Expressions of PD-L1 and Nectin-4 in urothelial cancer patients treated with pembrolizumab.

OBJECTIVES: Recently, the standard of care for advanced urothelial cancer (UC) has been changed by developing immune-checkpoint inhibitors (ICIs). However, its response rate is limited to 20-30%. The identification of biomarkers to predict the therapeutic effects of ICIs is urgently needed. The present study explored the association between immunohistochemical biomarkers and clinical outcomes in UC patients treated with pembrolizumab. PATIENTS AND METHODS: A total of 85 patients with UC who received pembrolizumab after chemotherapy from January 2018 to May 2020 were retrospectively reviewed. Tumor tissues were obtained for immunohistochemical study from 47 out of 85 patients. The protein expressions of PD-L1, WT1, Nectin-4, CD4, CD8, Foxp3, and CD68 in tumor cells and/or tumor infiltrating lymphocytes were immunohistochemically examined. The associations between protein expressions and overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) were statistically analyzed. RESULTS: Patients with positive PD-L1 in tumor cells showed significantly worse OS (Log-rank test: HR 5.146, p = 0.001, Cox regression analysis: HR 4.331, p = 0.014) and PFS (Log-rank test: HR 3.31. p = 0.022), along with significantly lower DCR (14.3%) compared to the PD-L1 negative patients (67.5%). In addition, patients with strong expression of Nectin-4 in tumor cells showed significantly higher DCR (100%) than the other patients (50%). CONCLUSION: PD-L1 expression in tumor cells was associated with poor prognosis (OS and PFS) and low DCR. Interestingly, the strong expression of Nectin-4 was correlated with high DCR. PD-L1 and Nectin-4 expression in tumor cells could be prognostic biomarkers useful for pembrolizumab in patients with advanced UC.

Effects of nitrogen on caesium allocation in rice plants (Oryza sativa).

After the nuclear accident in Fukushima Prefecture, Japan, in 2011, 137 Caesium (Cs) contaminated nearby agricultural regions. Studies in these rice fields found that low K and high N fertilizer application enhanced Cs uptake in rice shoots. However, the influence of root and soil physics on these findings, as well as precise nutrient levels, remain to be clarified. We sought to analyse these relationships utilizing hydroponically grown rice plants. The rice plants were subjected to various concentrations of K and N nutrient solutions. We measured Cs allocation within the plants and performed transcript analyses using root tissues. Under low-K conditions, low-N plants accumulated less Cs in shoots and more in roots when compared to control-N conditions, even though overall Cs uptake remained unchanged. Expression analyses of root mRNAs showed that low-N plants accumulated reduced levels of OsAKT1 mRNA, encoding a K transporter. We also found a negative relationship between shoot Cs and K status in control-N but not in low-N conditions. Our results suggest that the application of N shifts Cs from roots into the shoots and that OsAKT1 in root vascular tissues influences Cs allocation. In practice, fine tuning N/K application and targeted breeding of K transporters might mitigate Cs contamination in rice plants.

Efficacy and safety of abiraterone acetate plus prednisolone in patients with early metastatic castration-resistant prostate cancer who failed first-line androgen-deprivation therapy: a single-arm, phase 4 study.

AIM: The aim was to evaluate the efficacy and safety of abiraterone acetate plus prednisolone in patients with chemotherapy-naïve early metastatic castration-resistant prostate cancer who failed first-line androgen deprivation therapy. METHODS: Patients with early metastatic castration-resistant prostate cancer with confirmed prostate-specific antigen progression within 1-year or prostate-specific antigen progression without having normal prostate-specific antigen level (<4.0 ng/mL) during first-line androgen deprivation therapy were enrolled and administered abiraterone acetate (1000 mg) plus prednisolone (10 mg). A minimum of 48 patients were required according to Simon's minimax design. The primary endpoint was prostate-specific antigen response rate (≥50% prostate-specific antigen decline by 12 weeks), secondary endpoints included prostate-specific antigen progression-free survival and overall survival. Safety parameters were also assessed. RESULTS: For efficacy, 49/50 patients were evaluable. Median age was 73 (range: 55-86) years. The median duration of initial androgen deprivation therapy was 32.4 (range: 13.4-84.1) weeks and 48 patients experienced prostate-specific antigen progression within 1-year after initiation of androgen deprivation therapy. prostate-specific antigen response rate was 55.1% (95% confidence interval: 40.2%-69.3%), median prostate-specific antigen-progression-free survival was 24.1 weeks, and median overall survival was 102.9 weeks (95% confidence interval: 64.86 not estimable [NE]). Most common adverse event was nasopharyngitis (15/50 patients, 30.0%). The most common ≥grade 3 adverse event was alanine aminotransferase increased (6/50 patients, 12.0%). CONCLUSIONS: Abiraterone acetate plus prednisolone demonstrated a high prostate-specific antigen response rate of 55.1%, suggesting tumor growth still depends on androgen synthesis in patients with early metastatic castration-resistant prostate cancer. However, prostate-specific antigen-progression-free survival was shorter than that reported in previous studies. Considering the benefit-risk profile, abiraterone acetate plus prednisolone would be a beneficial treatment option for patients with chemotherapy-naive metastatic prostate cancer who show early castration resistance.

Coordinated existence of multiple gangliosides is required for cartilage metabolism.

OBJECTIVE: Gangliosides, ubiquitously existing membrane components that modulate transmembrane signaling and mediate cell-to-cell and cell-to-matrix interactions, are key molecules of inflammatory and neurological disorders. However, the functions of gangliosides in the cartilage degradation process remain unclear. We investigated the functional role of gangliosides in cartilage metabolism related to osteoarthritis (OA) pathogenesis. DESIGN: We generated knockout (KO) mice by targeting the ß1, 4-N-acetylgalactosaminyltransferase (GalNAcT) gene, which encodes an enzyme of major gangliosides synthesis, and the GD3 synthase (GD3S) gene, which encodes an enzyme of partial gangliosides synthesis. In vivo OA and in vitro cartilage degradation models were used to evaluate the effect of gangliosides on the cartilage degradation process. RESULTS: The GalNAcT and GD3S KO mice developed and grew normally; nevertheless, OA changes in these mice were enhanced with aging. The GalNAcT KO mice showed significantly enhanced OA progression compared to GD3S mice in vivo. Both GalNAcT and GD3S KO mice showed severe IL-1α-induced cartilage degradation ex vivo. Phosphorylation of MAPKs was enhanced in both GalNAcT and GD3S KOs after IL-1α stimulation. Gangliosides modulated by GalNAcT or GD3S rescued an increase of MMP-13 induced by IL-1α in mice lacking GalNAcT or GD3S after exogenous replenishment in vitro. CONCLUSION: These data show that the deletion of gangliosides in mice enhanced OA development. Moreover, the gangliosides modulated by GalNAcT are important for cartilage metabolism, suggesting that GalNAcT is a potential target molecule for the development of novel OA treatments.

Health related quality of life after radical cystectomy: comparative study between orthotopic sigmoid versus ileal neobladders.

AIMS: To comparatively assess the health-related quality of life (HRQOL) between patients with sigmoid and ileal neobladders (NBs) following radical cystectomy. METHODS: At out institution, the HRQOL of all patients with an orthotopic NB was evaluated using a Short-Form 36 (SF-36) survey 12 months after surgery. Of these, this study included 212 patients, consisting of 88 with sigmoid NB and 124 with ileal NB. RESULTS: There were no significant differences in all eight scores between sigmoid and ileal NB groups (SNBG and INBG, respectively); however, when compared with the scores in an age-matched control in Japan, one and two scores in SNBG and INBG, respectively, were significantly inferior, whereas one score in INBG was significantly favorable. Despite the lack of any significant differences in all scores between male SNBG and INBG, three scores in female SNBG were significantly superior to those in female INBG. Multivariate analyses were performed to evaluate the contribution of several factors on each scale score in the SF-36 survey, and they revealed that the age and voiding status had independent impacts on two and three scores, respectively, despite the lack of an independent association between any scores and the remaining factors, including the type of NB. CONCLUSIONS: The postoperative HRQOL of patients with NB was shown to be generally favorable irrespective of the type of NB; however, the HRQOL, particularly that associated with physical and social functions, appeared to be significantly impaired in elderly patients and/or those not able to spontaneously void.

Prognostic significance of tumor extension into venous system in patients undergoing surgical treatment for renal cell carcinoma with venous tumor thrombus.

AIMS: The objective of this study was to evaluate the prognostic significance of the extent of a tumor thrombus in renal cell carcinoma (RCC) involving the venous system. METHODS: This study included 135 consecutive RCC patients with a venous tumor thrombus undergoing radical nephrectomy and tumor thrombectomy between 1985 and 2009. These patients were classified based on the maximal level of the tumor thrombus extending into the venous system, as follows: group 1, renal vein; group 2, infradiaphragmatic; and group 3, supradiaphragmatic. RESULTS: Of the 135 patients, 65, 49 and 21 were classified into groups 1, 2 and 3, respectively. The 1, 3 and 5-year cancer-specific survival (CSS) rates in these 135 patients were 89.2, 56.9 and 49.2%, respectively. Among several factors examined, tumor size, tumor grade, perirenal fat invasion and presence of metastasis, but not extent of tumor thrombus, were significantly associated with CSS on univariate analysis. Of these significant factors, only tumor size and presence of metastasis appeared to be independently related to CSS on multivariate analysis. When the patients without metastasis were analyzed separately, CSS in groups 2 and 3 was significantly poorer than that in group 1. CONCLUSIONS: These findings suggest the absence of a significant prognostic impact of the level of the tumor thrombus in a complete cohort of RCC patients with a venous tumor thrombus; however, it is warranted to determine whether the level of the tumor thrombus has different effects on the prognosis according to the presence of metastatic diseases.

Enhanced sensitivity to androgen withdrawal due to overexpression of interleukin-6 in androgen-dependent human prostate cancer LNCaP cells.

BACKGROUND: The objective of this study was to investigate the effects of interleukin-6 (IL-6) overexpression in androgen-dependent prostate cancer LNCaP cells on their phenotype under an androgen-deprived condition. METHODS: We established IL-6-overexpressing LNCaP (LNCaP/IL-6) by introducing the expression vector containing IL-6 cDNA. Changes in the phenotype in LNCaP/IL-6 were compared with that in LNCaP transfected with control vector alone (LNCaP/Co). RESULTS: In vitro, the growth of LNCaP/IL-6 was significantly inferior to that of LNCaP/Co under an androgen-deprived condition. Similarly, LNCaP/IL-6 tumour in nude mice rapidly regressed after castration; however, LNCaP/Co tumour growth was transiently inhibited after castration and then continuously accelerated. After androgen withdrawal, expression levels of phosphorylated p44/42 mitogen-activated protein kinase (MAPK) and Akt in LNCaP/IL-6 were markedly upregulated compared with those in LNCaP/Co; however, additional treatment with specific inhibitor of the MAPK or Akt signalling pathway significantly inhibited the growth of LNCaP/IL-6 compared with that of LNCaP/Co. Furthermore, gene microarray analyses showed that androgen deprivation resulted in differential expression of genes involved in growth, apoptotsis and tumorigenesis between LNCaP/Co and LNCaP/IL-6. CONCLUSION: Excessive secretion of IL-6 by LNCaP cells in an autocrine manner may have a suppressive function in their growth and acquisition of androgen-independent phenotype under an androgen-deprived condition.

[A patient with esophageal cancer with subcutaneal abscess and esophago-tracheal fistula who survived more than 2 years following treatment by drainage and chemoradiation therapy].

A 48-year-old man presented at the hospital because of neck swelling and pain. A diagnosis of esophageal cancer with subcutaneous abscess was made based on examination and biopsy results. The cancer was Ce T4NxMx Stage III-IVa. Curative surgery was considered impossible, so chemoradiation therapy was performed (5-FU 500 mg + CDDP 5 mg/day + 2 Gy/day x 31 days) after drainage. During the therapy, an esophago-tracheal fistula was observed, but it later vanished. After chemoradiation therapy, the abscess and tumor vanished. No serious adverse reactions were observed. Now, 2 years after therapy, no recurrence has been found. The patient is now in good health with no symptoms and undergoes regular check-ups. Chemoradiation therapy is effective for inoperable advanced esophageal cancer.

[Diagnosis of the postoperative local recurrence of rectal cancer by FDG-PET--a case report].

Positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) as the tracer of glucose metabolism was performed to identify a postoperative recurrent lesion of rectal cancer. A 66-year-old-man underwent trans-sacral local resection of the rectum for rectal cancer in 1992. A local recurrent mass was discovered, and abdomino-perineal resection of the rectum was performed in 1999. The serum CEA level increased gradually August in 2000, but there was no sign of recurrence on CT or MRI. FDG-PET was performed to reveal a presacral recurrent lesion. Total pelvic evisceration combined with resection of the sacrum, and a bilateral ureterostomy were performed in April 2001. The beneficial role of FDG-PET in the diagnosis of the postoperative local recurrence of rectal cancer is emphasized.

[A case of recurring breast cancer causing pericardial metastasis showing a good response following local treatment with methotrexate].

A 52-year-old woman was admitted with a chief complaint of dyspnea. She had undergone right mastectomy for Stage IIB breast cancer 2 years and five months earlier. Chest roentgenogram revealed cardiomegaly and bilateral pleural effusion, and a cardiac echogram showed marked retention of pericardial effusion. A diagnosis of cardiac tamponade was made and pericardiocentesis for continuous drainage was carried out cytologically, the effusion was class V and showed evidence of pericardial metastasis of breast cancer. Pericardiocentesis followed by methotrexate instillation 6 times in a dose of 110 mg successfully controlled the cardiac tamponade, after which the catheter could be removed from the pericardial space. Systemic chemotherapy (CEF) was started at the same time. The patient was discharged very much improved after these treatments, but she died of brain metastasis after 9 months. This case suggests that intrapericardial application of methotrexate may be very useful in the management of carcinomatous cardiac tamponade without any serious side effects.

[Sigmoid colon cancer with multiple liver metastasis (H3) effectively treated with CPT-11 and DSM (degradable starch microsphere) HAI therapy and intensive high dosage 5-FU HAI therapy--a case report].

A weekly HAI therapy (CPT-11 80 mg, MMC 4 mg, degradable starch microsphere (DSM) 600 mg) was given to a patient with sigmoid colon cancer and multiple liver metastasis (H3) who had been taking tegafur 300 mg/day and 5-FU 750 mg HAI/week, which resulted in PD. This therapy was carried out on an outpatient basis with minimum side effects (< grade 2). After 8 weeks, the tumor marker dropped to one tenth and the liver metastasis decreased in size (PR). The time courses of the concentrations of CPT-11, SN-38 and SN-38G were determined by drawing blood after HAI with or without DSM. The Cmax and AUC inf. of SN-38 at HAI without DSM were 17 ng/ml and 90.55 ng/h/ml, respectively, which was comparable to that at i.v. administration. The Cmax and AUC inf. of SN-38 at HAI with DSM were 12 ng/ml and 129.19 ng/h/ml, respectively, implying that DSM might have an enhancing effect on CPT-11 due to stasis of the hepatic artery that slows the conversion of CPT-11 to SN-38 resulting in a longer existence of SN-38.

Quantitative analysis of water dispersion conditions and pressure transmission characteristics of a wet kneaded mass.

In our previous paper [Watano S. et al., J. Powder Technology Japan, 37, 362-370 (2000)], a novel compaction tester was developed to quantitatively evaluate the water dispersion condition of a wet kneaded mass prepared by a paddle type kneader. It has been demonstrated that the physical properties of pellets prepared by extrusion granulation after the kneading can be well predicted by the pressure transmission obtained through the compaction tester. This paper describes a more detailed investigation of the water dispersion, its mechanism and pressure transmission characteristics of wet kneaded masses prepared under various operating conditions. First, kneading by a paddle type kneader was conducted to prepare wet masses under various binder contents using different additional methods and different starting materials. Secondly, water dispersion and pressure transmission characteristics of wet masses were investigated. After the wet kneading, the wet kneaded masses were extruded through a dome type extruder and were dried by a fluidized bed to prepare dry pellets. The relationship between water dispersion and pressure transmission can be expressed by a single line, regardless of binder content or methods of addition. This implies that these parameters have no effect on the water dispersion condition of the wet kneaded mass prepared by a high shear paddle type kneader. Different water dispersion characteristics and the mechanism obtained by different starting materials can also be evaluated by the pressure transmission data. Properties of dry pellets can also be predicted by the pressure transmission. It can be concluded that the developed compaction tester can quantitatively evaluate the water dispersion condition of a wet kneaded mass and also predict properties of the final extruded products.

High dose chemotherapy as adjuvant treatment in operable breast cancer with 10 or more involved axillary lymph nodes.

BACKGROUND: it is well known that breast cancer patients with more than 10 axillary lymph nodes involved have poor prognosis even with extensive adjuvant chemotherapy. To improve this poor outcome, high-dose adjuvant chemotherapy has been applied to the these patients. This study was intended to clarify the efficacy and usefulness of high dose adjuvant chemotherapy (HDC) for high-risk breast cancer patients and its efficacy was compared with conventional adjuvant chemotherapy (non-HDC group). PATIENTS AND METHODS: Twelve patients with breast cancer involving more than 10 axillary nodes received high-dose chemotherapy with peripheral progenitor-stem cell transplantation (PBSCT). This regimen consists of BCNU (carmustine) 130 mg/m(2) x 3, CBDCA (carboplantin) 500 mg/m(2) x 3 and CPA (chyclophosphamide) 50 mg/kgx 2 after induction chemotherapy with 3 cycles of CE (chyclophosphamide 600 mg/m(2), epirubicin 60 mg/m(2)). RESULTS: Twelve patients completed the high-dose chemotherapy regimen as planned, no patient died of chemotherapy related toxicity. After a median follow-up period of 44 months, disease-free and overall survival at 48 months after the operation for 12 patients determined by Kaplan-Meier methods was 63 % and 83 %, respectively. Disease-free survival was superior in the high-dose chemotherapy group compared with the control group but a statistical difference was not observed. CONCLUSION: High-dose chemotherapy seems to be an effective and feasible treatment for high-risk breast cancer patients. However, the usefulness of high-dose adjuvant chemotherapy for high-risk breast cancer patients should be confirmed by a large-scale randomized trial.

[A case of locally advanced breast cancer successfully resected after selective intra-arterial chemotherapy].

A 25-year-old female with a large tumor on her left breast was examined at our hospital from August, 1999. Ipsilateral supraclavicular, infraclavicular and axillary lymph nodes were swollen. She was diagnosed as having locally advanced breast cancer of stage IIIb by fine needle aspiration cytology. After the administration of docetaxel (60 mg/m2/3 weeks x 3) failed to improve her condition, we changed the treatment to selective intra-arterial chemotherapy with THP-ADR (60 mg/body/day, day 1 & 8, 41 & 48) by Seldinger's method. The target vessels were the internal thoracic, lateral thoracic, thoracodorsal and deep cervical arteries. We also combined 5-FU 500 mg/body div and CPA 500 mg/body i.v. on the same days with intra-arterial chemotherapy. As a result, the main tumor and metastatic lymph node swelling was remarkably reduced (down-staging was obtained). No recurrence was found for 5 months after curative resection.

[Repetitive chemo-embolization with degradable starch microspheres (DSM) to each left and replaced right hepatic artery in a patient with multiple liver metastases of colon cancer].

In a patient with a right hepatic artery arising from the superior mesenteric artery bearing multiple liver metastases from colon cancer, hepatic arterial chemo-embolization was performed in combination with degradable starch microspheres (DSM) administered independently to the left and replaced right hepatic artery via a percutaneal approach. As the first line chemotherapy from hepatic artery with DSM 300 mg, 5-FU 500 mg and MMC 10 mg resulted in PD. DSM 300 mg, epirubicin (EPI) 50 mg, MMC 4 mg was administered with the RHA:LHA ratio of 3:1 as a second line. Four weeks later it was evaluated as NC by angiography and by tumor-marker dropped extremely. The same regimen was repeated every four weeks, and the NC status remained for 20 weeks in total. Each time, the left and replaced right hepatic artery got perfect re-perfusion and DSM enabled an effective whole liver distribution of anti-cancer drugs and repetitive administrations of them. This regimen could be an alternative choice for patients with a replaced right hepatic artery who have liver metastasis of colon cancer.

[A case of locally advanced rectal carcinoma with liver metastasis treated with a combination of CRT, HAI, and systemic chemotherapy].

A 55-year-old man with locally advanced rectal carcinoma and liver metastasis was treated with a combination of chemo-radiotherapy (5-FU suppository 100 mg/day and 63 Gy of RT), hepatic arterial infusion chemotherapy (5-FU 1,000 mg/3 h, biweekly), and systemic chemotherapy (5'-DFUR 800 mg/day + cimetidine 800 mg/day). His rectal tumor was reduced and his symptoms such as pain and bleeding had markedly decreased. The river metastasis did not change during the entire course. HAI and administration of 5-FU suppository, 5'-DFUR, and cimetidine were continued. As of 18 months after the onset of the combination therapy, NC has been maintained, and the general condition of the patient is favorable.

Detection of microsatellite alterations in nipple discharge accompanied by breast cancer.

Nipple discharge in breast cancer cases was examined loss of heterozygosity (LOH). DNA samples were extracted from both supernatant and cell pellet components of the discharge, and examined for LOH at microsatellite markers, D11S1818, D11S2000, D16S402, D16S504, D16S518, D17S520, and D17S786. At least one LOH was found in either the supernatant or cell pellet in seven out of 10 patients (70%). Five of seven samples, which were cytologically negative, were LOH positive, and only one case, which was cytologically positive, showed no LOH on the markers examined. All three samples, which were judged 'negative' by CEA measurement (<400 ng/ml), were LOH positive. This method could be a useful novel diagnostic modality for nonpalpable breast cancer with nipple discharge.

[Evaluation of intermittent hepatic arterial infusion chemotherapy for multiple liver metastasis of colorectal cancer].

Five patients with synchronous multiple hepatic metastasis of colorectal cancer were treated with hepatic arterial infusion chemotherapy. All cases received intermittent 5-FU infusion (5-FU 250-1,000 mg/2-3 hrs/1-2 weeks) on an outpatient basis. In the evaluation of 5 cases, 3 PR and 1 NC were observed. One case administered arterial infusion for adjuvant chemotherapy has no recurrence in liver. In two patients, extra-hepatic metastases were found. In conclusion, this therapy was effective and useful for hepatic metastasis. Moreover, other forms of treatment for extra-hepatic metastasis must be used.

[Intraperitoneal cisplatinum chemotherapy in patients with carcinomatous peritonitis due to colorectal scirrhous cancer--case report].

Two patients received intraperitoneal cisplatinum chemotherapy for carcinomatous ascites due to colorectal cancer recurrence. The patients were a 47-year-old man who had rectal cancer and 51-year-old woman who had colon cancer. They had received the operation and adjuvant chemoradiation therapy and chemotherapy respectively. However, five months and two years after resection, respectively, they presented massive ascites due to carcinomatous peritonitis and were given cisplatin injection intraperitoneally. The amount of ascites was significantly diminished. One patient had been discharged and been able to stay at home, and the other patient underwent gastrostomy for ileus. The results suggested that intraperitoneal cisplatinum chemotherapy may be useful for the patient with carcinomatous ascites due to colorectal cancer.

[Palliative chemo-radiotherapy for abdominal recurrence of esophageal carcinoma--case report].

A 71-year-old man with stage IV esophageal carcinoma was treated by chemo-radiotherapy (5-FU 500 mg/day + CDDP 10 mg/day for 4 weeks and 67.6 Gy of RT). The esophageal tumor showed a complete response to the treatment. Six months later, he had obstructive jaundice due to an abdominal recurrent mass. A secondary (palliative) CRT was performed (5-FU 500 mg/day + CDDP 10 mg/day for 3 weeks and 45 Gy of RT). The abdominal tumor became remarkably smaller and jaundice disappeared. Though the patient died from pulmonary carcinomatous lymphangitis, the primary lesion showed CR. CRT was very effective for local treatment and for palliative therapy.