Upper tract urothelial carcinoma following intravesical bacillus Calmette-Guérin therapy for nonmuscle-invasive bladder cancer: Results from a multi-institutional retrospective study

Objectives

The aim of this study was to clarify the prognostic indicators for upper tract urothelial carcinoma (UTUC) following intravesical bacillus Calmette-Guérin (BCG) therapy for nonmuscle-invasive bladder cancer (NMIBC).

Case report: differential diagnosis of isolated iliac lymphadenopathy following Bacillus Calmette-Guérin treatment for high-risk superficial bladder cancer

We report the unusual case of a patient with G3 pT1 transitional cell carcinoma (TCC) of the bladder, which was treated with repeated transurethral resection and maintenance intravesical Bacillus Calmette-Guérin (BCG) therapy. At 30 months follow-up, a symptomatic, solitary iliac lymph node mass was identified and biopsied. Histology demonstrated granulomatous tissue only, in the absence of any intravesical bladder tumour recurrence. Following 6 months of anti-tuberculous medication, the mass had progressed, and repeat biopsy revealed undifferentiated carcinoma (of a bladder primary). This is a rare case of metastatic superficial bladder cancer progression without local recurrence after BCG therapy. As such, it can be viewed as a diagnostic challenge.     

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.

     

卡介苗灌注治疗肾移植继发膀胱癌患者的初步经验

目的:总结卡介苗膀胱灌注治疗肾移植继发膀胱癌患者的经验。方法:回顾性分析2015年1月至2019年12月天津市第一中心医院5例肾移植后继发膀胱癌行卡介苗膀胱灌注患者的临床资料。男1例,女4例;移植后应用免疫抑制剂期间1例(例1)继发高级别非肌层浸润性膀胱癌(NMIBC),3例(例2、3、5)继发低级别NMIBC,1例(...     

Early postoperative complications after middle lobe-preserving surgery for secondary lung cancer

Purpose

Preservation of the middle lobe during lung surgery is traditionally avoided, because its presence in the hemithoracic cavity is considered a cause of complications. We report a series of lung cancer patients who underwent a secondary pulmonary resection with the preservation of the middle lobe to explore the complications and feasibility of these procedures.

Methods

We reviewed the clinical courses of six patients who underwent surgery for metachronous lung cancers. Five patients underwent right upper lobectomy, including one sleeve lobectomy, after having undergone prior right lower lobectomy. The remaining patient underwent a right lower lobectomy after having undergone a prior right upper lobectomy.

Results

There were no treatment-related deaths. One patient was readmitted for surgery to treat delayed air leakage progressing to pyothorax. One patient was treated for persistent air leakage. Two patients required intermittent drainage of pulmonary effusion, because of middle lobe atelectasis. The postoperative forced vital capacity and forced expiratory volume in 1 s were greater than the values predicted post-pneumonectomy in four evaluable patients.

Conclusions

While postoperative complications after middle lobe-preserving surgery are manageable, their high incidence should be considered when performing this surgery.

     

Granulomatous renal mass during endovesical BCG therapy for bladder carcinoma. Diagnosis by fine-needle aspiration

One case of pseudotumoral granulomatous renal mass during endovesical bacillus Calmette-Guérin (BCG) therapy for superficial bladder neoplasm is reported. Such an adverse effect is exceptional and is clearly related to a vesicorenal reflux in our patient. In this case ultrasound-guided fine-needle aspiration was able to settle the diagnosis and avoid surgery. The patient responded to triple antituberculous therapy.     

The use of immediate postoperative instillations of intravesical chemotherapy after TURBT of NMIBC among European countries

Purpose

The aim of this study was to assess the use of immediate postoperative instillation of intravesical chemotherapy (IPOIC) after transurethral resection of bladder tumour (TURBT) of nonmuscle invasive bladder cancer (NMIBC) in Europe.

Methods

Urologists based in five European Union nations were asked to extract information from the records of patients with NMIBC–urothelial carcinoma who received at least one TURBT. Multivariate logistic regression models were developed to determine the significant predictors of IPOIC usage. Data were weighted to control for country-to-country and other differences.

Results

Overall, 324 urologists (58 France, 72 Germany, 62 Italy, 65 Spain, 67 United Kingdom) were involved; the participation rate was 55 %. Overall, 771 patients received 954 TURBTs (mean—1.2/patient), of which 413 of the TURBTs (43.3 %) were administered IPOIC . Sixty-six of the 413 IPOICs (16.0 %) were for a recurrent tumour. Five of the tested variables were significantly associated with a patient’s likelihood of receiving IPOIC after TURBT. Variables in the order of significance are as follows: (1) country (United Kingdom, patients most likely to receive IPOIC; France, least likely); (2) progression risk (physician assessed) [lower-risk conditions (no CIS, tumour < 3 cm) or intermediate risk—more likely]; (3) whether urologist completed a uro-oncology fellowship (completed—more likely); (4) recurrence risk (physician assessed) [higher-risk conditions (≥T2, ≥3 cm, CIS)—more likely]; and (5) physician’s NMIBC patients volume (higher volume—more likely).

Conclusions

This study revealed wide practice variation and substantial noncompliance with European Association of Urology Guidelines on the use of IPOIC after TURBT for NMIBC.     

Granulomatous prostatitis after intravesical BCG immunotherapy of superficial bladder cancer: a case report

We report a case of granulomatous prostatitis after intravesical BCG immunotherapy for superficial bladder cancer. A 58-year-old man presented with gross hematuria. Cystoscopic examination revealed multiple tumors at the posterior wall of the bladder. The patient underwent transurethral resection of the tumor. Intravesical BCG immunotherapy was postoperatively followed and it eradicated the disease. Digital examination revealed that the prostate became stony-hard and larger 10 weeks after the initial BCG immunotherapy. A needle aspiration cytology and biopsy of the prostate revealed the granulomatous prostatitis due to BCG immunotherapy.     

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.

     

Outcomes After Hepatic and Pulmonary Metastasectomies Compared With Pulmonary Metastasectomy Alone in Patients With Colorectal Cancer Metastasis to Liver and Lungs

Background

Surgical resection is the most effective treatment for colorectal cancer that has metastasized to the liver. Similarly, surgical resection improves survival for selected patients with pulmonary colorectal metastases. However, the indication for pulmonary metastasectomy is not clear in patients with both hepatic and pulmonary colorectal metastases. Therefore, we evaluated outcomes after pulmonary resection of colorectal metastases in patients with or without a history of curative hepatic metastasectomy.

Methods

We retrospectively analyzed 96 patients who underwent pulmonary metastasectomy from March 1999 to November 2009. Patients were grouped according to treatment: resection of pulmonary metastases alone (lung metastasectomy group) or resection of both hepatic and pulmonary metastases (liver and lung metastasectomy group). Overall survival (OS) and disease-free survival (DFS) were evaluated by Kaplan–Meier analysis. Survival curves were compared using the log-rank test.

Results

The 5-year OS for all patients was 61.3 %, and the 5-year DFS was 26.7 %. Group comparisons showed that the 5-year OS of the lung metastasectomy group was significantly better than that of the liver and lung metastasectomy group (69 vs. 43 %; p = 0.030). However, the 5-year DFS rates of the lung metastasectomy group (25.8 %) and liver and lung metastasectomy group (28.0 %) did not differ significantly. Recurrence was higher after resection of both hepatic and pulmonary metastases than after pulmonary metastases alone (79 vs. 45 %; p = 0.025).

Conclusions

Resection of pulmonary colorectal metastases may increase survival. However, the combination of liver and lung metastasectomies had a worse prognosis than pulmonary metastasectomy alone. In selected patients, combined liver and lung metastasectomy can be beneficial and result in acceptable DFS.     

Primary adenocarcinoma of the epididymis: the therapeutic role of retroperitoneal lymphadenectomy

Aims

This case report describes a rare case of adenocarcinoma of the epididymis and the role of locoregional surgery in the therapeutic algorithm.

Clinical case

We report a case of primary adenocarcinoma of the epididymis in a 61-year-old man who was primarily examined for nodular enlargement of the head of the epididymis. Retroperitoneal lymphadenectomy which the patient underwent after radical orchiectomy revealed lymph node metastases, subsequently he received adjuvant chemotherapy. The patient remains free of disease for 20?months after surgery.

Conclusions

Primary adenocarcinoma of epididymis is a rare finding with an unfavorable prognosis in higher stages as it responds poorly to radiotherapy and chemotherapy. Our case report confirms the importance of retroperitoneal lymphadenectomy in patients with local or locoregional disease. It may be curative even in case of proven lymphadenopathy and should be performed in all patients without distant metastases.     

A rare complication from total extraperitoneal (TEP) laparoscopic inguinal hernia repair: bladder rupture associated with a balloon dissector

Purpose

We report a rare complication of TEP herniorrhaphy.

Methods

A 47-year-old man underwent TEP inguinal hernia repair.

Results

Bladder rupture was noted after balloon dissection. The defect was sutured, and the hernia was repaired under laparoscopy. Cystoscopy showed the site of injury at anterior bladder neck.

Conclusion

This is the first report of bladder rupture associated with balloon dissector in a patient with no prior abdominal surgery.     

Prognostic Value of Renin–Angiotensin System Blockade in Non-muscle-invasive Bladder Cancer

Background

To determine whether the administration of renin?Cangiotensin system (RAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), affect disease outcome in non-muscle-invasive bladder cancer (NMIBC).

Methods

A total of 330 patients with initially diagnosed NMIBC were identified. We retrospectively investigated the clinical outcomes after transurethral resection of bladder tumor (TUR-BT) in patients who did or did not receive RAS inhibitors. The median follow-up period was 4.1?years.

Results

A total of 128 patients (38.8?%) experienced subsequent tumor recurrence, and stage progression was observed in 17 patients (5.2?%) during follow-up. Fifty-one patients (15.5?%) had received ACEI or ARB administration at transurethral resection. Multivariate analysis demonstrated that tumor multiplicity, absence of bacillus Calmette-Guérin instillation, and no administration of ACEI or ARB (P?=?0.010, hazard ratio 2.26) were independent risk factors for subsequent tumor recurrence. The 5-year recurrence-free survival rate was 78.4?% in patients administered ACEIs or ARBs, and 53.3?% in their counterparts (P?=?0.011).

Conclusions

The absence of RAS inhibitor administration was an independent risk factor for subsequent tumor recurrence in patients with initially diagnosed NMIBC. Our data support further investigation of the role of RAS inhibitors as a potential therapy to decrease tumor recurrence in NMIBC.     

Female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated with bacillus Calmette-Guérin

Background

Controversy exists over the most important prognostic factors in T1 high-grade non–muscle-invasive bladder cancer (NMIBC) patients treated with bacillus Calmette-Guérin (BCG).

Objective

Evaluate prognostic factors for recurrence, progression, and disease-specific mortality after adjuvant intravesical BCG immunotherapy in patients with T1G3 NMIBC and long-term follow-up.

Design, setting, and participants

A single-institution retrospective analysis of 146 patients with primary stage T1G3 NMIBC.

Intervention

All patients were treated with complete transurethral resection (TUR) plus multiple bladder biopsies that included the prostatic urethra. No second TUR was done. Patients underwent an induction course of intravesical BCG (Connaught strain, 81 mg) without maintenance therapy.

Measurements

The variables analysed for time to recurrence, progression, and death due to bladder cancer (BCa) were gender, age, tumour multiplicity, diameter, aspect, substaging, concomitant carcinoma in situ (CIS), and CIS in the prostatic urethra. Cox regression models were used to assess the univariate and multivariate prognostic importance of these factors and estimate hazard ratios (HRs). Time-to-event distributions were estimated using cumulative incidence functions.

Results and limitations

The median follow-up was 8.7 yr. Sixty-five patients (44.5%) had recurrence, 25 patients (17.1%) had progression, and 18 patients (12.3%) died because of BCa. Female gender and presence of CIS in the prostatic urethra were associated with an increased risk of recurrence (p = 0.0003, HR: 2.53), progression (p = 0.001, HR: 3.59), and death due to BCa (p = 0.004, HR: 3.53).

Conclusions

In primary T1G3 bladder tumours treated with induction BCG, female gender or having CIS in the prostatic urethra were the only prognostic factors for time to recurrence, progression, and disease-related mortality. It is very important to perform a biopsy of the prostatic urethra in patients with primary high-grade NMIBC as a first step to obtain this prognostic information.     

Case report: Unusual complication during outpatient continuous regional popliteal analgesia

Purpose

Continuous regional anesthesia applied as pain therapy at home is clinically established standard practice after upper and lower limb surgery. Persistent motor block at discharge or after continuous infusion of local anesthetics, however, might lead to complications related to the insensate extremity. We report a rare case of a foot fracture due to stumbling after continuous sciatic nerve block at home and discuss the related clinical implications.

Clinical features

After uncomplicated ambulatory foot surgery under regional anesthesia, a patient was discharged with a continuous sciatic popliteal nerve block for pain therapy at home. After stumbling, the patient remained symptom-free even until catheter removal three days after surgery. Radiography done one week after surgery revealed a styloid fracture of the fifth metatarsal bone. Her subsequent recovery was uneventful.

Conclusions

The true incidence of complications related to falls at home associated with lower extremity blockade remains unknown, as symptoms of possible complications may be masked by the effects of the local anesthetic. However, with increasing use of postoperative regional anesthesia, it is mandatory to develop and adhere to clinical care maps, and to elaborate and teach strategies to further enhance patient safety.     

Immune phenotype of peripheral blood mononuclear cells in patients with high-risk non-muscle invasive bladder cancer

Purpose

To explore the immune phenotype of peripheral blood mononuclear cells (PBMC) in patients with high-risk non-muscle invasive bladder cancer (NMIBC).

Methods

We prospectively collected blood samples from patients with high-risk NMIBC treated at our institution. PBMC were analyzed by flow cytometry to determine the frequency of T cells and NK cells and the expression of immunoregulatory molecules (Tim-3, TIGIT and PD-1). PBMC from healthy donors (HD) were included for comparison, and associations with response to BCG were investigated.

Results

A total of 38 patients were included, 19 BCG responders and 19 BCG refractory. Compared to 16 PBMC from HD, the frequency of total NK cells was significantly higher in patients with NMIBC [15.2% (IQR: 11.4, 22.2) vs. 5.72% (IQR: 4.84, 9.79); p?=?0.05], whereas the frequency of T cells was not statistically different. Both Tim-3 and TIGIT expressions were significantly higher in NMIBC compared to HD, particularly in NK cells [13.8% (11.0; 22.4) vs. 5.56% (4.20; 10.2) and 34.9% (18.9; 53.5) vs. 1.82% (0.63; 5.16), respectively; p?<?0.001]. Overall, the expression of PD-1 in all cell types was low in both NMIBC patients and HD. The immune phenotype was not significantly different before and after initiation of BCG. However, the proportion of CD8⁺ T cells before BCG was significantly higher in responders.

Conclusion

The immune phenotype of PBMC from patients with high-risk NMIBC was significantly different from HD, regardless of the presence of disease or the initiation of BCG. Peripheral CD8⁺ T cells could play a role in response to BCG.

     

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.

     

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.

     

Treatment Options Available for Bacillus Calmette-Guérin Failure in Non–muscle-invasive Bladder Cancer

Context

Intravesical bacillus Calmette-Guérin (BCG) is a standard conservative treatment for patients with high-risk non–muscle-invasive bladder cancer (NMIBC). Many patients will experience recurrence or progression following BCG and are termed BCG failures.

Objective

To summarise the current treatment options available for patients with high-risk NMIBC who experience BCG failure.

Evidence acquisition

We searched the Medline, Embase, and Cochrane Trials databases for studies of BCG failure using predetermined relevant Medical Subject Heading terms and free text terms.

Evidence synthesis

Radical cystectomy (RC) should be strongly recommended when a patient has been deemed to fail BCG, if the patient is fit and fully informed of the risks, benefits, and quality-of-life issues. RC achieves long-term survival in excess of 90% with ongoing improvements in morbidity. While other salvage intravesical therapies have to be considered oncologically inferior to RC, several options are now available if bladder preservation is the objective. The options can be categorised as immunotherapy, chemotherapy, device-assisted therapy, and sequential combinations of these newer modalities with conventional therapy. Some agents have shown specific promise in BCG-failure patients (eg, gemcitabine, thermochemotherapy, taxane chemotherapy), and some modalities have been shown to be effective only in non–BCG-failure cohorts (eg, electromotive mitomycin).

Conclusions

The definition, prediction, and treatment of BCG failure remain unclear secondary to inconsistent studies and the heterogeneous entity of patients with NMIBC. RC should be the default position upon failing BCG, but if bladder preservation is sought, then several promising intravesical salvage options are available. It will be necessary to individually tailor the management of such patients based on tumour risk and medical profiles. Currently data are still inadequate to formulate definitive recommendations, and larger studies of salvage intravesical agents are urgently required.     

Atypical Pneumocystis jiroveci pneumonia with multiple nodular granulomas after rituximab for refractory nephrotic syndrome

Background

Rituximab, an anti-CD20 antibody that targets B cells, is a promising agent against steroid-dependent and steroid-resistant nephrotic syndrome in children.

Case-Diagnosis/Treatment

We report a 3-year-old boy who presented with atypical Pneumocystis jiroveci pneumonia (PCP) following administration of rituximab for refractory nephrotic syndrome. He had received cyclosporine and daily prednisolone for over 1?year. Following rituximab therapy, a hazy shadow was observed on his chest X-ray. Chest-computed tomography revealed multiple nodular lesions in bilateral lungs, although his clinical symptoms were subtle. PCR analysis demonstrated the presence of Pneumocystis DNA in his bronchoalveolar lavage. Lung wedge resection of the nodular lesion exhibited granulomas containing a few cysts of P. jiroveci that primarily consisted of T cells and histiocytes and lacked B cells. A deficiency of B cells following rituximab treatment suggests a dramatic effect on the immune response and, therefore, could result in granulomatous PCP. Nodular granulomatous lesions of PCP comprise an emerging concept previously reported in adults with hematological disease, bone marrow transplant, or treatment with rituximab. We report the first pediatric case of nodular PCP. Granulomatous PCP can be life-threatening. Moreover, bronchoalveolar lavage often fails to demonstrate the presence of P. jiroveci DNA. Wedge biopsy is warranted for definitive diagnosis. Our patient fully recovered with sulfamethoxazole/trimethoprim treatment because of early detection.

Conclusions

The indication of rituximab for refractory nephrotic syndrome has increased recently. Therefore, recognition of the risk of atypical PCP is important. Our findings suggest that PCP prophylaxis should be considered following rituximab therapy.