A case of pulmonary tuberculosis that developed during nivolumab and ipilimumab treatment for pulmonary adenocarcinoma that recurred two months after completion of anti-tuberculous treatment.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become key agents in the treatment of non-small cell lung cancer worldwide. However, immune-related adverse events (irAEs) must be addressed to maximize the efficacy of ICIs. Mycobacterium tuberculosis (Mtb) infection is considered as a type of irAE associated with ICIs, but the underlying mechanism is not completely understood. Here, we present a case of pulmonary tuberculosis (TB) that developed during administration of nivolumab and ipilimumab for pulmonary adenocarcinoma that recurred just 2 months after completion of anti-TB treatment. CASE DESCRIPTION: A 67-year-old man with lung adenocarcinoma was referred to our hospital for chemotherapy. He was a former smoker and had been diagnosed with stage IVA (cT4N1M1a) lung adenocarcinoma. Interferon-gamma release assay (IGRA) yielded positive results at the start of treatment. One month after initiating treatment with nivolumab and ipilimumab, he presented with productive cough and Mtb complex was cultured from sputum samples. Two months after completing anti-TB treatment, recurrence of TB was observed. The series of strains were found to be identical. CONCLUSIONS: This represents the first report of pulmonary TB that developed during nivolumab and ipilimumab treatment, and recurred 2 months after completing anti-TB treatment. Physicians should be mindful of the potential for TB recurrence following the use of ICIs, particularly in patients showing positive results from IGRA.

Decreased GM3 correlates with proteinuria in minimal change nephrotic syndrome and focal segmental glomerulosclerosis.

BACKGROUND: Glycolipids on cell membrane rafts play various roles by interacting with glycoproteins. Recently, it was reported that the glycolipid GM3 is expressed in podocytes and may play a role in podocyte protection. In this report, we describe the correlation between changes in GM3 expression in glomeruli and proteinuria in minimal change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS) patients. METHODS: We performed a case-control study of the correlation between nephrin/GM3 expression levels and proteinuria in MCNS and FSGS patients who underwent renal biopsy at our institution between 2009 and 2014. Normal renal tissue sites were used from patients who had undergone nephrectomy at our institution and gave informed consent. RESULTS: Both MCNS and FSGS had decreased GM3 and Nephrin expression compared with the normal (normal vs. MCNS, FSGS; all p < 0.01). Furthermore, in both MCNS and FSGS, GM3 expression was negatively correlated with proteinuria (MCNS: r = - 0.61, p < 0.01, FSGS: r = - 0.56, p < 0.05). However, nephrin expression had a trend to correlate with proteinuria in FSGS (MCNS: r = 0.19, p = 0.58, FSGS: r = - 0.48, p = 0.06). Furthermore, in a simple linear regression analysis, GM3 expression also correlated with proteinuric change after 12 months of treatment (MCNS: r = 0.40, p = 0.38, FSGS: r = 0. 68, p < 0.05). CONCLUSION: We showed for the first time that decreased GM3 expression correlates with proteinuria in MCNS and FSGS patients. Further studies are needed on the podocyte-protective effects of GM3.

Renal functional outcome after laparoscopic partial nephrectomy using dynamic renal scintigraphy.

INTRODUCTION To explore postoperative operation-side renal functional outcome after laparoscopic partial nephrectomy (LPN) using dynamic renal scintigraphy. MATERIALS AND METHODS: Between July 2006 and December 2014, 62 patients with localized renal tumor received ischemic LPN at our institution. Preoperative, 6 months postoperative, and 12 months postoperative split renal functions were evaluated by dynamic renal scintigraphy using radionuclide technetium-99m-mercaptoacetyltriglycine. Postoperative operation-side renal function was calculated. To assess the significant factors affecting postoperative operation-side renal functional decrease, simple regression and multiple regression analyses were carried out. RESULTS: Postoperative operation-side renal functions were significantly decreased to 86.6% at 6 months and 86.9% at 12 months postoperatively (p < 0.0001). Simple regression analyses revealed that postoperative operation-side renal functions were significantly decreased with prolonged warm ischemia time at 6 months and 12 months postoperatively (p = 0.0058 and 0.0032, respectively). Multiple regression analysis identified warm ischemia time as an independent predictive factor for operation-side renal functional decreases at 6 months and 12 months postoperatively (p = 0.0158 and 0.0109, respectively). CONCLUSIONS: Irreversible renal damage using dynamic renal scintigraphy after LPN was observed. With prolongation of warm ischemia time during LPN, postoperative operation-side renal function was significantly decreased.

Pembrolizumab for Previously Untreated Patients with Advanced Non-small-cell Lung Cancer and Preexisting Interstitial Lung Disease.

Objective Pembrolizumab has benefited patients with advanced non-small-cell lung cancer (NSCLC) with a programmed death-ligand (PD-L) 1 high expression, but little information is available regarding its safety for patients with interstitial lung disease (ILD). The aim of this study was to assess the efficacy and tolerability of pembrolizumab for patients with advanced NSCLC and preexisting ILD. Methods We retrospectively reviewed the medical records of five patients with advanced NSCLC and preexisting ILD who received pembrolizumab monotherapy in a first-line setting. Patients All patients had mild ILD and pulmonary emphysema with a forced vital capacity within the normal range. Pembrolizumab was administered at a dose of 200 mg/body on day 1 every 3 weeks. Results The overall response rate was 60%. Four patients developed pembrolizumab-induced lung injury, which was improved in all cases by corticosteroid therapy. One patient received pembrolizumab for two years, did not experience lung injury and achieved a complete response. Conclusion Pembrolizumab has a high risk of inducing lung injury in patients with preexisting ILD, although it may be very effective in NSCLC patients with a high PD-L1 expression, even concurrent with preexisting ILD. Further large-scale studies are needed to determine risk factors of pembrolizumab-induced lung injury in such patients.

[A Case of Retroperitoneal Mature Teratoma Successfully Treated by Laparoscopic Adrenalectomy].

We report a case of retroperitoneal mature teratoma which was successfully treated by laparoscopic adrenalectomy. A 37-year-old woman complaining of right abdominal discomfort was referred to our hospital because computed tomography showed an adrenal tumor at another hospital. Magnetic resonance imaging showed a 10 cm adrenal tumor that consisted of fat with calcification. Endocrine examination showed no abnormal findings. Under the suspicion of myelolipoma, we performed laparoscopic right adrenalectomy. Histological diagnosis was mature teratoma. The patient had no recurrence at 5 years after surgery.

Outcome of third-line sunitinib after sequential therapy with cytokines and sorafenib in metastatic renal cell carcinoma.

Third-line sunitinib is occasionally used for selected patients with metastatic renal cell carcinoma (mRCC). The aim of the present study was to evaluate the clinical significance of third-line sunitinib after failure of first-line cytokine therapy and second-line sorafenib in patients with clear-cell mRCC. A total of 14 consecutive patients with clear-cell mRCC treated with third-line sunitinib between December 2008 and February 2012 were enrolled in the present study. Disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and relative dose intensity (RDI) were compared with those of first-line (n=20) and second-line (n=14) sunitinib treatment. The DCR was 42.9%, the median PFS was 12.0 months, and the median OS was 20.0 months for third-line sunitinib; there were no statistically significant differences compared with first-line and second-line sunitinib. The mean RDI was significantly lower for third-line sunitinib compared with first- and second-line sunitinib (P=0.0003 and 0.0109, respectively). Therefore, third-line sunitinib is an effective treatment option for selected patients with mRCC, as optimized therapeutic efficacy was obtained with a relatively low dose of sunitinib.

Pemetrexed Plus Platinum for Patients With Advanced Non-small Cell Lung Cancer and Interstitial Lung Disease.

BACKGROUND/AIM: Pemetrexed plus platinum followed by pemetrexed maintenance has been one of the standard first-line treatments in advanced nonsquamous non-small cell lung cancer (NSCLC), but little is known regarding its safety and efficacy for patients with interstitial lung disease (ILD). PATIENTS AND METHODS: The medical records of 24 patients with advanced nonsquamous NSCLC and preexisting ILD who received pemetrexed and platinum doublet therapy with and without pemetrexed maintenance in the first-line setting between December 2009 and June 2016, were retrospectively reviewed. RESULTS: The median progression-free survival time was 4.7 months, and the median overall survival time was 9.5 months. Of the 24 patients analyzed, six received pemetrexed maintenance. Acute exacerbation of ILD (AE-ILD) occurred in five (20.8 %) of 24 patients, including two fatal cases. CONCLUSION: The treatment with pemetrexed plus platinum has a high risk of AE-ILD in patients with advanced nonsquamous NSCLC and preexisting ILD.

Pembrolizumab-induced interstitial lung disease following thoracic surgery in a patient with non-small cell lung cancer.

The safety of treatment with immune-checkpoint inhibitors prior to thoracic surgery in patients with non-small cell lung cancer (NSCLC) remains unclear. Here, we describe the case of a 62-year-old woman with NSCLC with programmed death ligand 1 expression on 85% of tumor cells. The patient was initially considered to have unresectable stage IIIB disease and received pembrolizumab monotherapy. After 12 cycles of pembrolizumab, the primary tumor was reduced, but a small lung nodule in another lobe was unchanged. Based on the course of image findings, the nodule was considered to be an old inflammatory change. The clinical stage was changed to stage IB and partial resection was performed. Three days after thoracic surgery, the patient began to complain of coughing and shortness of breath. A CT of the chest revealed ground-glass opacity in the bilateral lung fields, suggesting interstitial lung disease (ILD) associated with pembrolizumab. Corticosteroid therapy was started and a chest X-ray showed a reduction in the opacity with improved oxygenation. This is the first case of immune-checkpoint inhibitor-related ILD triggered by thoracic surgery following long-term immune-checkpoint therapy.

A Fatal Case of Life-Threatening Interstitial Pneumonitis Induced by Everolimus for Metastatic Renal Cell Carcinoma: A Comment about the Increased Risk of Interstitial Lung Disease in Japanese.

We describe an 81-year-old woman with metastatic renal cell carcinoma who did not recover from life-threatening interstitial pneumonitis induced by everolimus therapy. She received everolimus due to disease progression after sunitinib, but 2 months after starting everolimus treatment, she visited the emergency department after developing a sudden fever and dyspnea. Chest CT revealed diffuse ground-glass opacities, thickening of the interlobular septa, and consolidation throughout both lung fields. The diagnosis was surmised to be everolimus-induced interstitial pneumonitis. Everolimus administration was stopped and 3 courses of steroid pulse therapy were administered, along with intensive care, but the patient died due to rapid respiratory failure.

Robot-assisted laparoscopic radical cystectomy is a safe and effective procedure for patients with bladder cancer compared to laparoscopic and open surgery: Perioperative outcomes of a single-center experience.

OBJECTIVE: We compared the perioperative outcomes of patients with bladder cancer according to three different procedures: robot-assisted laparoscopic radical cystectomy (RALC), laparoscopic radical cystectomy (LRC), and open radical cystectomy (ORC). METHODS: From April 2008 to March 2017, 36 consecutive patients underwent radical cystectomy and ileal conduit with RALC (n = 10), LRC (n = 10), or ORC (n = 16). All patients underwent RALC and LRC with extracorporeal urinary diversion. Perioperative data were patient demographics, perioperative laboratory data including hematocrit and creatinine, intraoperative crystalloids and colloids, estimated blood loss (EBL), allogeneic transfusion, respiratory parameters including maximum end-tidal carbon dioxide (EtCO2) and respiratory rate, arterial blood gas data including highest pH, partial pressure of CO2 (PaCO2), partial pressure of oxygen (PaO2), operative time, opiate consumption including intraoperative and postoperative anesthesia, time of hospital stay, time to oral intake and normal diet, and adverse events. RESULTS: EBL was less for RALC than for other procedures (p = 0.0004). No blood transfusions were performed for RALC, but ORC required significant blood transfusions (p = 0.003). Respiratory rate was highest and PaCO2 was lowest for RALC. Preoperative creatinine levels were significantly worse for the RALC group, but no significant differences were noted after surgery. There were no significant differences among the groups in regard to hematocrit levels. Operative time, laparoscopic time, intraoperative anesthesia, and postoperative anesthesia did not differ among the groups. High-grade adverse events were only seen for ORC. CONCLUSION: Although RALC required a steep Trendelenburg position, which might add elements of risk, RALC was safe even for this small cohort.

Efficacy and safety of sunitinib in elderly patients with advanced renal cell carcinoma.

Elderly individuals represent a consistent proportion of all cancer patients. However, they are under-represented in clinical trials. The present study evaluated the actual tolerability of sunitinib in elderly Japanese patients with advanced renal cell carcinoma (RCC). A total of 56 consecutive patients with advanced RCC treated with sunitinib were enrolled. Patients were divided into two groups according to their age at the time of sunitinib initiation: i) elderly cohort (≥70 years); and ii) younger cohort (<70 years). Disease control rate, progression-free survival, overall survival and relative dose intensity (RDI) were compared between the two cohorts. The elderly cohort comprised of 14 patients (25.0%), and the younger cohort included 42 patients (75.0%). The elderly cohort had a significantly higher Charlson comorbidity index than the younger cohort (mean, 9.7 vs. 7.9; P<0.0001). Disease control rate, progression-free survival, and overall survival were not significantly different. The elderly cohort had a significantly lower RDI than the younger cohort (mean, 51.7 vs. 65.0%; P=0.0340). Thus, treatment with sunitinib is feasible and effective in elderly Japanese patients with advanced RCC. However, the RDI of elderly patients was significantly lower, and a relatively low dose of sunitinib provided optimal therapeutic efficacy.

[Recurrent Urothelial Carcinoma in the Uretero-Vesical Junction Treated with Partial Ureterectomy and Ureteroneocystostomy during Long-Term Follow-Up : A Case Report].

A 54-year-old woman who had been treated with transurethral resection of bladder tumor for nonmuscle invasive urothelial carcinoma approximately nine years before presented with gross hematuria. Cystoscopy demonstrated a papillary tumor at the left side of the ureteral orifice. Magnetic resonance imaging showed a 1.3 cm non-muscle invasive lesion in the lower ureter from the ureteral orifice. She suffered from connective tissue disease treated with steroids. To avoid renal failure, we performed partial ureterectomy and ureteroneocystostomy. Pathological findings revealed pT1 urothelial carcinoma with negative surgical margin. There have been no signs of recurrence during eight years of follow-up after the last treatment.

The Antemortem Diagnosis of Primary Malignant Pericardial Mesothelioma: A Multidisciplinary Evaluation.

A 64-year-old woman complaining of progressive dyspnea was admitted with recurrence of massive pericardial effusion. The patient had been diagnosed with radiation pericarditis based on a previous case of pericardiocentesis. To make a diagnosis and improve her symptoms, imaging examinations and pericardial fenestration were performed. Because of difficulty making a diagnosis, after some months, pericardiotomy and incision of the epicardium were performed. The patient was ultimately diagnosed with primary malignant pericardial mesothelioma of the epithelioid type. Primary malignant pericardial mesothelioma is a rare tumor that is difficult to diagnose. An antemortem diagnosis can be made by a multidisciplinary evaluation.

The Safety and Efficacy of Treatment with Nab-paclitaxel and Carboplatin for Patients with Advanced Squamous Non-small Cell Lung Cancer Concurrent with Idiopathic Interstitial Pneumonias.

Objective Although lung squamous cell carcinoma (SCC) accounts for 20-30% of lung cancer cases, new treatment options are limited. The CA031 study showed that nanoparticle albumin-bound-paclitaxel (nab-PTX) plus carboplatin produced a significantly higher overall response rate (41%) than solvent-based paclitaxel plus carboplatin in patients with lung SCC. However, the safety and efficacy of combination chemotherapy of nab-PTX and carboplatin has not yet been established for patients with concurrent lung SCC and idiopathic interstitial pneumonias (IIPs). The aim of this study was to assess the safety and efficacy profiles of nab-PTX and carboplatin in patients with lung SCC and concurrent IIPs. Methods Eight patients with inoperable-stage lung SCC and IIPs were treated with nab-PTX plus carboplatin in a first-line setting between June 2013 and December 2016. One of the eight was a woman, and the median age was 77 (range=72-80) years. Their clinical outcomes, including chemotherapy-associated acute exacerbation of IIPs, were retrospectively investigated. Results The overall response rate was 50%, the median progression-free survival time was 5.6 months, and the median overall survival time was 8.1 months. No patients experienced chemotherapy-related exacerbation of IIPs in the first-line treatment with nab-PTX plus carboplatin. However, IIPs worsened in two of four patients who received second-line chemotherapy. Conclusion Combination chemotherapy of nab-PTX and carboplatin may be an effective and safe treatment option for patients with inoperable lung SCC with IIPs. To confirm this, a large-scale prospective study is needed.

Impact of five-tiered Gleason grade groups on prognostic prediction in clinical stage T3 prostate cancer undergoing high-dose-rate brachytherapy.

BACKGROUND: We evaluated a five-tiered Gleason grade groups arising from the 2014 International Society of Urological Pathology consensus conference on prognostic prediction in clinical stage T3a (extracapsular invasion) and T3b (seminal vesicle involvement) prostate cancer undergoing high-dose-rate brachytherapy (HDR-BT). METHODS: From November 2003 to December 2012, 283 patients with stage T3 prostate cancer received HDR-BT and external beam radiation therapy (EBRT) with long-term androgen deprivation therapy (ADT). Of these, 203 (72%) and 80 (28%) patients had stage T3a and T3b disease, respectively. The mean dose to 90% of the planning target volume was 7.5 Gy/fraction of HDR-BT. After five fractions, EBRT with 10 fractions of 3 Gy was administered. All patients first underwent ≥6 months of neoadjuvant ADT, and adjuvant ADT continued for 36 months. Median follow-up was 74 months from the start of radiotherapy. RESULTS: The 10-year biochemical recurrence (BCR) -free rate for stage T3a and T3b disease was 79% and 64%, respectively (P = 0.0083). The 10-year cancer-specific survival (CSS) rate for stage T3a and T3b was 96% and 91%, respectively (P = 0.0305). Although grade groups ≥4 were independent predictors for BCR in cT3a patients (P = 0.0270), they failed to significantly predict prostate cancer-specific mortality (PCSM) among cT3a patients. Among cT3b patients, grade group 5 was a significant predictor of both BCR (P = 0.0017) and PCSM (P = 0.0233). Among stage T3a patients, no significant difference existed in 10-year CSS between grade groups 5 and 4 (94% vs 97%, P = 0.3960). In contrast, grade group 5 had a significantly worse outcome in 10-year CSS than grade group 4 among stage T3b patients (74% vs 100%, P = 0.0350). CONCLUSIONS: Stage T3a patients with grade groups 4/5 and stage T3b with grade group 4 had fairly low PCSM risk. Approximately one of four patients among stage T3b patients with grade group 5 showed PCSM after combined HDR-BT and EBRT with long-term ADT. Stage T3b patients with grade group 5 may have a greater risk for PCSM.

Prognostic effect of serum C-reactive protein kinetics on advanced renal cell carcinoma treated with sunitinib.

C-reactive protein (CRP) is an independent prognostic factor for renal cell carcinoma (RCC). The aim of the present study was to investigate the prognostic effect of pretreatment serum CRP level and CRP kinetics on patients with advanced RCC treated with sunitinib. A total of 56 consecutive patients with advanced RCC treated with sunitinib between December, 2008 and December, 2012 were enrolled in the present study. The patients were retrospectively divided into 3 cohorts according to pretreatment serum CRP level and CRP kinetics: i) Normal CRP cohort (pretreatment CRP ≤0.30 mg/dl); ii) normalized CRP cohort (pretreatment CRP >0.30 mg/dl that normalized within 2 cycles of treatment); and iii) non-normalized CRP cohort (pretreatment CRP >0.30 mg/dl that did not normalize after sunitinib initiation). Disease control rate, progression-free survival and overall survival times were compared for the 3 cohorts. The normal (n=17, 30.4%) and the normalized (n=8, 14.3%) CRP cohorts exhibited significantly better disease control rates compared with the non-normalized CRP cohort (n=31, 55.4%; P<0.0001 and P=0.0445, respectively). The normal CRP cohort exhibited significantly longer progression-free survival compared with the non-normalized CRP cohort (P=0.0050). The normal and normalized CRP cohorts exhibited significantly longer overall survival compared with the non-normalized CRP cohort (P=0.0005 and 0.0466, respectively). Therefore, CRP kinetics and normal pretreatment CRP level are prognostic indicators in patients with advanced RCC treated with sunitinib.

Antifibrotic effects of cyclosporine A on TGF-ß1-treated lung fibroblasts and lungs from bleomycin-treated mice: role of hypoxia-inducible factor-1α.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder that is characterized by aberrant tissue remodeling and the formation of fibroblastic foci that are composed of fibrogenic myofibroblasts. TGF-ß1 is one of the factors that are responsible for fibrosis as it promotes fibroblast to myofibroblast differentiation (FMD) and is associated with up-regulation of α-smooth muscle actin. Therefore, inhibition of FMD may represent an effective strategy for the treatment of IPF. Here, we describe the treatment of human lung fibroblasts (WI-38 and HFL-1 cells) with cyclosporine A (CsA), which reduces TGF-ß1-induced FMD via degradation of hypoxia-inducible factor-1α (HIF-1α). In addition, in primary myofibroblast-like cells that were obtained from a patient with pulmonary fibrosis, treatment with CsA and an HIF-1α inhibitor (HIFi) decreased the expression levels of α-smooth muscle actin and fibronectin, which indicated that CsA and HIFi promote dedifferentiation of myofibroblasts. In mice intratracheally administered CsA or HIFi at an early fibrotic stage [7, 8, and 9 d postinstillation (dpi) of bleomycin], marked alleviation of lung fibrosis was observed at 14 dpi. These results suggest that CsA exhibits antifibrotic effects by degrading HIF-1α and that the CsA-HIF-1α axis provides new insights into therapeutic options for the treatment of IPF.-Yamazaki, R., Kasuya, Y., Fujita, T., Umezawa, H., Yanagihara, M., Nakamura, H., Yoshino, I., Tatsumi, K., Murayama, T. Antifibrotic effects of cyclosporine A on TGF-ß1-treated lung fibroblasts and lungs from bleomycin-treated mice: role of hypoxia-inducible factor-1α.