Safety and feasibility of minimally invasive gastrectomy following preoperative chemotherapy for highly advanced gastric cancer.

BACKGROUND: This study aimed to determine the safety and feasibility of minimally invasive gastrectomy in patients who underwent preoperative chemotherapy for highly advanced gastric cancer. METHODS: Preoperative chemotherapy was indicated for patients with advanced large tumors (≥ cT3 and ≥ 5 cm) and/or bulky node metastasis (≥ 3 cm × 1 or ≥ 1.5 cm × 2). Between January 2009 and March 2022, 150 patients underwent preoperative chemotherapy followed by gastrectomy with R0 resection, including conversion surgery (robotic, 62; laparoscopic, 88). The outcomes of these patients were retrospectively examined. RESULTS: Among them, 41 and 47 patients had stage IV disease and underwent splenectomy, respectively. Regarding operative outcomes, operative time was 475 min, blood loss was 72 g, morbidity (grade ≥ 3a) rate was 12%, local complication rate was 10.7%, and postoperative hospital stay was 14 days (Interquartile range: 11-18 days). Fifty patients (33.3%) achieved grade ≥ 2 histological responses. Regarding resection types, total/proximal gastrectomy plus splenectomy (29.8%) was associated with significantly higher morbidity than other types (distal gastrectomy, 3.2%; total/proximal gastrectomy, 4.9%; P < 0.001). Specifically, among splenectomy cases, the rate of postoperative complications associated with the laparoscopic approach was significantly higher than that associated with the robotic approach (40.0% vs. 0%, P = 0.009). In the multivariate analysis, splenectomy was an independent risk factor for postoperative complications [odds ratio, 8.574; 95% confidence interval (CI), 2.584-28.443; P < 0.001]. CONCLUSIONS: Minimally invasive gastrectomy following preoperative chemotherapy was feasible and safe for patients with highly advanced gastric cancer. Robotic gastrectomy may improve surgical safety, particularly in the case of total/proximal gastrectomy combined with splenectomy.

The safe implementation of peripherally inserted central catheters by nurse practitioners for patients with gastroenterological diseases in Japan: a single-center retrospective study.

PURPOSE: As a safe and reliable alternative to central venous catheters (CVCs), peripherally inserted central catheters (PICCs) are commonly used in clinical practice. However, the insertion of PICCs by nurse practitioners (NPs), especially in Japan, has not been reported extensively. Thus, we investigated the safety and efficiency of PICC insertions by NPs. METHODS: The participants were 1322 patients who underwent PICC insertion by NPs at Fujita Health University Hospital (FNPs). The basilic vein in the brachium was the preferred vein for insertion; the brachial vein was the alternative. Patients were monitored from the time of PICC insertion until its removal. Ultrasonography-guided puncture was used for all catheter insertions, and the catheter tip was replaced into the superior vena cava under fluoroscopic imaging with maximal sterile barrier precautions. The outcomes of the PICC insertions by the FNPs were evaluated retrospectively. RESULTS: Overall, 23 FNPs inserted a collective total of 1322 PICCs, which remained in place for a collective total of 23,619 catheter days. The rate of successful PICC insertion was 99% (1310 patients). The median time taken for PICC insertion was 12 min (interquartile range, 10-15 min). Intraoperative complications occurred in two patients (0.2%). The confirmed incidence of central line-associated bloodstream infection was 3.4% (45 patients), and these infections occurred on 1.9 per 1000 catheter days. The median duration of PICC placement was 15 days (range, 10-23 days). CONCLUSION: PICC insertion by NPs is safe and a potential alternative to CVC insertion by surgeons.

Phase III clinical trial of autologous CD34 + cell transplantation to accelerate fracture nonunion repair.

BACKGROUND: We previously demonstrated that CD34 + cell transplantation in animals healed intractable fractures via osteogenesis and vasculogenesis; we also demonstrated the safety and efficacy of this cell therapy in an earlier phase I/II clinical trial conducted on seven patients with fracture nonunion. Herein, we present the results of a phase III clinical trial conducted to confirm the results of the previous phase studies using a larger cohort of patients. METHODS: CD34 + cells were mobilized via administration of granulocyte colony-stimulating factor, harvested using leukapheresis, and isolated using magnetic cell sorting. Autologous CD34 + cells were transplanted in 15 patients with tibia nonunion and 10 patients with femur nonunion, who were followed up for 52 weeks post transplantation. The main outcome was a reduction in time to heal the tibia in nonunion patients compared with that in historical control patients. We calculated the required number of patients as 15 based on the results of the phase I/II study. An independent data monitoring committee performed the radiographic assessments. Adverse events and medical device failures were recorded. RESULTS: All fractures healed during the study period. The time to radiological fracture healing was 2.8 times shorter in patients with CD34 + cell transplantation than in the historical control group (hazard ratio: 2.81 and 95% confidence interval 1.16-6.85); moreover, no safety concerns were observed. CONCLUSIONS: Our findings strongly suggest that autologous CD34 + cell transplantation is a novel treatment option for fracture nonunion. TRIAL REGISTRATION: UMIN-CTR, UMIN000022814. Registered on 22 June 2016.

Long-term results of minimally invasive transanal surgery for rectal tumors in 249 consecutive patients.

PURPOSE: To delineate the long-term results of minimally invasive transanal surgery (MITAS) for selected rectal tumors. METHODS: We analyzed data, retrospectively, on consecutive patients who underwent MITAS between 1995 and 2015, to establish the feasibility, excision quality, and perioperative and oncological outcomes of this procedure. RESULTS: MITAS was performed on 243 patients. The final histology included 142 cancers, 47 adenomas, and 52 neuroendocrine tumors (NET G1). A positive margin of 1.6% and 100% en bloc resection were achieved. The mean operative time was 27.4 min. Postoperative morbidity occurred in 7% of patients, with 0% mortality. The median follow-up was 100 months (up to ≥ 5 years or until death in 91.8% of patients). Recurrence developed in 2.9% of the patients. The 10-year overall survival rate was 100% for patients with NET G1 and 80.3% for those with cancer. The 5-year DFS was 100% for patients with Tis cancer, 90.6% for those with T1 cancer, and 87.5% for those with T2 or deeper cancers. MITAS for rectal tumors ≥ 3 cm resulted in perioperative and oncologic outcomes equivalent to those for tumors < 3 cm. CONCLUSION: MITAS is feasible for the local excision (LE) of selected rectal tumors, including tumors ≥ 3 cm. It reduces operative time and secures excision quality and long-term oncological outcomes.

Long-term outcomes and central nervous system relapse in extranodal natural killer/T-cell lymphoma.

To elucidate the long-term outcomes of non-anthracycline-containing therapies and central nervous system (CNS) events in patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL), the clinical data of 313 patients with ENKTL diagnosed between 2000 and 2013 in a nationwide retrospective study in Japan were updated and analyzed. At a median follow-up of 8.4 years, the 5-year overall survival (OS) and progression-free survival (PFS) were 71% and 64%, respectively, in 140 localized ENKTL patients who received radiotherapy-dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) in clinical practice. Nine (6.4%) patients experienced second malignancies. In 155 localized ENKTL patients treated with RT-DeVIC, 10 (6.5%) experienced CNS relapse (median, 12.8 months after diagnosis). In five of them, the events were confined to the CNS. Nine of the 10 patients who experienced CNS relapse died within 1 year after CNS relapse. Multivariate analysis identified gingival (hazard ratio [HR], 54.35; 95% confidence interval [CI], 8.60-343.35) and paranasal involvement (HR, 7.42; 95% CI, 1.78-30.89) as independent risk factors for CNS relapse. In 80 advanced ENKTL patients, 18 received steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy as first-line treatment. Patients who received SMILE as their first-line treatment tended to have better OS than those who did not (p = 0.071). Six (7.5%) advanced ENKTL patients experienced isolated CNS relapse (median, 2.6 months after diagnosis) and died within 4 months of relapse. No second malignancies were documented in advanced ENKTL patients. In the entire cohort, the median OS after first relapse or progression was 4.6 months. 12 patients who survived 5 years after PFS events were disease-free at the last follow-up. Of those, 11 (92%) underwent hematopoietic stem cell transplantation. Our 8-year follow-up revealed the long-term efficacy and safety of RT-DeVIC and SMILE. The risk of CNS relapse is an important consideration in advanced ENKTL.

Biweekly TAS-102 and bevacizumab as third-line chemotherapy for advanced or recurrent colorectal cancer: a phase II, multicenter, clinical trial (TAS-CC4 study).

BACKGROUND: TAS-102 improves overall survival (OS) of patients with refractory colorectal cancer (CRC), resulting in median progression-free survival (PFS) of 2.0 months (RECOURSE trial). Subsequently, a combination of TAS-102 and bevacizumab was shown to extend median PFS by 3.7 months. However, approximately half of these patients experience grade 3/4 neutropenia. In this study, we evaluated whether biweekly TAS-102 and bevacizumab therapy has efficacy equal to that of conventional TAS-102 and bevacizumab therapy and whether it reduces adverse hematological effects. METHODS: This phase II, investigator-initiated, open-label, single-arm, multicenter study was conducted in Japan. Eligible patients had previously received first- and second-line chemotherapy for metastatic CRC. TAS-102 (35 mg/m2) was given twice daily on days 1-5 and days 15-19 in a 4-week cycle, and bevacizumab (5 mg/kg) was administered by intravenous infusion for 30 min every 2 weeks. The primary end point was progression-free survival (PFS), and secondary end points were time-to-treatment failure (TTF), response rate (RR), OS, and safety. RESULTS: 44 patients with metastatic colorectal cancer were enrolled in this study. Median PFS was 4.6 months (95% confidence interval [95% CI] 3.6-5.3) and median OS was 10.5 months (95% CI 9.6-11.4). A partial response was observed in 2 patients (4.5%, 95% CI 0.4-16.0%). The most common adverse event above grade 3 was neutropenia (7 patients, 15.9%, 95% CI 7.6-29.7%). CONCLUSIONS: Biweekly TAS-102 and bevacizumab therapy as third-line chemotherapy appears as effective as conventional TAS-102 and bevacizumab therapy, and this approach reduces adverse hematological effects.

Expression status of p53 and organic cation transporter 1 is correlated with poor response to preoperative chemotherapy in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly malignant neoplasm. DNA-damaging drugs, such as cisplatin (CDDP) and 5-fluorouracil (5-FU), are most frequently used in preoperative chemotherapy for ESCC. However, the response to preoperative chemotherapy varies among patients. p53, encoded by TP53, participates in apoptotic pathways following chemotherapy with DNA-damaging drugs, and mutation of TP53 contributes to chemoresistance. Organic cation transporter 1 (OCT1) participates in the uptake of CDDP, and its reduced expression is associated with CDDP resistance. The aim of this study was to evaluate the predictive impact of the expression status of p53 and OCT1 in response to preoperative chemotherapy in ESCC. METHODS: We retrospectively assessed 66 ESCC patients who received preoperative chemotherapy with CDDP/5-FU (CF) or docetaxel/CDDP/5-FU (DCF). p53 and OCT1 expression in pretreatment biopsy specimens was immunohistochemically determined and correlated with histological response to preoperative chemotherapy. RESULTS: p53 with wild-type (p53WT-ex) and mutant-type (p53MT-ex) expression patterns was identified in 40.9% and 59.1% of patients, respectively. High expression of OCT1 (OCT1High) was detected in 45.5%, and the remaining 54.5% showed low expression (OCT1Low). In a univariate analysis of the entire cohort, p53MT-ex was significantly correlated with poor response (P = 0.026), whereas OCT1Low showed marginal significance (P = 0.091). In a combined analysis, tumors with either p53MT-ex or OCT1Low showed a significant correlation with poor response compared with tumors with both p53WT-ex and OCT1High (P < 0.001). The sensitivity, specificity, and accuracy of combined p53/OCT1 were 93.9%, 47.1%, and 81.8%, respectively. Multivariate analysis identified p53 (P = 0.017), OCT1 (P = 0.032), and combined p53/OCT1 (P < 0.001) as independent predictors of histological response. When samples were stratified according to chemotherapy regimen in the univariate analysis, combined p53/OCT1 was the only significant factor for poor response in the CF (P = 0.011) and DCF (P = 0.021) groups, whereas p53 showed no statistical significance. CONCLUSIONS: Our results suggest that either p53MT-ex or OCT1Low expression in pretreatment biopsy specimens may be a potential predictor of poor response to preoperative chemotherapy with the CF-based regimens in ESCC, although the specificity needs to be improved.

[Robot-Assisted Surgery for Stage â £ Gastric Cancer with Liver Metastases-Report of a Case].

We report a successful case of robot-assisted surgery for Stage Ⅳ gastric cancer with liver metastasis. A 70s man diagnosed with advanced gastric cancer with S3 solitary liver metastasis, and received a chemotherapy with S-1 and cisplatin. After 4 courses of chemotherapy, liver metastatic lesion was disappeared. Thus, robotic distal gastrectomy and partial liver resection were performed. Operating time was 391 minutes, and amount of intraoperative blood loss was 11 mL. The postoperative course was uneventful, and the patient was discharged 11 days after surgery. Histologic examination revealed no viable malignant cells in the resected liver, with a diagnosis of ypT2N1M0, ypStage ⅡA. The patient is alive with no recurrence 12 months after surgery, without adjuvant chemotherapy.

Impact of UGT1A1 genotype on the efficacy and safety of irinotecan-based chemotherapy in metastatic colorectal cancer.

The phase III AXEPT study showed the noninferiority of modified capecitabine plus irinotecan (mXELIRI) with or without bevacizumab relative to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab as a second-line treatment for metastatic colorectal cancer. We evaluated the associations between the UGT1A1 genotype linked to adverse events-caused by irinotecan-and the efficacy and safety of mXELIRI and FOLFIRI. The UGT1A1 genotype was prospectively determined and patients were categorized into three groups according to WT (*1/*1), single heterozygous (SH; *28/*1 or *6/*1), and double heterozygous or homozygous (DHH; *28/*28, *6/*6, or *28/*6). Overall survival (OS), progression-free survival, response rate, and safety were assessed. The UGT1A1 genotype was available in all 650 randomized patients (WT, 309 [47.5%]; SH, 291 [44.8%]; DHH, 50 [7.7%]). The median OS was 15.9, 17.7, and 10.6 months in the WT, SH, and DHH groups, respectively, with an adjusted hazard ratio (HR) of 1.53 (95% confidence interval [CI], 1.12-2.09; P = .008) for DHH vs WT or SH. The median OS in the mXELIRI and FOLFIRI arms was 18.1 vs 14.3 months (HR 0.80; 95% CI, 0.62-1.03) in the WT group, 16.3 vs 18.3 months (HR 1.04; 95% CI, 0.79-1.36) in the SH group, and 13.0 vs 9.1 months (HR 0.71; 95% CI, 0.39-1.31) in the DHH group, respectively. Modified capecitabine plus irinotecan with or without bevacizumab could be a standard second-line chemotherapy in terms of efficacy and safety regardless of the UGT1A1 genotype.

Identification of the RORα Transcriptional Network Contributes to the Search for Therapeutic Targets in Atherosclerosis.

The retinoic acid receptor-related orphan receptor α (RORα) is involved in the regulation of several physiological processes, including development, metabolism, and circadian rhythm. RORα-deficient mice display profound atherosclerosis, in which hypoalphalipoproteinemia is reportedly associated with decreased plasma levels of high-density lipoprotein, increased levels of inflammatory cytokines, and ischemia/reperfusion-induced damage. The recent characterization of endogenous ligands (including cholesterol, oxysterols, provitamin D3, and their derivatives), mediators, and initiation complexes associated with the transcriptional regulation of these orphan nuclear receptors has facilitated the development of synthetic ligands. These findings have also highlighted the potential of application of RORα as a therapeutic target for several diseases, including diabetes, dyslipidemia, and atherosclerosis. In this review, the current literature related to the structure and function of RORα, its genetic inter-individual differences, and its potential as a therapeutic target in atherosclerosis is discussed.

Transcription of CLDND1 in human brain endothelial cells is regulated by the myeloid zinc finger 1.

Increased permeability of endothelial cells lining the blood vessels in the brain leads to vascular oedema and, potentially, to stroke. The tight junctions (TJs), primarily responsible for the regulation of vascular permeability, are multi-protein complexes comprising the claudin family of proteins and occludin. Several studies have reported that downregulation of the claudin domain containing 1 (CLDND1) gene enhances vascular permeability, which consequently increases the risk of stroke. However, the transcriptional regulation of CLDND1 has not been studied extensively. Therefore, this study aimed to identify the transcription factors (TFs) regulating CLDND1 expression. A luciferase reporter assay identified a silencer within the first intron of CLDND1, which was identified as a potential binding site of the myeloid zinc finger 1 (MZF1) through in silico and TFBIND software analyses, and confirmed through a reporter assay using the MZF1 expression vector and chromatin immunoprecipitation (ChIP) assays. Moreover, the transient overexpression of MZF1 significantly increased the mRNA and protein expression levels of CLDND1, conversely, which were suppressed through the siRNA-mediated MZF1 knockdown. Furthermore, the permeability of FITC-dextran was observed to be increased on MZF1 knockdown as compared to that of the siGFP control. Our data revealed the underlying mechanism of the transcriptional regulation of CLDND1 by the MZF1. The findings suggest a potential role of MZF1 in TJ formation, which could be studied further and applied to prevent cerebral haemorrhage.

Robotic low anterior resection for rectal cancer with side-to-end anastomosis in a patient with anal stenosis.

BACKGROUND: Colorectal anastomosis using the double stapling technique (DST) has become a standard procedure. However, DST is difficult to perform in patients with anal stenosis because a circular stapler cannot be inserted into the rectum through the anus. Thus, an alternative procedure is required for colorectal anastomosis. CASE PRESENTATION: A 78-year-old woman presented with bloody stool. Colonoscopy and computed tomography revealed advanced low rectal cancer without lymph node or distant metastasis. We initially planned to perform low anterior resection using a double stapling technique or transanal hand-sewn anastomosis, but this would have been too difficult due to anal stenosis and fibrosis caused by a Milligan-Morgan hemorrhoidectomy performed 20 years earlier. The patient had never experienced defecation problems and declined a stoma. Therefore, we inserted an anvil into the rectal stump and fixed it robotically with a purse-string suture followed by insertion of the shaft of the circular stapler from the sigmoidal side. In this way, side-to-end anastomosis was accomplished laparoscopically. The distance from the anus to the anastomosis was 5 cm. The patient was discharged with no anastomotic leakage. Robotic assistance proved extremely useful for low anterior resection with side-to-end anastomosis. CONCLUSION: Performing side-to-end anastomosis with robotic assistance was extremely useful in this patient with rectal cancer and anal stenosis.

Outcomes of stapler repair with anastomosis for stoma prolapse.

PURPOSE: The published data on the outcomes of an operative repair for stoma prolapse are limited. This study aimed to clarify the long-term outcomes of stapler repair with anastomosis for stoma prolapse. METHODS: Twenty-four patients (15 men, median age 64 years, range 33-88 years) undergoing 25 stapler repairs with anastomosis were prospectively registered, and their medical records were retrospectively reviewed. RESULTS: The median length of prolapse was 10 cm (range 5-22). Stoma prolapse repair was performed by means of 16 loop colostomies, four end colostomies, three loop ileostomies, and one end ileostomy. A stapler was used 4.6 times on average (range 4-8). The average operative time and bleeding were 40.8 (range 15-75) min and 40 (range 0-214) mL, respectively. No mortality and morbidity were observed after surgery. A recurrence of stoma prolapse was reported in only one of 25 repairs (4%) at the proximal limb of loop ileostomy during a median follow-up period of 1 year (range 1-120 months). However, a new stoma prolapsed in one untreated limb of loop stoma. CONCLUSIONS: Stapler repair with anastomosis is a safe and minimally invasive treatment option for stoma prolapse with a low recurrence. However, the effectiveness of reparing stoma prolapse on the proximal limb of loop ileostomy might be limited.

Transvaginal peritoneocele repair with anterior levatorplasty for patients with a rectocele and an enterocele.

Enteroceles and rectoceles are often identified as the cause of a vaginal mass and pelvic discomfort. The combination of a rectocele and an enterocele as pelvic organ prolapses is not infrequent; however, there are few reports on possible simultaneous treatments of these two conditions. We report a new and simple procedure for repairing an enterocele during a transvaginal anterior levatorplasty with posterior colporrhaphy for a rectocele repair. This technique involves making an excision in the peritoneal sac, with high ligation, and attaching the uterine cervix and/or cardinal ligament to the upper most part of the approximation of the levator muscles, to reinforce and lift the deep peritoneal sac. This procedure allows for transvaginal repair of both an enterocele and a rectocele. The enterocele is visualized by applying barium to the posterior vaginal wall during defecography.

Impact of DPYD, DPYS, and UPB1 gene variations on severe drug-related toxicity in patients with cancer.

Cancer treatment with a fluoropyrimidine (FP) is often accompanied by severe toxicity that may be dependent on the activity of catalytic enzymes encoded by the DPYD, DPYS, and UPB1 genes. Genotype-guided dose individualization of FP therapy has been proposed in western countries, but our knowledge of the relevant genetic variants in East Asian populations is presently limited. To investigate the association between these genetic variations and FP-related high toxicity in a Japanese population, we obtained blood samples from 301 patients who received this chemotherapy and sequenced the coding exons and flanking intron regions of their DPYD, DPYS, and UPB1 genes. In total, 24 single nucleotide variants (15 in DPYD, 7 in DPYS and 2 in UPB1) were identified including 3 novel variants in DPYD and 1 novel variant in DPYS. We did not find a significant association between FP-related high toxicity and each of these individual variants, although a certain trend toward significance was observed for p.Arg181Trp and p.Gln334Arg in DPYS (P = .0813 and .087). When we focused on 7 DPYD rare variants (p.Ser199Asn, p.IIe245Phe, p.Thr305Lys, p.Glu386Ter, p.Ser556Arg, p.Ala571Asp, p.Trp621Cys) which have an allele frequency of less than 0.01% in the Japanese population and are predicted to be loss-of-function mutations by in silico analysis, the group of patients who were heterozygous carriers of at least one these rare variants showed a strong association with FP-related high toxicity (P = .003). Although the availability of screening of these rare loss-of-function variants is still unknown, our data provide useful information that may help to alleviate FP-related toxicity in Japanese patients with cancer.

Allogeneic hematopoietic stem cell transplantation at the first remission for younger adults with FLT3-internal tandem duplication AML: The JALSG AML209-FLT3-SCT study.

In this phase II multicenter study (JALSG AML209-FLT3-SCT), we aimed to prospectively elucidate the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1) for FLT3-internal tandem duplication (ITD)-positive AML. Newly diagnosed de novo AML patients with FLT3-ITD were enrolled at the achievement of CR1 and received allo-HSCT as soon as possible after the first consolidation therapy. Mutations of 57 genes in AML cells at diagnosis were also analyzed. Among 48 eligible patients with a median age of 38.5 (17-49) years, 36 (75%) received allo-HSCT at a median of 108 days after CR1. The median follow-up was 1726 days. The primary end-point, 3-year disease-free survival (DFS) based on an intent to treat analysis, was 43.8% (95% confidence interval [CI], 30%-57%), suggesting the efficacy of this treatment because the lower limit of the 95% CI exceeded the threshold response rate of 20%. The 3-year overall survival, post-transplant DFS, and non-relapse mortality rates were 54.2% (95% CI, 39%-67%), 58.3% (95% CI, 41%-72%), and 25.0% (95% CI, 12%-40%), respectively. The median ITD allelic ratio (AR) was 0.344 (0.006-4.099). Neither FLT3-ITD AR nor cooccurring genetic alterations was associated with a poor DFS. This prospective study indicated the efficacy and safety of allo-HSCT for FLT3-ITD AML patients in CR1. This study was registered at: www.umin.ac.jp/ctr/ as #UMIN000003433.

Correlation between immune-related adverse events and prognosis in patients with various cancers treated with anti PD-1 antibody.

BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) are used for the treatment of various cancer types. However, immune-related adverse events (irAEs) occur in patients treated with ICIs. Several small-scale studies have reported the onset of irAEs and therapeutic effects of ICIs. Here we report a large-scale retrospective study covering a wide range of cancers. We evaluated irAEs and the therapeutic effects of ICIs and determined whether irAEs could be predicted. METHODS: This study included patients treated with the anti-PD-1 antibodies nivolumab or pembrolizumab at Fujita Health University Hospital between December 2015 and March 2019. We retrospectively reviewed the electronic medical records for age, cancer type, pre-treatment blood test data, presence or absence of irAE onset, type and severity of irAEs, outcome of irAE treatment, response rate, progression-free survival and overall survival. RESULTS: Two hundred-eighty patients received ICIs. The overall incidence of irAEs was 41.1% (115 patients), and the incidence of severe irAEs of grade 3 and higher was 2.8% (eight patients). The most common irAEs were skin disorders, thyroid disorders and interstitial pneumonitis. Patients with irAEs were significantly older than those without irAEs (69.7 versus 66.0 years, P = 0.02). The objective response rate (ORR) in patients with irAEs was 30.4%, which was significantly higher than in patients without irAEs (12.7%; P < 0.01). Both the median overall and progression-free survival were significantly longer in patients with irAEs (P < 0.01, p < 0.01). Based on the blood test data obtained before ICI therapy, hypothyroidism, thyroid-stimulating hormone levels and thyroglobulin antibody levels were associated with the onset of irAEs. In many patients with irAEs of Common Terminology Criteria for Adverse Events Grade 3 or higher, re-administration of ICIs was difficult, and their outcomes were poor. In contrast, many patients with irAEs of a lower grade were able to resume ICI therapy. CONCLUSION: Although the onset of irAEs was difficult to be predicted based on pre-treatment tests. It appeared that the continuation of ICI therapy, along with early detection and adequate control of irAEs, might contribute to the improved prognosis of patients.

Stroke-prone spontaneously hypertensive rats have reduced hydroxysteroid 17-ß dehydrogenase 7 levels for low cholesterol biosynthesis.

Reduced serum cholesterol content was recently reported to be one of the factors responsible for cerebral haemorrhage. Stroke-prone spontaneously hypertensive rats (SHRSP) are known to have lower serum cholesterol content than normotensive Wistar-Kyoto rats (WKY). We previously reported that lower levels of mevalonate pyrophosphate decarboxylase (MPD) and squalene epoxidase (SQE), which are associated with cholesterol biosynthesis in the liver, are involved in the low serum cholesterol content in SHRSP. Here, we investigate the levels of sterol 14-demethylase (CYP51), methylsterol monooxygenase (SC4MOL), and hydroxysteroid 17-ß dehydrogenase 7 (HSD17B7), which contribute to the cholesterol synthesis pathway in the conversion of lanosterol to zymosterol, in SHRSP and WKY. The HSD17B7 mRNA levels in the liver of SHRSP were markedly lower than those in WKY, whereas no significant differences were observed in CYP51 and SC4MOL levels in the two types of rats. The relative levels of protein, heteronuclear RNA, and mRNA of HSD17B7 were also significantly lower in SHRSP than in WKY. The degradation rates of HSD17B7 were the same in SHRSP and WKY. The protein levels of HSD17B7 were not significantly reduced in tissues other than the liver, including the brain, lung, heart, spleen, kidney, and testis, in SHRSP. Moreover, HSD17B7 activity was significantly lower in SHRSP than in WKY. Thus, our results indicated that low protein levels and activity of HSD17B7 are responsible for the reduced cholesterol content in SHRSP, indicating that HSD17B7, along with MPD and SQE, is involved in the decreased cholesterol synthesis in the liver of SHRSP.

Relationship between serum calcium and creatinine in hematopoietic stem cell transplantation patients treated with foscarnet
.

OBJECTIVE: The relationship between serum creatinine and calcium (Ca) was investigated in hematopoietic stem cell transplantation (HSCT) patients treated with foscarnet. MATERIALS AND METHODS: A retrospective study was performed to investigate the development of foscarnet-induced renal dysfunction in patients who received HSCT from April 2010 to November 2018 at the Kindai University Nara Hospital. A total of 80 patients were identified from the medical records, and 42 patients who met the inclusion criteria were enrolled in this study. Renal dysfunction was classified according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. RESULTS: A significant inverse relationship was observed between serum creatinine and Ca levels (r = -0.372; p < 0.0001; y = -0.537x + 9.268). A separate analysis divided into renal dysfunction and non-renal dysfunction groups showed that there was a significant relationship between serum creatinine and Ca levels in the renal dysfunction group (r = -0.531; p < 0.0001; y = -0.617x + 9.239) but not in the non-renal dysfunction group (r = -0.011; p = 0.561; y = -0.023x + 8.934). The optimal cutoff for the minimum Ca level was calculated to be 8.1 mg/mL. CONCLUSION: A significant inverse relationship was observed between serum creatinine and Ca levels in HSCT patients with foscarnet-induced renal dysfunction. Foscarnet-induced renal dysfunction should be noted if Ca levels fall below 8.1 mg/dL. Monitoring Ca levels may be useful for detecting renal dysfunction at early stages in patients treated with foscarnet.

Disseminated cryptococcosis resembling miliary tuberculosis in a patient with acute myeloid leukemia.

Disseminated cryptococcosis, usually involving the lungs and central nervous system, carries a high risk of morbidity and mortality in immunocompromised hosts. In this report, we describe a case of miliary pulmonary cryptococcosis in a patient with acute myeloid leukemia, initially resembling miliary tuberculosis. The diagnosis of disseminated cryptococcosis was made based on transbronchial lung biopsy with subsequent detection of Cryptococcus neoformans in blood and cerebrospinal fluid. The patient was treated with liposomal amphotericin B as induction therapy, followed by fluconazole as consolidation and maintenance therapies thereafter. The infection was improved immediately, and he successfully underwent hematopoietic stem cell transplantation. The present case serves as a timely reminder that a radiological miliary pattern necessitates a thorough search for a definitive microbiological and histopathological diagnosis.