Immune checkpoint inhibitor (nivolumab)-associated kidney injury and the importance of recognizing concomitant medications known to cause acute tubulointerstitial nephritis: a case report.

BACKGROUND: Acute tubulointerstitial nephritis (ATIN) has been increasingly recognized as an important manifestation of kidney injury associated with the use of immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4). While the exact pathophysiology remains unknown, corticosteroids are the mainstay of management. CASE PRESENTATION: We describe a 67-year-old man with stage IV non-small-cell lung cancer who developed kidney injury during treatment with the anti-PD-1 antibody nivolumab. A kidney biopsy showed ATIN without granuloma formation. Considering their mechanism of action, immune checkpoint inhibitors can alter immunological tolerance to concomitant drugs that have been safely used for a long time. For more than 4 years before the initiation of nivolumab therapy, the patient had been receiving the proton pump inhibitor lansoprazole, known to cause drug-induced ATIN, without significant adverse events including kidney injury. He showed rapid improvement in kidney function in 3 days (creatinine decreased from 2.74 to 1.82 mg/dl) on discontinuation of lansoprazole. He then received 500 mg intravenous methylprednisolone for 3 days followed by 1 mg/kg/day oral prednisolone and his creatinine levels eventually stabilized around 1.7 mg/dl. Drug-induced lymphocyte stimulation test (DLST) for lansoprazole was positive. CONCLUSIONS: The rapid improvement of kidney function after discontinuation and DLST positivity indicate that lansoprazole contributed to the development of ATIN during nivolumab therapy. Considering the time course, it is plausible that nivolumab altered the long-lasting immunological tolerance against lansoprazole in this patient. To the best of our knowledge, this is the first case report of DLST positivity for a drug that had been used safely before the initiation of an immune checkpoint inhibitor. Although corticosteroid therapy is recommended, the recognition and discontinuation of concomitant drugs, especially those known to induce ATIN, is necessary for the management of kidney injury associated with anti-PD-1 therapy.

Immunohistochemical differentiation of eosinophilic esophageal myositis from eosinophilic esophagitis.

BACKGROUND AND AIM: Eosinophilic esophagitis (EoE) is a Th2-mediated allergic disease of the esophageal epithelium, associated with antigen. We previously reported a case series for eosinophilic esophageal myositis (EoEM)-a novel eosinophilic gastrointestinal disorder defined as eosinophilic infiltration localized in the esophageal muscle layer-and diagnosed it by peroral endoscopic muscle biopsy. Here, we investigated the immunopathology of EoEM to differentiate it from EoE. METHODS: Histological analysis was performed for three cases of EoEM and EoE, respectively. The results were compared with those of two control samples (non-eosinophilic gastrointestinal disorder full-layer esophagus). Using immunofluorescence, we analyzed the expression of the chemokine receptor CCR3 and its ligands eotaxin-1 and eotaxin-3 to investigate the eosinophilic reaction. Additionally, we determined the expression patterns of desmoglein-1 in the esophageal epithelium, which shows dysregulated expression in EoE. RESULTS: Eosinophil infiltration was observed in the muscle layer (maximum number, 30, 36, 73/high-power field) and the epithelium (50, 44, 40/high-power field) for EoEM and EoE, respectively. In EoE esophageal epithelium, the number of eotaxin-3-positive epithelial cells was significantly increased together with CCR3-positive infiltrating cells. However, in EoEM, a number of eotaxin-1-positive and eotaxin-3-positive myocytes and vascular endothelial cells were increased in the esophageal muscle layer. A significant loss of desmoglein-1 expression was only observed in EoE, not in EoEM. CONCLUSIONS: Eotaxin-1 and eotaxin-3 expression on the smooth muscle and vessels plays a role in the pathogenesis of EoEM, while EoE shows an epithelial eotaxin-3-dominant immunoreaction. Thus, the EoEM immunological pattern displays clear differences from that of EoE.

Differential expression of pentraxin 3 in neutrophils.

Pentraxins belong to the superfamily of conserved proteins that are characterized by a cyclic multimeric structure. Pentraxin 3 (PTX3) is a long pentraxin which can be produced by different cell types upon exposure to various inflammatory signals. Inside the neutrophil PTX3 is stored in form of granules localized in the cytoplasm. Neutrophilic granules are divided into three types: azurophilic (primary) granules, specific (secondary) granules and gelatinase (tertiary) granules. PTX3 has been considered to be localized in specific (secondary) granules. Immunofluorescent analyses using confocal laser microscopic examination were performed to clarify the localization of all three groups of granules within the cytoplasm of the mature neutrophils and neutrophils stimulated with IL-8. Furthermore, PTX3 was localized in primary granules of promyelocyte cell line HL-60. As a result, we suggest that PTX3 is localized not only in specific granules, but is also partly expressed in primary and tertiary granules. After the stimulation with IL-8, irregular reticular structures called neutrophil extracellular traps (NETs) were formed, three types of granules were trapped by NETs and PTX3 showed partial colocalization with these granular components. PTX3 localized in all three types of granules in neutrophils may play important roles in host defense.

Degradation of Jatropha curcas phorbol esters derived from Jatropha oil cake and their tumor-promoting activity.

Large amount of oil cake is generated during biodiesel production from Jatropha seeds. Although Jatropha oil cake is rich in plant nutrients, presence of toxic phorbol esters restricts the usage of oil cake as a fertilizer. The objective of this study is to evaluate the components and tumor promoting activity of phorbol esters in Jatropha oil cake-supplemented soil and plants grown in the treated soil. Contents and their biological activity of Jatropha phorbol esters in soil and plants were sequentially analyzed by high-performance liquid chromatography (HPLC) and in vitro cell transformation assay, respectively. Disappearance of Jatropha phorbol-ester-specific peaks were followed with HPLC during incubation of Jatropha oil cake with soil for five weeks. Along with the degradation of Jatropha phorbol ester in soil, tumor-promoting activity in the sample was also attenuated and ultimately disappeared. Jatropha phorbol esters and tumor promoting activity were not detected from mustard spinach grown in the Jatropha oil cake-supplemented soil. In addition, the esterase KM109 degrades DHPB (see definition below; Jatropha phorbol ester) and reduced its tumor-promoting activity. From these data, we conclude: (1) components and tumor promoting activity of Jatropha phorbol esters in the oil cake disappeared completely by incubation with soil for five-week, (2) Jatropha phorbol esters did not transfer into plants grown in the Jatropha oil cake-supplemented soil, and (3) DHPB can be degraded by esterase from soil bacterium. These observations are useful for utilization of Jatropha oil cake as a fertilizer.

Pembrolizumab Therapy Leading to Complete Remission for Recurrence of Pulmonary Metastases after their Resection and Radical Cystectomy following Gemcitabine and Cisplatin Therapy.

A 64-year-old man was diagnosed with invasive bladder and right lower ureteral urothelial cancer with right pelvic lymph node and lung metastases. He received four courses of gemcitabine and cisplatin therapy. He underwent lung metastasectomy and radical cystoprostatectomy, with not only primary lesions but also metastatic lesions showing a complete response. New multiple lung metastases were revealed five months after adjuvant chemotherapy. On starting pembrolizumab therapy, the metastatic lesions are notably reduced in size. He is currently receiving pembrolizumab therapy, and no recurrence has been observed for over one year.

Bladder Cancer Invading the Prostate and Penis and Multiple Bone Metastases Showing Significant Improvement after a Short-Term Pembrolizumab Therapy following Radiation and Gemcitabine and Cisplatin Therapy Leading to a Pathologically Complete Remission.

A 65-year-old man was diagnosed with bladder cancer invading the prostate and penis and multiple bone metastases. He underwent palliative radiation (30 Gy/10 fr) through vertebral bones (Th3 and Th12-L5) and pelvic bones for pain control. The patient received pembrolizumab therapy after three courses of gemcitabine and cisplatin therapy. CT four weeks after starting pembrolizumab therapy showed that both the primary and metastatic lesions had notably reduced in size, and no new lesion was detected. He subsequently fell, resulting in a femoral neck pathological fracture, and underwent hemiarthroplasty. Pathological examination of the pathological fracture site revealed no residual tumor tissue.

An anti-sulfatide antibody O4 immunoprecipitates sulfatide rafts including Fyn, Lyn and the G protein α subunit in rat primary immature oligodendrocytes.

The association of sulfatide with specific proteins in oligodendrocytes was examined by co-immunoprecipitation with an anti-sulfatide antibody. Protein kinase activity was detected in precipitates with a monoclonal antibody to sulfatide (O4) from the rat primary immature oligodendrocytes. We conducted in vitro kinase assay of tyrosine phosphorylated proteins of 80, 59, 56, 53 and 40 kDa by gel electrophoresis. Of these proteins, the proteins of 59 kDa and 53/56 kDa were identified as the Src family tyrosine kinases Fyn and Lyn on the basis of their sequential immunoprecipitation with anti-Fyn and anti-Lyn antibodies, respectively. The 40 kDa protein was identified as the α subunit of the heterotrimeric G protein. These observations suggest that O4 immunoprecipitates sulfatide rafts including Fyn, Lyn and the α subunit of the heterotrimeric G protein.

Epstein-Barr virus-associated primary central nervous system cytotoxic T-cell lymphoma.

Primary central nervous system lymphoma (PCNSL) expressing T-cell markers is rare, among which nasal-type extranodal NK/T-cell lymphoma is an extremely rare subtype associated with Epstein-Barr virus (EBV) infection. Here we report the clinicopathologic features of a case of EBV-associated PCNSL showing a cytotoxic T-cell phenotype. The patient, a 73-year-old woman, presented with rapidly progressive mental deterioration. Brain MRI revealed multiple lesions with swelling in the bilateral cerebral hemispheres, which were hypointense on T1-weighted images, hyperintense on T2-weighted and fluid-attenuated inversion recovery images, and slightly hyperintense on diffusion-weighted images. Biopsy specimens from the temporal region showed many medium-sized anaplastic lymphocytic cells with perivascular and angio-invasive patterns in the cortex. Immunohistochemically, the cells were positive for CD3, CD8, T-cell-restricted intracellular antigen-1 (TIA-1), granzyme B and perforin, but negative for CD56 and CD20. In situ hybridization revealed EBV-encoded RNAs in the tumor cell nuclei. A rearrangement study showed T-cell receptor γ-chain gene rearrangement with a clonal appearance. The patient died 6 months after surgery, and a general autopsy revealed no lymphoma cells outside the brain. These cellular profiles are inconsistent with those of extranodal NK/T-cell lymphoma, and have not been previously described. This case appears to represent an unusual CNS manifestation of EBV-associated T-cell lymphoma.

Complete remission following pembrolizumab therapy for a patient with nephroureterectomy positive-margin carcinoma in situ and bladder cancer unresponsive to Bacille Calmette-Guérin therapy.

An 82-year-old man was diagnosed with synchronous non-muscle-invasive bladder cancer and left lower ureteral carcinoma. He underwent transurethral resection of the bladder tumor, followed by total left nephroureterectomy after preoperative chemotherapy with four courses of gemcitabine and carboplatin. Histopathological findings showed positive-margin carcinoma in situ. In addition, since recurrence of non-muscle-invasive bladder cancer was observed in the bladder, Bacille Calmette-Guérin intravesical infusion therapy was performed, but the cancer persisted due to treatment resistance. After that, pembrolizumab therapy was performed, and complete remission was achieved.

A case of cabozantinib therapy leading to complete remission for massive intra-intestinal bleeding and worsening metastatic sites following nivolumab and ipilimumab therapy.

A woman in her 50s had recurrent renal cell carcinoma six years after nephrectomy. The patient was treated with nivolumab plus ipilimumab therapy starting in May 2022. She was rushed to hospital due to melena and severe anemia in September 2022. CT showed massive leakage of contrast medium into the gastrointestinal tract and mild enlargement of the metastatic tumors. Nivolumab was discontinued and she was started on cabozantinib as second-line therapy. After cabozantinib therapy, the anemia subsided. The metastatic tumors have shrunk significantly, with no further recurrence being observed as of September 2023.

Primary lung cancer treatable with radical resection after complete remission with pembrolizumab therapy following gemcitabine and carboplatin chemotherapy for multiple metastases of bladder cancer.

Introduction: We report a patient with the complete remission of multiple metastases and primary bladder lesions of bladder cancer who developed primary lung cancer requiring radical resection. Case presentation: A 68-year-old man diagnosed with invasive bladder cancer, right hydroureteronephrosis, and multiple metastases were administered six courses of gemcitabine and carboplatin chemotherapy and thereafter has been receiving pembrolizumab therapy. Bladder cancer and multiple metastases decreased in size, whereas a ground-glass opacity lesion in the lung gradually increased in size. Fluorodeoxyglucose-positron emission tomography revealed the accumulation of fluorodeoxyglucose in the ground-glass opacity lesion only. The patient was diagnosed with primary lung cancer and underwent a thoracoscopic lobectomy. Histopathological findings showed ALK-negative, EGFR L858R mutation-positive invasive adenocarcinoma with a programmed death-ligand 1 tumor proportion score of less than 1%. Conclusion: This is the first case report of patients with the complete remission of multiple metastases of bladder cancer who developed primary lung cancer requiring radical resection.

An adenocarcinoma in an inverted Meckel's diverticulum with intussusception.

BACKGROUND: Adenocarcinoma in an inverted Meckel's diverticulum with intussusception has not been reported to date. We discuss the clinical issues concerning this rare condition and review the relevant literature. CASE PRESENTATION: A 71-year-old Japanese female was referred to our hospital for further investigation of severe anemia. Computed tomography revealed a tumorous lesion in the terminal ileum. Capsule endoscopy did not provide detailed images. Exploratory laparoscopy revealed intussusception in the terminal ileum. An intraluminal tumor 70 cm proximal to the ileocecal valve was observed to be the lead point. Partial resection including the tumor was performed. Macroscopically, a polypoid tumor at the tip of an inverted diverticulum-like structure was observed. The tumor was histologically composed of adenocarcinoma accompanied by gastric and pyloric gland metaplasia in the background mucosa, which was confirmed by immunohistochemical staining. Based on these characteristics, this tumor is considered to have developed from the ectopic gastric mucosa in a Meckel's diverticulum. CONCLUSIONS: When we encounter patients with unfamiliar lesions in the small bowel, we need to differentiate Meckel's diverticulum related disease. Meckel's diverticulum can invert into the lumen of the small bowel and cause an intussusception, and has potential of malignant transformation.

Differential genotoxicity of chemical properties and particle size of rare metal and metal oxide nanoparticles.

Nanoparticles of rare metal compounds are used in various products. However, their carcinogenicity and genotoxicity have not been sufficiently evaluated. The tumor-initiating and -promoting potentials of four rare metals, indium oxide (In2O3), dysprosium oxide (Dy2O3), tungsten oxide (WO3) and molybdenum (Mo), with a well-defined particle diameter were evaluated. The mutagenicity of these rare metals was investigated by Ames test using five bacteria strains, and transformability of these rare metals was investigated by cell-transformation assay using v-Ha-ras-transfected BALB/c 3T3 cells (Bhas 42 cells). Nano-sized Dy2O3 showed strong mutagenesis in all five bacteria strains tested with and without metabolic activation, while micro-sized particles showed weak mutagenesis in two bacterial strains. Dy2O3 induced transformation colonies of Bhas 42 cell dose-dependently, although there was no difference in the number of transformed foci between nano-sized and micro-sized particles. Nano-sized In2O3 and WO3 showed positive mutagenic response in TA1537 and TA98, respectively, whereas the micro-sized metal oxide particles showed no mutagenesis in the test bacterial strains. Both nano-sized and micro-sized In2O3 showed similar levels of transformability. However, nano-sized and micro-sized WO3 did not show any transformability. Both nano-sized and micro-sized Mo particles showed neither mutagenesis nor transformability. These results suggest that mutagenicity of rare metals depends on their particle size, although transformability depends on their chemical components but not on their particle size.

Laparoscopic Nephroureterectomy with Heminephrectomy for Urothelial Carcinoma of the Upper Renal Pelvis on the Left Side of the Horseshoe Kidney.

A 70-year-old male was diagnosed with urothelial carcinoma of the upper renal pelvis on the left side of the horseshoe kidney. Preoperative thin-slice contrast-enhanced CT with three-dimensional reconstruction of the images revealed that two arteries arising from the aorta supplied the left moiety of the horseshoe kidney. He underwent laparoscopic transperitoneal nephroureterectomy with heminephrectomy on the left side of the horseshoe kidney visualized by indocyanine green fluorescence system. The histopathological findings of the renal pelvic tumor revealed invasive urothelial carcinoma with squamous differentiation, high grade, and pT3.

Primary Aldosteronism Presenting with Hypertension Five Days after Delivery: A Case Report and Literature Review.

A 35-year-old Japanese woman with no history of hypertension developed hypertension 5 days after normal delivery. Endocrinological and radiological examinations indicated primary aldosteronism (PA) and a 1.4-cm left adrenal tumor. The patient underwent laparoscopic adrenalectomy, and a diagnosis of aldosterone-producing adenoma was confirmed immunohistochemically. Her plasma aldosterone concentration and blood pressure normalized. Cases of PA presenting with hypertension in the postpartum period have been reported. This case suggests that PA should be considered in women with postpartum hypertension, especially in those with blood pressure that suddenly increases shortly after delivery, even if they were normotensive before and throughout pregnancy.

The predominant expression of hepatocyte nuclear factor 4α (HNF4α) in thyroid transcription factor-1 (TTF-1)-negative pulmonary adenocarcinoma.

AIMS: To investigate TTF-1-negative pulmonary adenocarcinoma, focusing upon mucin production and the expression of hepatocyte nuclear factor-4α (HNF4α). MATERIALS AND METHODS: Two hundred and sixty-two cases of pulmonary adenocarcinoma were examined histologically and immunohistochemically; TTF-1 was expressed in 222 cases (84.7%), and 40 cases (15.3%) were negative. Among TTF-1-negative cases there were 31 mucinous-type tumours, and HNF4α, MUC5AC and MUC2 were expressed in 34 cases (85%), 29 cases (72.5%) and four cases (10%), respectively. In contrast, their expression was rare in TTF-1-positive tumours. A statistically inverse correlation was confirmed between the expression of TTF-1 and that of HNF4α and MUC5AC. CONCLUSION: Most TTF-1-negative pulmonary adenocarcinomas are mucinous lesions with the predominant expression of HNF4α and MUC5AC.

Long pentraxin 3 (PTX3) expression and release by neutrophils in vitro and in ulcerative colitis.

Pentraxin 3 (PTX3) is the first identified long pentraxin, and it is rapidly produced and released by several cell types in response to proinflammatory signals. The aim of this study was to investigate the behavior of neutrophils to produce PTX3 protein in response to proinflammatory cytokine IL-8 in vitro, as well as identify the expression pattern of PTX3 in human ulcerative colitis lesions. Pentraxin 3 protein was found to be present following release upon IL-8 stimulation in cultured neutrophils together with lactoferrin(+)-specific granules localized in neutrophil extracellular traps (NETs) formed by extruded DNA. Neutrophils in colonic mucosal tissue of patients with ulcerative colitis were the main cellular source of PTX3 protein, the expression of which is correlated well with the histological grades of inflammation. Immunofluorescence analysis against anti-lactoferrin antibody revealed the formation of NETs released from neutrophils within crypt abscess lesions, which were found to be activated through the expression of IL-8 receptor B (CXCR2). Of interest, neutrophils depleted of PTX3 protein were displayed, supporting the release of PTX3 from neutrophils in crypt abscess. We suspected that PTX3 protein may contribute to cell-mediated immune defense in inflamed colon tissue, and in particular in crypt abscess lesions, of patients with ulcerative colitis.

Differential gene expression associated with inflammation and blood pressure regulation induced by concentrated ambient particle exposure.

Epidemiological studies have indicated that exposure to particle matter (PM) increased the risk of respiratory and cardiovascular morbidity and mortality. It is suggested that PM smaller than 2.5 µm in aerodynamic diameter (PM(2.5)) may contribute to these responses. However, the molecular mechanism is still unknown. To elucidate the changes in molecular level, we investigated the gene expression profile of concentrated ambient particles (CAPs)-exposed rats. Aged F344 rats were exposed with CAPs (594 µg/m(3)) or clean air 4 h per day for 3 days, and lung and heart tissues were then excised for DNA microarray analysis. Expression profiles related to inflammation and blood pressure regulation revealed differential expression of 7 genes in the lung and that of 3 genes in the heart ventricle. According to the complement activation-associated genes, complement factor B (Bf), complement component 2 and 4a (C4a), and C1 inhibitor genes were up-regulated in CAPs-exposed rat lung. Bf and C4a genes were also up-regulated in the heart. These suggest the treated animal ready for production of these proteins when activation of complement cascade is required. Pro-inflammatory cytokine, interleukin-1ß, was also up-regulated in CAPs-exposed rat lung. Gene related with blood pressure regulation (angiotensin I converting enzyme) was also up-regulated in CAPs-exposed rat lung. Negative regulator of blood pressure (neuropeptide Y) was down-regulated in CAPs-exposed rat heart. These results indicate that CAPs may affect respiratory and cardiovascular organs by activation of inflammatory responses and disintegration of blood pressure regulation in early stage of CAPs exposure.

Clear Cell Adenocarcinoma of the Ureter Similar to Clear Cell Renal Cell Carcinoma Histology.

A 70-year-old woman was referred to our hospital with gross hematuria and diagnosed with right invasive ureteral cancer and bladder urothelial carcinoma in situ. Intravesical BCG therapy and neoadjuvant chemotherapy with carboplatin and gemcitabine were performed at the same time. Subsequently, laparoscopic right nephroureterectomy was performed. Urothelial carcinoma in situ persisted; however, most of the tumor was clear cell carcinoma. The clear cell carcinoma lesion had clear cytoplasm with round nuclei and visible nucleoli in an insular arrangement as is the case with clear cell renal cell carcinoma. No transitional lesion between clear cell adenocarcinoma and urothelial carcinoma was presented. The clear cell carcinoma lesion was GATA3 negative and HNF4α positive; however, the urothelial cancer lesion was GATA3 positive and HNF4α negative. Clear cell carcinoma was diagnosed as clear cell adenocarcinoma similar to clear cell renal cell carcinoma histology.