Combination of BCG and interferon intravesical immunotherapy: an update

Objective

To provide an update on the use of interferon (IFN) in the treatment of non-muscle invasive bladder cancer (NMIBC).

Methods

A literature review of intravesical IFN was performed.

Results

In vitro evidence suggested that IFN combined with BCG may have a synergistic effect on the immune response, and treatment regimens with IFN have used reduced BCG dosage in an attempt to reduce toxicity. IFN combined with BCG may salvage some patients, single-course BCG failures or late relapsers, while those that relapse quickly may be destined to failure. However, based on the results of a recently reported randomized trial, the addition of IFN may not improve efficacy in BCG naïve patients.

Conclusions

BCG plus IFN remains an alternative in selected patients with NMIBC who fail intravesical BCG.

     

Tim-3 expression represents dysfunctional tumor infiltrating T cells in renal cell carcinoma

Purpose

Renal cell carcinoma (RCC) is the most common cancer of kidney. Evidences have shown that RCC is sensitive to various immunotherapies. Tim-3 plays a role in suppressing Th1-mediated immune responses. However, no study has yet examined the effect of Tim-3 on tumor infiltrating lymphocytes (TILs) in RCC.

Methods

We investigated the expression and function of Tim-3 on TIL CD4+ T cells and TIL CD8+ T cells from 30 RCC patients.

Results

Levels of Tim-3 were significantly increased on both TIL CD4+ T cells and TIL CD8+ T cells and were associated with higher stages of the cancer. Also, GATA-3 and interferon gamma (IFN-γ) were down-regulated, whereas T-bet was up-regulated in TIL Tim-3+ T cells, indicating that Tim-3 expression defined a population of dysfunctional TIL Th1/Tc1 cells. Mechanism analyses showed that TIL Tim-3-expressing CD8+ T cells exhibited impaired Stat5 and p38 signaling pathway. Blocking the Tim-3 pathway restored cell proliferation and increased IFN-γ production in TIL CD4+ and CD8+ T cells of RCC.

Conclusions

These results suggest that Tim-3 may be used as a novel target for increasing immune responses in RCC tumor microenvironment.

     

Acute exercise during hemodialysis prevents the decrease in natural killer cells in patients with chronic kidney disease: a pilot study

Purpose

To evaluate the acute response of natural killer (NK) cell subsets of chronic kidney disease patients submitted to intradialytic exercise in a randomized crossover study.

Methods

Nine patients were submitted to a single bout of 20-min intradialytic exercise and a control hemodialysis (HD) session with an interval of 7 days between them. Peripheral blood sample was collected at baseline, during HD and immediately after HD in each trial to evaluate the peripheral frequency of NK cells and their subsets (CD3-CD56^bright and CD3-CD56^dim), systemic cortisol concentrations, C-reactive protein (CRP), creatine kinase activity (CK), and urea and creatinine levels.

Results

HD therapy induced a significant decrease in NK cells frequency (p = 0.039), NK CD3-CD56^bright cells (p = 0.04), and CD3-CD56^dim cells (p = 0.036). On the other hand, no significant alterations were observed in NK cells and NK subsets during and after intradialytic exercise trial (p > 0.05). Neither trial altered CRP levels or serum CK activity during and after HD therapy (p > 0.05). However, HD therapy increased cortisol concentrations after HD therapy (p = 0.034).

Conclusions

This study suggests the potential role of intradialytic exercise to prevent the decrease in peripheral frequency of NK cell subsets during HD therapy. Moreover, moderate intensity intradialytic exercise did not exacerbate the systemic inflammation or induce muscle damage during HD therapy.

     

Efficacy and safety of a new device for intravesical thermochemotherapy in non-grade 3 BCG recurrent NMIBC: a phase I–II study

Purpose

We report for the first time the activity and safety of Unithermia^® (Elmedical Ltd, Hod-Hasharon, Israel), a novel device for administration of MMC-C with hyperthermia (HT), that employs conductive heating, in a series of non-grade 3 non-muscle-invasive bladder cancer (NMIBC) that failed Bacillus Calmette–Guerin (BCG).

Methods

Patients with non-grade 3 NMIBC recurring after at least a full induction course of BCG were eligible for this phase I–II prospective single-arm study. Six weekly instillations with Unithermia^® were scheduled following complete TUR. Primary end points were treatment safety and response rate (RR), and the latter defined as the absence of any unfavourable outcome at 12 months. Any grade 3 and/or muscle-invasive (T > 1) recurrence was considered disease progression. Kaplan–Meier estimation of the time to recurrence and progression, cancer-specific survival and overall survival was taken as secondary end points.

Results

Thirty-four eligible patients entered the study between January 2009 and April 2011. RR was documented in 20/34 (59 %). Among the 14/34 (41 %) non-responders, four developed G3 disease, one developed carcinoma in situ, and one progressed to muscle-invasive bladder cancer, with an overall 18 % progression rate at 1 year. At a median follow-up of 41 months, recurrence and progression rates were 35.3 and 23.5 %, respectively. Toxicity did not go beyond grade 2 except in five cases.

Conclusions

Initial experience with MMC-HT with Unithermia^® showed an interesting activity and safety profile in non-grade 3 NMIBC recurring after BCG, suggesting a role as second-line therapy in this selected subgroup of NMIBC.

     

Anti-inflammatory use may not negatively impact oncologic outcomes following intravesical BCG for high-grade non-muscle-invasive bladder cancer

Purpose

To evaluate whether anti-inflammatory agents affect outcomes in patients receiving intravesical BCG therapy for high-grade (HG) non-muscle-invasive bladder cancer (NMIBC).

Methods

We reviewed the records of 203 patients in a prospective database of HG NMIBC from 2006 to 2012 at a single institution. Patients who had muscle-invasive disease (n = 32), low-grade pathology (n = 4), underwent early cystectomy within 3 months (n = 25), had <3 months of follow-up (n = 11), or did not receive an induction course of intravesical BCG (n = 32) were excluded. Clinicopathologic data were tabulated including demographics, comorbidities, pathologic stage and grades, intravesical therapy, and concomitant use of aspirin, NSAIDs, COX inhibitors, and statins. Multivariate Cox regression analysis explored predictive factors for recurrence, progression (stage progression or progression to cystectomy), cancer-specific survival (CSS), and overall survival (OS).

Results

Ninety-nine patients with HG NMIBC who received at least one induction course of intravesical BCG were identified, with median follow-up of 31.4 months. There were 20 (20.2 %) deaths, including 6 (6.1 %) patients with bladder cancer-related mortality. 13 % patients experienced tumor progression and 27 % underwent cystectomy following failure of intravesical therapy. Anti-inflammatory use included statins (65 %), aspirin (63 %), or non-aspirin NSAIDs/COX inhibitors (26 %). Anti-inflammatory use was not significantly predictive of recurrence, progression, or mortality outcomes on Cox regression. CIS stage was associated with higher progression, while age, BMI, and Charlson score were independent predictors of overall mortality.

Conclusion

Despite speculation of inhibitory effects on BCG immunomodulation there was no evidence that anti-inflammatory agents impacted oncologic outcomes in patients receiving BCG for HG NMIBC.

     

Current Clinical Trials in Non-muscle Invasive Bladder Cancer

Purpose of Review

As our molecular understanding of bladder cancer continues to advance, more and more novel agents are entering clinical trials across the spectrum of bladder cancer stages. The clinical trial activity for non-muscle invasive bladder cancer (NMIBC) has been boosted further by the evolution of specific disease states that set more uniform inclusion criteria for clinical trial design. Here, we aimed to review the current clinical trials landscape in non-muscle invasive bladder cancer with respect to these disease states.

Recent Findings

Most active clinical trials focus on high-risk NMIBC in either the BCG-naïve or BCG-unresponsive setting. Strict criteria to define the disease state and a clear pathway to drug registration have encouraged trials for patients with BCG-unresponsive NMIBC. The most promising potential breakthroughs for BCG-naïve patients include alternative BCG strains, immune-priming with intradermal BCG vaccination, and systemic immune checkpoint blockade. The latter therapy is also being actively investigated in multiple trials in BCG-unresponsive NMIBC, along with novel viral agents such as INSTILADRIN (nadofaragene firadenovec) and targeted agents such as oportuzumab monatox.

Summary

After many years of relative stagnation, multiple new therapies currently under investigation in well-designed clinical trials appear poised for routine clinical implementation in the near future. These therapies should dramatically improve the outcome of patients with NMIBC. We can look forward to the challenges of biomarker-driven drug selection, optimal drug sequencing, and rational combination therapies.

     

A care bundle to improve perioperative mitomycin use in non-muscle-invasive bladder cancer

Purpose

Intravesical chemotherapy administered within 24 h of the first resection of non-muscle-invasive bladder cancer (NMIBC) reduces recurrence rates and prolongs recurrence-free intervals. However, there is considerable variation in the use of intravesical chemotherapy amongst urologists. In our hospital, we use mitomycin C (MMC), and our usage was inconsistent. Therefore, we devised a care bundle to improve MMC usage. The objective of this study was to evaluate the effectiveness of the care bundle on postoperative MMC use.

Methods

We measured baseline postoperative MMC use during the first quarter of 2013. In 2014, we implemented a care bundle by changing MMC delivery, through computer-based clinical information systems and repeated training of key stakeholders. We studied the performance of the bundle through snapshot audits in the last quarter of 2014, a 6-month period in the middle of 2015 and again in the final quarter of 2016.

Results

We observed an increase in intravesical chemotherapy usage after implementing the care bundle. Instillation rates in our samples increased from 46% (6/13), in 2013 to 89% (8/9), in 2014, 90% (9/10), in 2015 and 100% (12/12), in 2016.

Conclusion

Compliance rates of intravesical chemotherapy in NMIBC can improve by devising care bundles to modify team behaviour.

     

Patellaformen

Background

Patella height is discussed as a possible factor in the development of osteoarthritis of the knee.

Methods

PubMed literature search

Results

Contradictory results are found in the literature.

Conclusion

According to the literature, there is currently no evidence that abnormal patella height can induce osteoarthritis of the knee.

     

Relationship between fatigue symptoms and subjective and objective indicators in hemodialysis patients

Purpose

The purpose of the study was to investigate the major factors affecting fatigue symptoms and to examine the relationships between fatigue symptoms and subjective and objective indicators in patients on hemodialysis (HD).

Methods

Patients on HD who met the inclusion criteria were chosen from two grade A tertiary general hospitals by convenience sampling and cross-sectional survey methods.

Results

A total of 511 patients were included in the study. The morbidity rate of fatigue in patients on HD was 61.6%, and the median fatigue level was 3.91. Fatigue and subjective indicators showed a mild-moderate relationship (0.3?<?all |r|?<?0.6, all P?<?0.001), whereas a weak correlation was found between fatigue and objective indicators (all |r|?<?0.2, all P?<?0.05). Multivariate analysis showed that subjective indicators, including employment, exercise time, appetite, the vitality of 36-item Short Form Health Survey, perceived social support, intrafamilial support, cramping, headache, chest tightness, and whole-body pain, as well objective indicator, such as serum intact parathyroid hormone levels, were the influence factors of fatigue in patients on HD.

Conclusion

The prevalence of fatigue symptoms was high and the level of fatigue was moderate in patients on HD. Subjective and objective indicators can both affect fatigue symptoms in patients on HD.

     

Entzündlich-rheumatische Erkrankungen

Background

Inflammatory rheumatic diseases can lead to cartilage changes.

Methods

PubMed literature search

Results

The rheumatoid arthritis can produce degrading enzymes and cause cartilage damage; longitudinal studies do not exist.

Conclusion

There are no high level studies. The expert opinion is that infammatory rheumatic diseases can lead to osteoarthritis of the knee.

     

Komplikationsmanagement im Internet Marketing

Background

New patients come more and more often over the internet; therefore internet marketing plays an increasingly important role.

Question

How can physicians build an effective internet marketing strategy and avoid complications?

Method

Selection and authorization of a reputable agency.

Results

New customer acquisition through high visibility in the internet, at the same time increasing the image and awareness.

Conclusions

In the overall “marketing mix” internet marketing has become indispensable to physicians who want to be successful. Those who are well positioned in Google are well known by their target audience and thus receive a higher response.

     

Harnröhrenrekonstruktion bei vorausgegangener Hypospadieoperation

Background

The tasks involved in reconstructing the urethra after failed hypospadias repair range from correction of a trivial meatal stenosis to reconstruction of the entire anterior urethra.

Objectives

To describe pathological findings in the urethra after failed hypospadias repair and the respective surgical methods used for their correction.

Materials and methods

The various pathological findings after unsuccessful hypospadias surgery are classified according to their location and complexity.

Results

The general rules of reconstruction that should be applied in each particular situation are described.

Conclusions

Successful reconstruction of the urethra in patients with failed hypospadias surgery requires experience and good knowledge of the anatomy of the normal and hypospadic urethra and penis. Mastery of plastic surgical techniques and profound knowledge of the various surgical methods of hypospadias surgery are essential.

     

Versorgung von Notfallpatienten in Bedrohungslagen

Background

The increasing threat of terrorist attacks necessitates adaption of preclinical emergency medicine.

Objective

Presentation of international lessons learned, the current approach of the military and police and deductions for the German authorities and organizations.

Material and methods

Review of the currently available literature and comparison with the author’s experience in tactical medicine.

Results

Guidelines for tactical combat casualty care (TCCC) provide a powerful tool that reduces the risk for responders and casualties and increases the probability of survival by directing the provider towards diagnosis and treatment of the most relevant injury patterns.

Conclusion

The principles of military guidelines are also applicable and successful in civil terrorist scenarios. The key to success is not only the training of medical personnel in these guidelines but also appropriate training and equipment for police forces.

     

miR-363 induces transdifferentiation of human kidney tubular cells to mesenchymal phenotype

Background

microRNAs (miRNAs) are non-coding small RNAs that regulate embryonic development, cell differentiation and pathological processes via interaction with mRNA. Epithelial–mesenchymal transition (EMT) is pathological process that involves in a variety of diseases such as cancer or fibrosis.

Methods

In this study, we identified miR-363 as a potent inducer of EMT by microarray analysis in human kidney tubular cells, and analyzed the function and mechanisms of miR-363.

Results

Overexpression of miR-363 induced mesenchymal phenotypes with loss of epithelial phenotypes in human kidney tubular cells. In addition, in vitro scratch assay demonstrated that miR-363 promotes cell migration of primary culture of human kidney tubular cells. We identified TWIST/canonical WNT pathway as the downstream effecter of miR-363, and inhibition of canonical WNT by small molecule, IWR-1, attenuated EMT induced by miR-363.

Conclusion

miR-363 induces transdifferentiation of human kidney tubular cells via upregulation of TWIST/canonical WNT pathway.

     

Feasibility of intermittent back-filtrate infusion hemodiafiltration to reduce intradialytic hypotension in patients with cardiovascular instability: a pilot study

Background

Intradialytic hypotension (IDH) is one of the major problems in performing safe hemodialysis (HD). As blood volume depletion by fluid removal is a major cause of hypotension, careful regulation of blood volume change is fundamental. This study examined the effect of intermittent back-filtrate infusion hemodiafiltration (I-HDF), which modifies infusion and ultrafiltration pattern.

Methods

Purified on-line quality dialysate was intermittently infused by back filtration through the dialysis membrane with a programmed dialysis machine. A bolus of 200 ml of dialysate was infused at 30 min intervals. The volume infused was offset by increasing the fluid removal over the next 30 min by an equivalent amount. Seventy-seven hypotension-prone patients with over 20-mmHg reduction of systolic blood pressure during dialysis or intervention-requirement of more than once a week were included in the crossover study of 4 weeks duration for each modality. In a total of 1632 sessions, the frequency of interventions, the blood pressure, and the pulse rate were documented.

Results

During I-HDF, interventions for symptomatic hypotension were reduced significantly from 4.5 to 3.0 (per person-month, median) and intradialytic systolic blood pressure was 4 mmHg higher on average. The heart rate was lower during I-HDF than HD in the later session. Older patients and those with greater interdialytic weight gain responded to I-HDF.

Conclusions

I-HDF could reduce interventions for IDH. It is accompanied with the increased intradialytic blood pressure and the less tachycardia, suggesting less sympathetic stimulation occurs. Thus, I-HDF could be beneficial for some hypotension-prone patients.

UMIN registration number

000013816.

     

Enhanced Endoscopy in Bladder Cancer

Purpose of Review

Endoscopy coupled with targeted resections represents a cornerstone in the diagnosis, staging, and treatment of patients with bladder cancer. Direct visualization can be challenging and imprecise due to patient-, tumor-, and surgeon-specific factors. We will review contemporary endoscopic technologies and techniques used to improve our ability to safely identify and resect malignant lesions in patients with bladder cancer.

Recent Findings

Enhanced endoscopic imaging technology may improve detection rates for bladder cancer throughout the upper and lower urinary tract, which may lead to improvements in recurrence and progression rates for non-muscle invasive bladder cancer (NMIBC). New techniques including narrow-band imaging (NBI), photodynamic diagnosis (PDD), Storz Professional Image Enhancement System (SPIES), optical coherence tomography (OCT), and others have shown benefit and may further improve our ability to detect and stage bladder tumors.

Summary

Enhanced endoscopy technologies have already demonstrated value in improving the sensitivity of bladder cancer detection and early results suggest they may improve short- and long-term oncologic outcomes.

     

Identification of physical and psychosocial problems associated with diabetic nephropathy using the International Classification of Functioning,Disability and Health Core Set for Diabetes Mellitus

Background

We previously demonstrated validation of the Comprehensive International Classification of Functioning, Disability and Health Core Set for Diabetes Mellitus (ICF-CS for DM) in patients with diabetic nephropathy (DMN). The objective of the present study was to identify differences in experience of physical and psychosocial problems between DMN patients with and without hemodialysis (HD), and diabetes patients without nephropathy using the ICF-CS for DM.

Methods

A total of 302 diabetes outpatients (men, 68 %; mean age, 62 years) were interviewed using four components of the ICF-CS for DM including “Body functions”, “Body structures”, “Activities and participation”, and “Environmental factors”.

Results

The mean number of categories in which difficulty was experienced in the four components was significantly greater in DMN patients with HD followed by DMN patients without HD, and diabetes patients without nephropathy (23.9 vs. 18.0 vs. 13.1, respectively). Multivariate logistic regression models revealed that, compared with diabetes patients without nephropathy, diabetes patients with nephropathy were more likely to have difficulty with physical problems and social activities and participation. Among DMN patients, dialysis patients were found to have larger numbers of problems, and face difficulty with employment status after adjusting for sex, age, type, and duration of diabetes.

Conclusion

The results of this study using the ICF-CS for DM identified the areas for improvement among physical and psychosocial problems in DMN patients with and without HD in contrast to diabetes patients without nephropathy.

     

Arthroskopische subakromiale Dekompression

Objective

Coracoacromial ligament release to widen the subacromial space, resection of the anterior undersurface of the acromion and, if needed, caudal exophytes at the acromioclavicular joint.

Indications

All types of outlet impingement after 3 months of conservative treatment.

Contraindications

Impingement syndrome with instability/muscular imbalance, massive rotator cuff tear, unstable os acromionale, posterior–superior impingement, joint infection, freezing phase of a secondary frozen shoulder.

Surgical technique

Lateral decubitus position with traction device for the arm. Diagnostic arthroscopy of the glenohumeral joint via standard portals. With arthroscope moved to the subacromial space, bursectomy, electrosurgical release of coracoacromial ligament, resection of acromial hook through standard posterior portal.

Postoperative management

Physiotherapy or self-exercises on postoperative day 1, pain-adapted analgesia to avoid shoulder stiffness.

Results

Several studies present positive long-term results compared to conservative treatment (and open acromioplasty) for partial rotator cuff tears and for elderly patients. With a 20-year follow-up, successful results have been achieved for all patients with isolated impingement syndrome.

     

Cam morphology and inguinal pathologies: is there a possible connection?

Background

To analyse the prevalences of the cam and pincer morphologies in a cohort of patients with groin pain syndrome caused by inguinal pathologies.

Materials and methods

Forty-four patients (40 men and 4 women) who suffered from groin pain syndrome were enrolled in the study. All the patients were radiographically and clinically evaluated following a standardised protocol established by the First Groin Pain Syndrome Italian Consensus Conference on Terminology, Clinical Evaluation and Imaging Assessment in Groin Pain in Athlete. Subsequently, all of the subjects underwent a laparoscopic repair of the posterior inguinal wall.

Results

The study demonstrated an association between the cam morphology and inguinal pathologies in 88.6% of the cases (39 subjects). This relationship may be explained by noting that the cam morphology leads to biomechanical stress at the posterior inguinal wall level.

Conclusions

Athletic subjects who present the cam morphology may be considered a population at risk of developing inguinal pathologies.

Level of evidence

Level IV, Observational cross-sectional study.