Programmed cell death-1 (PD-1), an immunoreceptor, is located on T cells and pro-B cells and interacts with its ligands to inhibit T cell activation and proliferation, thereby promoting immunological ...self-tolerance. Nivolumab, an anti-PD1 antibody, blocks PD-1 and can restore anticancer immune responses by abrogating PD-1 pathway-mediated T-cell inhibition. Autoimmune adverse events are expected with PD-1 therapy. Fulminant type 1 diabetes is the subtype of type 1 diabetes. The clinical feature is the extremely rapid progression of hyperglycemia and ketoacidosis. Here we describe a 66-year-old woman with advanced melanoma who was treated with nivolumab. After 4 months and six doses of the medicine, the patient was admitted to the hospital with complaints of nausea and vomiting. The laboratory data showed ketonuria, hyperglycemia (531 mg/dl), high anion gap metabolic acidosis, HbA1c (7.3%), and absence of insulin-secreting capacity. These data are compatible with the criteria of fulminant type 1 diabetes. The patient was diagnosed with diabetic ketoacidosis because of fulminant type 1 diabetes. The findings of this case indicated that nivolumab can cause fulminant type 1 diabetes. Diabetic ketoacidosis due to fulminant type 1 diabetes is potentially fatal condition. Thus, diabetic ketoacidosis due to fulminant type 1 diabetes should be considered in the differential diagnosis when patients treated with nivolumab complain of gastrointestinal symptoms.
Treatment‐related neuroendocrine prostate cancer is a lethal form of prostate cancer that emerges in the later stages of castration‐resistant prostate cancer treatment. Treatment‐related ...neuroendocrine prostate cancer transdifferentiates from adenocarcinoma as an adaptive response to androgen receptor pathway inhibition. The incidence of treatment‐related neuroendocrine prostate cancer has been rising due to the increasing use of potent androgen receptor pathway inhibitors. Typically, treatment‐related neuroendocrine prostate cancer is characterized by either low or absent androgen receptor expression, small cell carcinoma morphology and expression of neuroendocrine markers. Clinically, it manifests with predominantly visceral or lytic bone metastases, bulky tumor masses, low prostate‐specific antigen levels or a short response duration to androgen deprivation therapy. Furthermore, although the tumor initially responds to platinum‐based chemotherapy, the duration of the response is short. Based on the poor prognosis, it is imperative to identify novel molecular targets for treatment‐related neuroendocrine prostate cancer. Recent advances in genomic and molecular research, supported by novel in vivo models, have identified some of the key molecular characteristics of treatment‐related neuroendocrine prostate cancer. The gain of MYCN and AURKA oncogenes, along with the loss of tumor suppressor genes TP53 and RB1 are key genomic alterations associated with treatment‐related neuroendocrine prostate cancer. Androgen receptor repressed genes, such as BRN2 and PEG10, are also necessary for treatment‐related neuroendocrine prostate cancer. These genetic changes converge on pathways upregulating genes, such as SOX2 and EZH2, that facilitate lineage plasticity and neuroendocrine differentiation. As a result, on potent androgen receptor pathway inhibition, castration‐resistant prostate cancer transdifferentiates to treatment‐related neuroendocrine prostate cancer in a clonally divergent manner. Further understanding of the disease biology is required to develop novel drugs and biomarkers that would help treat this aggressive prostate cancer variant.
The success of immunotherapy using immune checkpoint inhibitors has changed the practice of cancer treatment tremendously. However, there are still many clinical challenges, such as drug resistance, ...predictive biomarker development, exploration of combination therapies, and prediction of immune-related adverse events in preclinical settings. To overcome these problems, it is essential to establish faithful preclinical mouse models that recapitulate the clinical features, molecular genetics, biological heterogeneity, and immune microenvironment of human cancers. Here we review the advantages and disadvantages of current preclinical mouse models, including syngeneic murine tumor cell lines, autochthonous tumor models, cancer cell line-derived xenografts, patient-derived-xenografts, and various kinds of immunologically humanized mice. We discuss how these models should be characterized and applied in preclinical settings, and how we should prepare preclinical studies for successful translation from bench to bedside.
This study aimed to evaluate an outdoor mist-spraying environment and its effect on thermal sensations, thermal environment, and skin temperature. A mist-spraying system with four modes was operated ...with various amounts of water spraying, both in the absence and presence of an air blowing control. Thermal sensations were reported by subjects for each operation mode and then investigated using three scales: modified thermal sensation vote (mTSV), thermal sensation vote (TSV), and comfort sensation vote (CSV). Environmental factors were compared between the outdoor and mist-spraying environments, and skin temperatures were monitored throughout the experiment. The correlation between the thermal sensations and overall skin temperatures was analyzed. The results showed that the air temperature inside the mist-spraying environment decreased (−2.9 ± 1.2 °C) when the mist system was operated with a larger amount of spraying water and the air temperature decreased further (−3.6 ± 1.4 °C) with the addition of an air blowing fan. Survey results (n = 65) suggested that the mTSV changed from slightly hot to neutral, TSV changed from warm to neutral, and CSV changed from slightly uncomfortable to slightly comfort, respectively, due to the cooling effect of the mist-spraying system. The overall skin temperature decreased by approximately −0.53 °C (n = 65) from the baseline operation mode. Moreover, the overall skin temperature showed a higher correlation with the mTSV than with the TSV, and their correlation was higher in the mist-spraying environment compared with that in an outdoor environment.
•Four different operation modes of a mist-spraying system were investigated.•Sixty-five subjects reported on thermal sensations and comfort.•Environmental factors were measured in outdoor and mist environments.•Skin temperature variations were monitored for all subjects.•Overall skin temperature showed a higher correlation with modified thermal sensation.
Objectives
Despite just a 4‐year interval from the last version (2015) of the Clinical Practice Guidelines for Bladder Cancer, several dramatic paradigm shifts have occurred in the latest clinical ...practice regarding both the diagnosis and treatment of bladder cancer. Herein, we updated the 2019 version of the Clinical Practice Guidelines for Bladder Cancer under the instruction of the Japanese Urological Association.
Methods
We previously reported in a revision working position paper for Clinical Practice Guidelines for Bladder Cancer 2019 edition and described the methods of revision detail.
Results
The major points of change in the 2019 version are presented and explanations are given as follows: (i) introduction of the new reference assessment system; (ii) modification of the risk classification for non‐muscle‐invasive bladder cancer; (iii) addition of clinical questions for the new tumor‐visible techniques in non‐muscle‐invasive bladder cancer; (iv) inclusion of minimally invasive surgeries for muscle‐invasive bladder cancer and immune checkpoint inhibitors for locally advanced/metastatic muscle‐invasive bladder cancer; (v) overview chapter of the histological variant of urothelial cancer and rare cancers of the bladder; and (vi) recommendation of follow up in non‐muscle‐invasive bladder cancer and muscle‐invasive bladder cancer.
Conclusions
Guidelines should be updated based on the current evidence and updates carried out without delay. The hope is that this guidelines will be assessed by many urologists and will be the cornerstone for the next revision.
The therapeutic landscape of metastatic clear cell renal cell carcinoma (ccRCC) has rapidly expanded, and there is an urgent need to develop noninvasive biomarkers that can select an optimal therapy ...or evaluate the response in real time. To evaluate the clinical utility of circulating tumor DNA (ctDNA) analysis in ccRCC, we established a highly sensitive assay to detect mutations in von Hippel‐Lindau gene (VHL) using a combination of digital PCR and multiplex PCR–based targeted sequencing. The unique assay could detect VHL mutations with a variant allele frequency (VAF) <1.0%. Further, we profiled the mutation status of VHL in 76 cell‐free DNA (cfDNA) and 50 tumor tissues from 56 patients with ccRCC using the assay. Thirteen VHL mutations were identified in cfDNA from 12 (21.4%) patients with a median VAF of 0.78% (range, 0.13%‐4.20%). Of the 28 patients with VHL mutations in matched tumor tissues, eight (28.6%) also had VHL mutation in cfDNA with a median VAF of 0.47% (range, 0.13%‐2.88%). In serial ctDNA analysis from one patient, we confirmed that the VAF of VHL mutation changed consistent with tumor size by radiographic imaging during systemic treatment. In conclusion, VHL mutation in cfDNA was detected only in a small number of patients even using the highly sensitive assay; nevertheless, we showed the potential of ctDNA analysis as a novel biomarker in ccRCC.
Somatic genome profiling of cell‐free DNA (cfDNA) and matched tumor tissues from patients with clear cell renal cell carcinoma focusing on VHL mutations was conducted. By combination of digital PCR and targeted sequencing, thirteen VHL mutations were identified in cfDNA from 12 (21.4%) patients with a median VAF of 0.78% (range, 0.13%‐4.20%). Of the 28 patients with VHL mutations in matched tumor tissues, eight (28.6%) also had VHL mutation in cfDNA with a median VAF of 0.47% (range, 0.13%‐2.88%).
Type 1 diabetes mellitus (T1DM) is manifested as a decrease in endogenous insulin secretion. With this report, we present a case of T1DM where a rapid decline in insulin secretion was observed in a ...short span of time. A 56-year-old female patient presented with cold-like symptoms with subsequent dry mouth and malaise to the hospital. Three weeks later, she was diagnosed with diabetic ketoacidosis based on the presence of hyperglycemia, metabolic acidosis, and positive ketone bodies. Her serum connecting peptide (CPR) levels substantially decreased (1.31 to 0.19 ng/mL after two weeks) and she was eventually diagnosed with T1DM. We hypothesized that a subtype T1DM with a longer beta cell loss rate than conventional fulminant type 1 diabetes was involved. This subtype showed characteristics of immune checkpoint inhibitor-associated fulminant type 1 diabetes and is suggested to exist among those diagnosed with conventional acute-onset type 1 diabetes. Finally, we recommend that diabetic ketoacidosis of unknown etiology should be investigated for the concurrent presence of T1DM.
Objective
The objective of this study was to evaluate the early surgical outcomes of robot-assisted partial nephrectomy (RAPN) for small renal masses in a large Japanese multicenter series.
Methods
A ...total of 804 consecutive cases of RAPN were examined at 42 institutes between 2011 and 2016. Medical records for clinical, pathological characteristics and perioperative outcomes were retrospectively reviewed. Univariable and multivariable analyses were performed to determine factors predicting Trifecta achievement.
Results
The median tumor size was 2.6 cm. The median RENAL score was 7. The median warm ischemia time was 21 min. The median estimated blood loss was 30 mL. Eight patients (1.0%) were converted to radical nephrectomy. The overall and Clavien–Dindo grade ≥ 3 complication rates were 13.0% and 5.8%, respectively. Pathologically, 91.4% of tumors were malignant and the positive surgical margin (PSM) rate was 1.1%. During the median 27.1-month observation period, the recurrence rate was 1.6%. Postoperative preservation rates of eGFR at 1, 6, 12 and 24 months were 90.3, 89.8, 89.4 and 89.2%, respectively. Trifecta was achieved in 62.1%. Multivariable analysis demonstrated that tumor diameter, estimated blood loss and hilar location of the tumor were significant negative factors predicting Trifecta achievement. The rate of Trifecta achievement for T1b tumors and hilar tumors was significantly lower (48.4% and 50.0%, respectively).
Conclusions
RAPN was safely performed with acceptable oncological and functional outcomes, but the rate of Trifecta accomplishment for T1b or hilar tumors was significantly lower than that for T1a or non-hilar tumors, respectively.
Neutrophil-to-lymphocyte ratio (NLR) was reported to be associated with prognosis of urothelial cancer (UC) patients receiving systemic chemotherapy or immunotherapy. However, it has not been ...elucidated how preceding first-line chemotherapy affects NLR and subsequent second-line pembrolizumab treatment. This multicenter study analyzed 458 patients with metastatic UC who received first-line chemotherapy and second-line pembrolizumab with regard to pre-chemotherapy and pre-pembrolizumab NLR in association with the efficacy of chemotherapy and pembrolizumab treatment. NLR was increased in 47% while decreased in 53% of patients before and after first-line chemotherapy. High pre-chemotherapy NLR (≥ 3) was significantly associated with unfavorable overall (OS,
P
= 0.0001) and progression-free (
P
< 0.0001) survivals after first-line chemotherapy. However, pre-chemotherapy NLR showed only modest influence on radiological response and survival after second-line pembrolizumab treatment, whereas pre-pembrolizumab NLR showed higher association. NLR decrease was associated with partial response or greater objective response by first-line chemotherapy, while NLR increase was associated with higher patient age. In conclusion, immediate pre-chemotherapy and pre-pembrolizumab NLR was significantly associated with efficacy of the following treatment, respectively. However, even patients with high pre-chemotherapy NLR achieved favorable OS if they had their NLR reduced by chemotherapy, whereas those with high pre-chemotherapy NLR yielded unfavorable OS if they had their NLR remained high after chemotherapy, suggesting that chemotherapy may have differential effect on the efficacy of subsequent pembrolizumab treatment in UC patients.
Advances in our understanding of the mechanisms driving castration-resistant prostate cancer have promoted the development of several new drugs including androgen receptor-directed therapy and ...chemotherapy. Concomitant docetaxel treatment at the beginning of hormonal therapy for metastatic prostate cancer has resulted in longer overall survival than with hormonal therapy alone. Elucidating an appropriate treatment sequence using these therapies is important for maximizing clinical benefit in castration-sensitive and castration-resistant prostate cancer patients. The development of advanced high-throughput ‘omics’ technology has enabled the use of novel markers to guide prognosis and treatment of this disease. In this review, we outline the genomic landscape of prostate cancer and the molecular mechanisms of castration-resistant progression, and how these affect the development of new drugs, and their clinical implications for selecting treatment sequence. We also discuss many of the potential tissue-based or liquid biomarkers that may soon enter clinical use, with the hope that several of these prognostic or predictive markers will guide precision medicine for prostate cancer patients in the near future.
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