor eradication with two targeted drugs. Publicly available data sets were surveyed to parameterize the model.

Results

Our calculations reveal that the greatest influence on successful treatment is the genetic background including the number of mutations overcoming resistance. Another important criteria is the tumor size at which it is still possible to achieve tumor eradication, for example, 2‐4 cm large tumors have at best a 10% probability to be eradicated when 50 mutations can confer resistance to each drug.

Conclusion

Overall, this study finds that genetic background and tumor heterogeneity are more important than drug potency in treating mCRPC. It also points toward identifying metastatic sites early using biochemical assays and/or dPET.

     

A five‐CpG DNA methylation score to predict metastatic‐lethal outcomes in men treated with radical prostatectomy for localized prostate cancer

Background

Prognostic biomarkers for localized prostate cancer (PCa) could improve personalized medicine. Our group previously identified a panel of differentially methylated CpGs in primary tumor tissue that predict disease aggressiveness, and here we further validate these biomarkers.

Methods

Pyrosequencing was used to assess CpG methylation of eight biomarkers previously identified using the HumanMethylation450 array; CpGs with strongly correlated (r >0.70) results were considered technically validated. Logistic regression incorporating the validated CpGs and Gleason sum was used to define and lock a final model to stratify men with metastatic‐lethal versus non‐recurrent PCa in a training dataset. Coefficients from the final model were then used to construct a DNA methylation score, which was evaluated by logistic regression and Receiver Operating Characteristic (ROC) curve analyses in an independent testing dataset.

Results

Five CpGs were technically validated and all were retained (P < 0.05) in the final model. The 5‐CpG and Gleason sum coefficients were used to calculate a methylation score, which was higher in men with metastatic‐lethal progression (P = 6.8 × 10^?6) in the testing dataset. For each unit increase in the score there was a four‐fold increase in risk of metastatic‐lethal events (odds ratio, OR = 4.0, 95%CI = 1.8–14.3). At 95% specificity, sensitivity was 74% for the score compared to 53% for Gleason sum alone. The score demonstrated better prediction performance (AUC = 0.91; pAUC = 0.037) compared to Gleason sum alone (AUC = 0.87; pAUC = 0.025).

Conclusions

The DNA methylation score improved upon Gleason sum for predicting metastatic‐lethal progression and holds promise for risk stratification of men with aggressive tumors. This prognostic score warrants further evaluation as a tool for improving patient outcomes.

     

The Relationship Between Metformin and Serum Prostate‐Specific Antigen Levels

BACKGROUND

Metformin is the first‐line oral antihyperglycemic of choice for individuals with type 2 diabetes. Recent evidence supports a role for metformin in prostate cancer chemoprotection. However, whether metformin indeed influences prostate biology is unknown. We aimed to study the association between metformin and serum prostate‐specific antigen (PSA) levels—the primary prostate cancer biomarker.

METHODS

We conducted a cross‐sectional study of 326 prostate cancer‐free men with type 2 diabetes were recruited between 2004 and 2013 at St. Michael's Hospital. Men were excluded if they had a PSA ≥10‐ng/ml, or used >2,550‐mg/d metformin or supplemental androgens. Multivariate linear regressions quantified the association between metformin dose and log‐PSA. Secondary analyses quantified the association between other antihyperglycemics (sulfonylureas, thiazolidinediones) and PSA; sensitivity analyses tested covariate interactions.

RESULTS

Median PSA was 0.9‐ng/ml (IQR: 0.5–1.6‐ng/ml). Metformin dose associated positively with BMI, HbA1c, diabetes duration, and number of statin, acetylsalicylic acid, diuretic users, and number of antihyperglycemics used, and negatively with LDL‐C. In multivariate models, PSA changed by ?8% (95%CI: ?13 to ?2%, P = 0.011) per 500‐mg/d increase in metformin. Men with diabetes for ≥6 years (n = 163) saw a greater difference in PSA per 500‐mg/d metformin (?12% [95% CI: ?19 to ?4%, P = 0.002], P‐interaction = 0.018). Serum PSA did not relate with sulfonylureas, thiazolidinediones, or total number of antihyperglycemic agents used. Our findings are limited by the cross‐sectional design of this study.

CONCLUSIONS

Metformin dose‐dependently inversely associated with serum PSA, independent of other antihyperglycemic medications. Whether metformin confers a dose‐dependent benefit on prostate tumorigenesis and progression warrants investigation. Prostate 76:1445–1453, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc.

     

The efficacy and safety of cold‐induced lipolysis in the treatment of pseudogynecomastia

Background

The treatment options for pseudogynecomastia have been limited. Cold‐induced lipolysis provides a noninvasive, localized subcutaneous adipocyte destruction by inducing adipocyte apoptosis.

Objective

This study has been designed to evaluate the efficacy of cold‐induced lipolysis as a treatment modality for pseudogynecomastia.

Methods

In this 28‐week prospective trial, a total of 12 male pseudogynecomastia patients (Korean) were treated twice with cold‐induced lipolysis. Efficacy was determined by chest circumference, ultrasonographic measurement of fat thickness, Simon's Gynecomastia class (SGC), photographic assessment, and the patient's satisfaction (baseline, weeks 4, 8, 16, and 28). Using a questionnaire, safety was evaluated at each visit.

Results

For 10 subjects that completed the trial, chest circumference and fat thickness significantly improved by week 8. This same improvement was gradually noticed through week 28. The patients SGC scores continuously decreased after two sessions. Photographic assessment showed an improvement until week 28. The result of the patient's satisfaction score was also meaningful. While there were no adverse events observed, transient pain and bruising at the treatment site were noticed.

Limitations

We recruited a limited number of participants. Also, we could not exclude there might be other individual factors in association with the patients pseudogynecomastia.

Conclusion

Cold‐induced lipolysis is a safe, effective therapeutic option in the treatment of pseudogynecomastia. Lasers Surg. Med. 48:584–589, 2016. © 2016 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals Inc.

     

Influence of the neural microenvironment on prostate cancer

Background

Nerves are key factors in prostate cancer (PCa), but the functional role of innervation in prostate cancer is poorly understood. PCa induced neurogenesis and perineural invasion (PNI), are associated with aggressive disease.

Method

We denervated rodent prostates chemically and physically, before orthotopically implanting cancer cells. We also performed a human neoadjuvant clinical trial using botulinum toxin type A (Botox) and saline in the same patient, before prostatectomy.

Result

Bilateral denervation resulted in reduced tumor incidence and size in mice. Botox treatment in humans resulted in increased apoptosis of cancer cells in the Botox treated side. A similar denervation gene array profile was identified in tumors arising in denervated rodent prostates, in spinal cord injury patients and in the Botox treated side of patients. Denervation induced exhibited a signature gene profile, indicating translation and bioenergetic shutdown. Nerves also regulate basic cellular functions of non‐neoplastic epithelial cells.

Conclusion

Nerves play a role in the homeostasis of normal epithelial tissues and are involved in prostate cancer tumor survival. This study confirms that interactions between human cancer and nerves are essential to disease progression. This work may make a major impact in general cancer treatment strategies, as nerve/cancer interactions are likely important in other cancers as well. Targeting the neural microenvironment may represent a therapeutic approach for the treatment of human prostate cancer.

     

Purely off‐clamp robotic partial nephrectomy: Preliminary 3‐year oncological and functional outcomes

Objectives

To describe our surgical technique and to report perioperative, 3‐year oncological and functional outcomes of a single‐center series of purely off‐clamp robotic partial nephrectomy.

Methods

A prospective renal cancer institutional database was queried, and data of consecutive patients treated with purely off‐clamp robotic partial nephrectomy between 2010 and 2015 in a high‐volume center were collected. Perioperative complications, and 3‐year oncological and functional outcomes were assessed. Univariable and multivariable analyses were carried out to identify independent predictors of renal function deterioration.

Results

Out of 308 patients treated, 41 (13.3%) experienced perioperative complications, 2.9% of which were Clavien grade ≥3. The 3‐year local recurrence‐free survival and renal cell carcinoma‐specific survival rates were 99.5% and 97.9%, respectively. No patient with preoperative chronic kidney disease stage ≤3B developed severe renal function deterioration (chronic kidney disease stage 4) at 1‐year follow up. At multivariable analysis, preoperative estimated glomerular filtration rate (P = 0.005) was the only independent predictor of a new‐onset chronic kidney disease stage ≥3 in patients with preoperative chronic kidney disease stages 1 or 2.

Conclusions

Off‐clamp robotic partial nephrectomy is a safe surgical approach in tertiary referral centers, with adequate oncological outcomes and negligible impact on renal function.

     

Partial nephrectomy for small children: Robot‐assisted versus open surgery

Objectives

To compare the outcomes of robot‐assisted heminephrectomy for duplex kidney in children with those of open heminephrectomy.

Methods

The present retrospective multicentric analysis reviewed the records of robot‐assisted versus open heminephrectomy carried out for duplex kidney in children from 2007 to 2014. Demographic data, weight, surgical time, hospital stay, complications and outcome were recorded. Follow up was based on a clinical review, renal sonography and dimercaptosuccinic acid renal scintigraphy.

Results

A total of 15 patients underwent robot‐assisted heminephrectomy, and 13 patients underwent retroperitoneal heminephrectomy by open approach. All patients weighed <15 kg. The mean age at the time of surgery was 20.2 months (range 7–39 months) in the robotic group, and 18.4 months (range 6–41 months) in the open group. The mean hospital stay was statistically longer for the open surgery group (6.3 days, range 5–8 days vs 3.4 days, range 1–7 days; P < 0.001). Regarding postoperative pain control, total morphine equivalent intake was statistically greater for the open group (0.52 mg/kg/day vs 1.08 mg/kg/day; P < 0.001). No patient lost the remaining healthy moiety. There was no significant difference in terms of operating time, complication rate or renal outcomes.

Conclusions

Robot‐assisted heminephrectomy in small children seems to offer comparable renal outcomes with those of its standard open surgery counterpart. Specific technical adjustments are necessary, which typically increase the set‐up time.

     

Primary whole‐gland ablation for localized prostate cancer with high‐intensity focused ultrasound: The important predictors of biochemical recurrence

Objectives

To identify predictive factors of biochemical recurrence for patients undergoing high‐intensity focused ultrasound treatment for localized prostate cancer.

Methods

We retrospectively identified patients receiving whole‐gland prostate ablation with high‐intensity focused ultrasound for localized prostate cancer from 2009 to 2015. All the patients received pre‐high‐intensity focused ultrasound radical transurethral resection of the prostate. We included perioperative parameters as follows: age, preoperative prostate volume, stage of operation, initial prostate‐specific antigen, T stage, postoperative prostate‐specific antigen nadir, Gleason score, time to prostate‐specific antigen nadir and the presence of prostate‐specific antigen biochemical recurrence. Multivariable Cox regression and Kaplan–Meier analysis were used for investigating predictors of recurrence, and receiver operating characteristic analysis was used for the cut‐off values of prostate‐specific antigen nadir.

Results

Among 182 patients, 26.9% had prostate‐specific antigen biochemical recurrence after high‐intensity focused ultrasound during the median follow‐up period of 32.21 months. Gleason score ≥7 (Gleason score 7, hazard ratio 2.877, P = 0.027), stage ≥T2b (T2b, hazard ratio 3.16, P = 0.027) and prostate‐specific antigen nadir (hazard ratio 1.11, P < 0.001) were statistically significant, whereas there was no significance in prostate volume and initial prostate‐specific antigen. We posit that a cut‐off level of prostate‐specific antigen nadir 0.43 ng/mL might be considered as an independent predictive factor for prostate‐specific antigen biochemical recurrence in high‐intensity focused ultrasound patients in multivariate analysis (P < 0.001, hazard ratio 7.39, 95% confidence interval 3.56–15.37), and created a new nadir‐related prediction model for biochemical recurrence prediction.

Conclusions

Postoperative prostate‐specific antigen nadir of 0.43 ng/mL can be considered an important predictive factor for biochemical recurrence in primary whole‐prostate gland high‐intensity focused ultrasound treatment, and the nadir‐related prediction model might provide a reference for early salvage treatment. Furthermore, Gleason score ≥7, stage ≥T2b might be associated with unfavorable outcomes, although prostate volume and higher initial prostate‐specific antigen appear not to be associated with biochemical recurrence for the high‐intensity focused ultrasound treatment.

     

Impact of a novel biopsy instrument with a 25‐mm side‐notch needle on the detection of prostate cancer in transrectal biopsy

Objectives

To evaluate the impact of a novel biopsy instrument that extends the length of the side‐notch on the detection of prostate cancer in transrectal needle biopsy.

Methods

We collaborated with a biopsy needle manufacturer and developed a novel biopsy instrument (PRIMECUT II long‐notch type) with a 25‐mm side‐notch length and 28‐mm stroke length to take longer tissue cores. The sampled core length, cancer detection rate, pain and complications of 489 patients who underwent transrectal biopsy using the long‐notch needle were compared with those of 469 patients who underwent biopsy using a normal instrument with a 19‐mm side‐notch length and 22‐mm stroke length.

Results

The mean length of tissue taken by the long‐notch needle was significantly longer than that of tissue taken by the normal‐notch needle (16.3 vs 22.4 mm, P < 0.001). The overall cancer detection rate was 42.0% for the normal‐notch needle and 51.1% for the long‐notch needle (P = 0.005). In patients with a prostate volume of 20–40 mL, the cancer detection rate for the long‐notch needle was especially higher than that for the normal‐notch needle (74.2% vs 47.5%, P < 0.001). Multivariate analysis showed that the long‐notch needle improved cancer detection significantly (odds ratio 1.702, P < 0.001). There were no differences of pain during biopsy and complication between the two groups.

Conclusions

The novel biopsy instrument with a 25‐mm side‐notch can take longer tissue samples safely and has a significantly higher rate of prostate cancer detection in transrectal biopsy.

     

Recurrent stone‐forming patients have high visceral fat ratio based on computed tomography images compared to first‐time stone‐forming patients

Objectives

To compare various fat parameters based on computed tomography images between recurrent stone‐forming patients and patients forming stones for the first time.

Methods

Included in the present study were 300 patients with upper urinary tract calculi who had undergone active stone removal in our hospital. Using pretreatment computed tomography images, we measured visceral fat area and volume, subcutaneous fat area and volume, visceral fat area ratio and visceral fat volume ratio. We compared patient backgrounds and these fat parameters between those who recurrently formed stones and those who formed stones for the first time. We also performed logistic regression analysis to identify factors that contribute to severe stones.

Results

A total of 148 (49.3%) patients were recurrent stone‐forming patients. Recurrent stone‐forming patients were statistically significantly younger (P < 0.01) and there were more male patients (P < 0.01). In addition, visceral fat area ratio and visceral fat volume ratio in recurrent stone‐forming patients were significantly higher than those in first‐time stone‐forming patients (P = 0.03 and P = 0.01, respectively). On the other hand, there was no significant difference in visceral fat area (P = 0.32), subcutaneous fat area (P = 0.36), visceral fat volume (P = 0.38) or subcutaneous fat volume (P = 0.23). Receiver operating characteristics analysis showed that area under the curve of visceral fat volume ratio (0.583) for recurrent stones was larger than that of visceral fat area ratio (0.571). In multivariate analysis, increasing visceral fat volume ratio was an independent significant predictor of recurrent stones (P = 0.04).

Conclusions

Recurrent stone‐forming patients have high visceral fat ratios compared to first‐time stone‐forming patients, shown here for the first time.

     

Contralateral adrenal width predicts the duration of prolonged post‐surgical steroid replacement for subclinical Cushing syndrome

Objectives

To identify pre‐treatment factors affecting the duration of post‐surgical steroid replacement in patients undergoing adrenalectomy for subclinical Cushing syndrome.

Methods

The present retrospective analysis included 64 patients who underwent unilateral laparoscopic adrenalectomy for subclinical Cushing syndrome. Adrenal tumor and contralateral adrenal sizes together with various clinical factors were studied in association with the duration of post‐surgical steroid replacement. Adrenal tumor and contralateral adrenal size were measured at the level of the maximum transverse plane of the adrenal glands using computed tomography scan or magnetic resonance imaging. Cox's proportional hazards model was used for the statistical analysis.

Results

All 64 patients were treated with post‐surgical steroid replacement after adrenalectomy. The median duration of the steroid treatment was 6 months. When assessing the duration of post‐surgical steroid replacement, contralateral adrenal volume <0.745 cm³, contralateral adrenal width <6.15 mm and serum cortisol after a 1‐mg dexamethasone suppression test >2.65 μg/dL were significant predictors of prolonged post‐surgical steroid treatment on univariate analysis. On multivariate analysis, contralateral adrenal width <6.15 mm was the only independent predictive factor for the prolonged post‐surgical steroid replacement.

Conclusions

Contralateral adrenal width seems to represent a significant predictive factor for the duration of post‐surgical steroid replacement in subclinical Cushing syndrome patients. Pre‐surgical assessment of image findings might help clinicians determine the total duration of steroid therapy after adrenalectomy.

     

Transurethral seminal vesiculoscopy acts as a therapeutic investigation for intractable hemospermia: Step‐by‐step illustrations and single‐surgeon experience

Objective

To describe the methodology of transurethral seminal vesiculoscopy and the anatomy of the seminal tract, and to report a single‐surgeon experience with this procedure.

Methods

A total of 38 consecutive patients with intractable macroscopic hemospermia were enrolled from January 2010 to July 2016. A 6/7.5‐Fr semirigid ureteroscope was used to enter the seminal tract by one of these two approaches: through either a trans‐ejaculatory duct opening or a trans‐utricle fenestration. Patient characteristics and their preoperative and postoperative measurements were analyzed retrospectively.

Results

The success rate of transurethral seminal vesiculoscopy was 92.1%, whereas the approaching method in most patients was the trans‐utricle fenestration (88.89%). A total of 34 (94.4%) transurethral seminal vesiculoscopy inspections ended with complete remission, even though nearly half of them (47.2%) only disclosed negative perioperative findings. The median period to complete remission was 4 weeks (interquartile range 4–6 weeks) after the procedure. Four patients had recurrent hemospermia, and the median time to recurrence was 21.5 (range 13–48.5) months.

Conclusions

Transurethral seminal vesiculoscopy is a valuable diagnostic tool for intractable hemospermia, and also plays a therapeutic role by blocking the vicious cycle of stasis, calculi and seminal vesiculitis. More familiarity of the anatomy and enough practice would make the learning curve less steep.

     

Systematic overview and critical appraisal of meta‐analyses of interventions in intensive care medicine

Rationale

Meta‐analysed intervention effect estimates are perceived to represent the highest level of evidence. However, such effects and the randomized clinical trials which are included in them need critical appraisal before the effects can be trusted.

Objective

Critical appraisal of a predefined set of all meta‐analyses on interventions in intensive care medicine to assess their quality and assessed the risks of bias in those meta‐analyses having the best quality.

Methods

We conducted a systematic search to select all meta‐analyses of randomized clinical trials on interventions used in intensive care medicine. Selected meta‐analyses were critically appraised for basic scientific criteria, (1) presence of an available protocol, (2) report of a full search strategy, and (3) use of any bias risk assessment of included trials. All meta‐analyses which qualified these criteria were scrutinized by full “Risk of Bias in Systematic Reviews” ROBIS evaluation of 4 domains of risks of bias, and a “Preferred Reporting Items for Systematic Reviews and Meta‐Analyses” PRISMA evaluation.

Results

We identified 467 meta‐analyses. A total of 56 meta‐analyses complied with these basic scientific criteria. We scrutinized the risks of bias in the 56 meta‐analyses by full ROBIS evaluation and a PRISMA evaluation. Only 4 meta‐analyses scored low risk of bias in all the 4 ROBIS domains and 41 meta‐analyses reported all 27 items of the PRISMA checklist.

Conclusion

In contrast with what might be perceived as the highest level of evidence only 0.9% of all meta‐analyses were judged to have overall low risk of bias.

     

Correlations of SELENOF and SELENOP genotypes with serum selenium levels and prostate cancer

Background

Selenium status is inversely associated with the incidence of prostate cancer. However, supplementation trials have not indicated a benefit of selenium supplementation in reducing cancer risk. Polymorphisms in the gene encoding selenoprotein 15 (SELENOF) are associated with cancer incidence/mortality and present disproportionately in African Americans. Relationships among the genotype of selenoproteins implicated in increased cancer risk, selenium status, and race with prostate cancer were investigated.

Methods

Tissue microarrays were used to assess SELENOF levels and cellular location in prostatic tissue. Sera and DNA from participants of the Chicago‐based Adiposity Study Cohort were used to quantify selenium levels and genotype frequencies of the genes for SELENOF and the selenium‐carrier protein selenoprotein P (SELENOP). Logistic regression models for dichotomous patient outcomes and regression models for continuous outcome were employed to identify both clinical, genetic, and biochemical characteristics that are associated with these outcomes.

Results

SELENOF is dramatically reduced in prostate cancer and lower in tumors derived from African American men as compared to tumors obtained from Caucasians. Differing frequency of SELENOF polymorphisms and lower selenium levels were observed in African Americans as compared to Caucasians. SELENOF genotypes were associated with higher histological tumor grade. A polymorphism in SELENOP was associated with recurrence and higher serum PSA.

Conclusions

These results indicate an interaction between selenium status and selenoprotein genotypes that may contribute to the disparity in prostate cancer incidence and outcome experienced by African Americans.

     

Delay in Diagnosis and Its Effect on Clinical Outcome in High‐grade Sarcoma of Bone: A Referral Oncological Centre Study

Objective

To investigate delay in diagnosis by both patients and doctors, and to evaluate its effect on outcomes of high‐grade sarcoma of bone in a single‐referral oncological center.

Methods

Fifty‐four patients with osteosarcoma, 29 with Ewing sarcoma and 19 with chondrosarcoma were enrolled in this retrospective study. Delay in diagnosis was defined as the period between initial clinical symptoms and histopathological diagnosis at our center. The delays were categorized as patient‐ or doctor‐related. Short total delays were defined as <4 months; prolonged delays >4 months were assumed to have prognostic relevance.

Results

Total delay in diagnosis was 688.0 days in patients with chondrosarcoma, which is significantly longer than the 163.3 days for osteosarcoma (P < 0.01) and 160.2 days for Ewing sarcoma (P < 0.01). Most doctor‐related delays were at the pre‐hospital stage, occurring at the general practitioner (GP)'s office. However, prolonged total delays (≥4 months) did not result in lower survival rates. Five‐year‐overall survival rates were 67.0% for osteosarcoma, 49.0% for Ewing sarcoma and 60.9% for chondrosarcoma. Survival was significantly lower for patients with metastatic disease for all three types of sarcoma.

Conclusion

Prolonged delay in diagnosis does not result in lower survival. Metastatic disease has a pronounced effect on survival. Aggressive tumor behavior results in shorter delays. Minimizing GP‐related delays could be achieved by adopting a lower threshold for obtaining plain radiographs at the pre‐hospital stage.

     

Effects of hexanic extract of serenoa repens (permixon® 160 mg) on inflammation biomarkers in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia

Background

Chronic prostatic inflammation (CPI) could be a cause of symptomatic or complicated benign prostatic hyperplasia (BPH). In previous in vitro and in vivo studies, Hexanic Extract of Serenoa repens (HESr) namely Permixon^® has demonstrated potent anti‐inflammatory properties. With the aim to provide new insight onto HESr anti‐inflammatory properties in human we explore its effect on CPI biomarkers in men with lower urinary tract symptoms (LUTS) related to BPH using a non‐invasive method and investigate links between biomarkers and clinical symptoms.

Methods

An international, randomized, double‐blind, parallel‐group, tamsulosin‐controlled study was carried out in 206 men with BPH‐related LUTS. Patients received oral daily HESr 320mg or tamsulosin 0.4 mg during 3 months. The first urine stream after digital rectal examination (DRE) was collected at Day 1 and Day 90 and mRNA was extracted from prostatic epithelial cells desquaming in the lumen of the glands and seminal plasma fluid after DRE. mRNA quantification of the 29 most significant published inflammation markers in BPH and protein detection in urine was performed.

Results

At D90, a decrease in mean gene expression was observed for 65.4% of the markers detected in the HESr group versus 46.2% in the tamsulosin group. In the 15 most frequently expressed genes, this difference was higher (80% vs. 33% respectively). Three proteins (MCP‐1/CCL2, IP‐10/CXCL10, and MIF) were detected. At D90, a decrease in the number of patients who expressed MCP‐1/CCL2 and IP‐10/CXCL10 was observed only in the HESr group. Moreover, MIF expression was significantly reduced by HESr compared with tamsulosin (P = 0.007). Finally, in contrast to tamsulosin, the subgroup of patients treated by HESr and who over expressed MIF at baseline, had a higher response to the International Prostate Symptom Score (I‐PSS) than those who did not over express this protein (mean I‐PSS change: ?6.4 vs. ?4.5 respectively). As the study is exploratory, results should be confirmed in a powered clinical study.

Conclusions

These results showed for the first time at clinical level the anti‐inflammatory properties of HESr, already indicated in BPH‐related LUTS. Thus, HESr could be of interest to prevent unfavourable evolution in patients with CPI. Prostate 75:1857–1867, 2015. © 2015 The Authors. The Prostate Published by Wiley Periodicals, Inc.

     

Optimal timing of HIV home‐based counselling and testing rounds in Western Kenya

Introduction

Weaknesses in care programmes providing anti‐retroviral therapy (ART) persist and are often instigated by late HIV diagnosis and poor linkage to care. We investigated the potential for a home‐based counselling and testing (HBCT) campaign to be improved through the optimal timing and enhancement of testing rounds to generate greater health outcomes at minimum cost.

Methods

Using a mathematical model of HIV care calibrated to longitudinal data from The Academic Model Providing Access To Healthcare (AMPATH) in Kenya, we simulated HBCT campaigns between 2016 and 2036, assessing the impact and total cost of care for each, for a further 20 years.

Results

We find that simulating five equally spaced rounds averts 1.53 million disability‐adjusted life‐years (DALYs) at a cost of $1617 million. By altering the timing of HBCT rounds, a four‐round campaign can produce greater impact for lower cost. With “front‐loaded” rounds, the cost per DALY averted is reduced by 12% as fewer rounds are required ($937 vs. $1060). Furthermore, improvements to HBCT coverage and linkage to care avert over two million DALYs at a cost per DALY averted of $621 (41% less than the reference scenario).

Conclusions

Countries implementing HBCT can reduce costs by optimally timing rounds and generate greater health outcomes through improving linkage, coverage, and retention. Tailoring HBCT campaigns to individual settings can enhance patient outcomes for minimal cost.

     

The cost‐effectiveness and budgetary impact of a dolutegravir‐based regimen as first‐line treatment of HIV infection in India

Introduction

Dolutegravir (DTG)‐based antiretroviral therapy (ART) is recommended for first‐line HIV treatment in the US and Europe. Efavirenz (EFV)‐based regimens remain the standard of care (SOC) in India. We examined the clinical and economic impact of DTG‐based first‐line ART in the setting of India's recent guidelines change to treating all patients with HIV infection regardless of CD4 count.

Methods

We used a microsimulation of HIV disease, the Cost‐Effectiveness of Preventing AIDS Complications (CEPAC)‐International model, to project outcomes in ART‐naive patients under two strategies: (1) SOC: EFV/tenofovir disoproxil fumarate (TDF)/lamivudine (3TC); and (2) DTG: DTG + TDF/3TC. Regimen‐specific inputs, including virologic suppression at 48 weeks (SOC: 82% vs. DTG: 90%) and annual costs ($98 vs. $102), were informed by clinical trial data and other sources and varied widely in sensitivity analysis. We compared incremental cost‐effectiveness ratios (ICERs), measured in $/year of life saved (YLS), to India's per capita gross domestic product ($1600 in 2015). We compared the budget impact and HIV transmission effects of the two strategies for the estimated 444,000 and 916,000 patients likely to initiate ART in India over the next 2 and 5 years.

Results

Compared to SOC, DTG improved 5‐year survival from 76.7% to 83.0%, increased life expectancy from 22.0 to 24.8 years (14.0 to 15.5 years, discounted), averted 13,000 transmitted HIV infections over 5 years, increased discounted lifetime care costs from $3040 to $3240, and resulted in a lifetime ICER of $130/YLS, less than 10% of India's per capita GDP in 2015. DTG maintained an ICER below 50% of India's per capita GDP as long as the annual three‐drug regimen cost was ≤$180/year. Over a 2‐ or 5‐year horizon, total undiscounted outlays for HIV‐related care were virtually the same for both strategies.

Conclusions

A generic DTG‐based regimen is likely to be cost‐effective and should be recommended for initial therapy of HIV infection in India.

     

Targeted HIV testing at birth supported by low and predictable mother‐to‐child transmission risk in Botswana

Introduction

Most African countries perform infant HIV testing at 6 weeks or later. The addition of targeted testing at birth may improve retention in care, treatment outcomes and survival for HIV‐infected infants.

Methods

HIV‐exposed infants were screened as part of the Early Infant Treatment (EIT) study in Botswana. Screened infants were ≥35 weeks gestational age and ≥2000 g at birth. Risk factors for mother‐to‐child transmission (MTCT) were assessed by maternal obstetric card or verbally. Risk factors included <8 weeks ART in pregnancy, last known CD4 <250 cells/mm³, last known HIV RNA >400 copies/mL, poor maternal ART adherence, lack of maternal zidovudine (ZDV) in labour, or lack of infant post‐exposure prophylaxis. Infants underwent dried blood spot testing by Roche Cobas Ampliprep/Cobas Taqman HIV‐1 qualitative PCR.

Results

From April 2015 to April 2016, 2303 HIV‐exposed infants were tested for HIV in the EIT study. Of these, 369 (16%) were identified as high risk for HIV infection by information available at birth, and 12 (0.5% overall, 3.25% of high risk) were identified as HIV positive at birth. All 12 positive infants were identified as high risk at the time of screening, and only 2 risk factors were required to identify all positive infants: either <8 weeks of maternal ART in pregnancy (75%) or lack of maternal HIV suppression at last test (25%).

Conclusions

In utero MTCT occurred only among infants identified as high risk at delivery, using information available from the mother or obstetric record. Birth testing that targets high‐risk infants based on maternal ART receipt is likely to identify the majority of in utero HIV transmissions, and allows early ART initiation for these infants.