The intestinal mucosa is continuously exposed to dietary antigens, commensal microorganisms, and enteric pathogens, thereby depending on innate immune pathways that detect danger without compromising tissue tolerance. In...The intestinal mucosa is continuously exposed to dietary antigens, commensal microorganisms, and enteric pathogens, thereby depending on innate immune pathways that detect danger without compromising tissue tolerance. Inflammasomes are cytosolic signaling platforms linking microbial- or stress-sensing to caspase activation, interleukin-1 family cytokine maturation, and gasdermin-dependent membrane responses. In the gut, these pathways support epithelial restitution, mucus and antimicrobial secretion, epithelial cell expulsion, and pathogen containment. Nonetheless, these pathways can drive chronic inflammation through sustained interleukin (IL)-1β production, pyroptosis, neutrophil recruitment, and pathogenic adaptive immunity reinforcement. This review synthesizes the current view of how canonical and noncanonical inflammasomes operate in intestinal epithelial and immune cells, with an emphasis on NLR family pyrin domain-containing (NLRP) 3, NLRP6, NLR family CARD domain-containing (NLRC) 4, Absent in melanoma (AIM) 2, and pyrin. We discuss how cell-intrinsic programs intersect with the microbiota, why protective and pathogenic findings coexist, and how human genetics is beginning to define inflammasome-rich subsets of intestinal diseases. Recent retrospective cohort data sharpen the clinical relevance of pyrin biology: among 396 Japanese patients with inflammatory bowel disease unclassified, 60.1% carried Mediterranean fever (MEFV) variants, and colchicine response among evaluable mutation-positive cases reached 84.6%, thus supporting a distinct colchicine-responsive, IL-1β-skewed enterocolitis subset. Finally, biomarkers and therapeutic opportunities are outlined, and unresolved questions most likely to shape precision-medicine approaches for inflammatory bowel disease and related intestinal autoinflammatory syndromes are identified.
Nonclassical 21-hydroxylase deficiency (21-OHD) is a mild form of congenital adrenal hyperplasia (CAH) that may remain unrecognized until adulthood. We herein report two elderly men with undiagnosed nonclassical 21-OHD a...Nonclassical 21-hydroxylase deficiency (21-OHD) is a mild form of congenital adrenal hyperplasia (CAH) that may remain unrecognized until adulthood. We herein report two elderly men with undiagnosed nonclassical 21-OHD and different adrenal morphologies. Case 1 had a large unilateral adrenal tumor, and an inadequate residual adrenal function became apparent after adrenalectomy, while Case 2 showed bilateral adrenal enlargement. Both patients had a short stature. Because newborn screening for CAH has been available in Japan for less than 40 years, an evaluation of adrenal insufficiency, in addition to hormonal excess, may help to identify latent 21-OHD, thereby allowing for the administration of appropriate management in elderly men with adrenal incidentalomas.
Osimertinib is widely used in cases of non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) gene mutations, including Thr790 Met mutations. We herein report a case of successful desensitiz...Osimertinib is widely used in cases of non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) gene mutations, including Thr790 Met mutations. We herein report a case of successful desensitization therapy combined with alternate-day dosing after osimertinib-induced hepatotoxicity and neutropenia. A 67-year-old woman with recurrent EGFR-mutated NSCLC after surgery discontinued osimertinib due to hepatotoxicity. Following disease progression and detection of the Thr790 Met mutation after afatinib treatment, desensitization therapy with osimertinib was initiated at 0.1 mg/day. Grade 3 neutropenia developed during dose escalation. However, alternate-day dosing enabled continuation and escalation to the standard dose. Alternate-day dosing may mitigate adverse events during dose escalation.
A 36-year-old pregnant woman at 34 weeks of gestation, who had been receiving tocilizumab for Takayasu arteritis, presented with pruritus and hyperbilirubinemia. She delivered a healthy infant the day after admission. Ho...A 36-year-old pregnant woman at 34 weeks of gestation, who had been receiving tocilizumab for Takayasu arteritis, presented with pruritus and hyperbilirubinemia. She delivered a healthy infant the day after admission. However, her bilirubin level increased to 32.2 mg/dL. Genetic testing revealed heterozygosity for a uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism, and a liver biopsy revealed canalicular cholestasis. The patient was diagnosed with intrahepatic cholestasis of pregnancy (ICP) with UGT1A1 polymorphism, and tocilizumab therapy might have contributed to the marked and prolonged hyperbilirubinemia. Liver histology was useful for the diagnosis of ICP in this case.
Primary mediastinal large B-cell lymphoma (PMBCL) during pregnancy is rare and presents therapeutic challenges due to fetal safety concerns. We report the case of a 29-year-old woman diagnosed with PMBCL at 19 weeks of g...Primary mediastinal large B-cell lymphoma (PMBCL) during pregnancy is rare and presents therapeutic challenges due to fetal safety concerns. We report the case of a 29-year-old woman diagnosed with PMBCL at 19 weeks of gestation who wished to continue her pregnancy despite her diagnosis. She received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy with multidisciplinary management and delivered a healthy infant at term. Although the tumor partially responded, residual disease persisted after eight cycles of treatment. She subsequently underwent chimeric antigen receptor T-cell therapy and achieved a complete response. This case highlights the importance of individualized treatment decisions and multidisciplinary collaboration in managing PMBCL during pregnancy.
Cardiac involvement in eosinophilic granulomatosis with polyangiitis (EGPA) strongly influences the prognosis. Takotsubo syndrome (TTS) is a reversible stress-induced cardiomyopathy that has rarely been reported in patie...Cardiac involvement in eosinophilic granulomatosis with polyangiitis (EGPA) strongly influences the prognosis. Takotsubo syndrome (TTS) is a reversible stress-induced cardiomyopathy that has rarely been reported in patients with EGPA. A 39-year-old woman was diagnosed with EGPA based on marked eosinophilia, systemic manifestations, and the histopathological eosinophilic infiltration of multiple organs. After remission with corticosteroids, immunosuppressants, and intravenous immunoglobulin, she suddenly developed chest pain with an ST elevation and severe left ventricular dysfunction, but normal coronary angiography findings. TTS was diagnosed. Her cardiac function recovered. However, an endomyocardial biopsy revealed advanced myocardial injury without eosinophilic infiltration. Therapy (corticosteroids, immunosuppressants, intravenous immunoglobulin, and mepolizumab) achieved long-term survival despite severe cardiac involvement.
Methimazole is widely used for treating Graves' disease and it is a well-recognized cause of agranulocytosis. However, this assumption may delay the diagnosis of underlying hematologic disorders. A woman in her early 50s...Methimazole is widely used for treating Graves' disease and it is a well-recognized cause of agranulocytosis. However, this assumption may delay the diagnosis of underlying hematologic disorders. A woman in her early 50s with Graves' disease had been treated with methimazole for 24 years. Routine laboratory testing revealed neutropenia, accompanied by mild anemia and thrombocytopenia. Despite the withdrawal of methimazole, cytopenia persisted. One month later, circulating blasts appeared, and a diagnosis of acute myeloid leukemia was made based on a bone marrow examination. Persistent cytopenia after the discontinuation of methimazole, particularly with multilineage involvement, should prompt an early evaluation for bone marrow disorders.
Acute kidney injury (AKI) caused by granulomatous interstitial nephritis (GIN) accompanied by chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is extremely rare. A 71-year-old man with severe AKI was dia...Acute kidney injury (AKI) caused by granulomatous interstitial nephritis (GIN) accompanied by chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is extremely rare. A 71-year-old man with severe AKI was diagnosed with CLL/SLL based on bone marrow and lymph node biopsy results. A renal biopsy revealed dense cortical infiltration of CLL/SLL cells and severe interstitial inflammation with granuloma formation, consistent with GIN. Acalabrutinib-Obinutuzumab combination therapy was effective for CLL/SLL, but prednisolone was required to achieve a renal function improvement. A renal biopsy is essential for the diagnosis, and corticosteroids play a key role in managing GIN-associated renal injury, even in the era of targeted therapies.
An 81-year-old woman was transferred to our hospital due to a consciousness disorder. MRI of her cranium revealed white matter lesions and lesions in the cerebellar paravermis, splenium of the corpus callosum, and a left...An 81-year-old woman was transferred to our hospital due to a consciousness disorder. MRI of her cranium revealed white matter lesions and lesions in the cerebellar paravermis, splenium of the corpus callosum, and a left temporal pole on fluid-attenuated inversion recovery (FLAIR) sequences. Diffusion-weighted imaging (DWI) revealed hyperintensity at the left frontal corticomedullary junction of the brain. She was diagnosed with neuronal intranuclear inclusion disease (NIID) via a skin biopsy and genetic analysis. These lesions were evident before the DWI hyperintensity was clear. When a lesion in the temporal pole is observed, then NIID should be considered in the differential diagnosis.
Yamaguchi R, Tamura Y, Asai Y
… +13 more, Takezaki K, Yura A, Kawaguchi H, Shimazu Y, Arai M, Mitsuya S, Funamoto T, Tsuji H, Matsunaga N, Tsuruoka K, Nakamura T, Ikeda S, Fujisaka Y
Cancer-related pain affects more than 70% of patients with advanced cancer and it is mediated by tumor invasion and inflammatory cytokine-induced neural sensitization. Anticancer therapies may transiently exacerbate pain...Cancer-related pain affects more than 70% of patients with advanced cancer and it is mediated by tumor invasion and inflammatory cytokine-induced neural sensitization. Anticancer therapies may transiently exacerbate pain through treatment-related inflammatory responses. Amivantamab, an EGFR-MET bispecific antibody approved for EGFR-mutated non-small cell lung cancer, commonly causes infusion-related reactions (IRRs), typically with flushing or respiratory symptoms. We report a case of a 70-year-old woman with EGFR-mutated lung adenocarcinoma who developed a reproducible, transient exacerbation of pre-existing cancer-related pain during initial amivantamab infusions without any systemic abnormalities or clear evidence of radiologic progression. This suggests that acute pain flare is an atypical manifestation of amivantamab-induced IRR.
Mirabegron, a β3-adrenoceptor agonist used for treating overactive bladder, has recently been identified in pharmacovigilance analyses as a potential signal for drug-induced myeloperoxidase (MPO) antineutrophil cytoplasm...Mirabegron, a β3-adrenoceptor agonist used for treating overactive bladder, has recently been identified in pharmacovigilance analyses as a potential signal for drug-induced myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), although detailed clinical reports are lacking. We herein describe a patient who developed MPO-ANCA-positive vasculitis approximately 1 year after mirabegron initiation. The patient presented with inflammatory symptoms, elevated MPO-ANCA and C-reactive protein levels, and hematuria, with an improvement following drug discontinuation, thus allowing for the withdrawal of immunosuppressive therapy within 1 year. Causality was assessed as "probable/likely" using the WHO-UMC system. This case highlights the importance of early recognition and prompt drug withdrawal in cases of drug-induced AAV.
Disseminated carcinomatosis of the bone marrow (DCBM) is a rare complication of advanced malignancies that may present with microangiopathic hemolytic anemia (MAHA). A 65-year-old man with esophageal adenocarcinoma was a...Disseminated carcinomatosis of the bone marrow (DCBM) is a rare complication of advanced malignancies that may present with microangiopathic hemolytic anemia (MAHA). A 65-year-old man with esophageal adenocarcinoma was admitted due to melena and severe anemia, initially suspected to be caused by tumor bleeding. However, persistent anemia despite multiple transfusions and the presence of schistocytes on a peripheral blood smear suggested MAHA. A bone marrow biopsy revealed cytokeratin-positive tumor cells, confirming the diagnosis of DCBM. Chemotherapy with S-1, oxaliplatin, and trastuzumab improved hemolysis and achieved transfusion independence. Clinicians should consider cancer-related MAHA when the degree of anemia is disproportionate to the amount of bleeding in patients with advanced cancer.
Diverticulitis is usually managed conservatively. However, recurrent or complicated cases may require surgery. Daiobotanpito (DBT) is a traditional Japanese medicine used to treat inflammatory conditions of the lower abd...Diverticulitis is usually managed conservatively. However, recurrent or complicated cases may require surgery. Daiobotanpito (DBT) is a traditional Japanese medicine used to treat inflammatory conditions of the lower abdomen. We report a case of recurrent sigmoid diverticulitis with a history of diverticular abscess managed with DBT as an adjunctive therapy. A 54-year-old woman was treated with antibiotics and DBT, after which oral intake was resumed without a recurrence of symptoms, thus allowing for discharge without surgery. She remained recurrence-free for one year while continuing the Kampo therapy. DBT may therefore be a potential adjunctive therapeutic option for patients with recurrent diverticulitis who wish to avoid surgery.
Immune checkpoint inhibitors (ICIs) can cause endocrine adverse events, including isolated adrenocorticotropic hormone deficiency (IAD). We report a case of transient ACTH and cortisol suppression mimicking ICI-induced I...Immune checkpoint inhibitors (ICIs) can cause endocrine adverse events, including isolated adrenocorticotropic hormone deficiency (IAD). We report a case of transient ACTH and cortisol suppression mimicking ICI-induced IAD during pembrolizumab therapy for metastatic triple-negative breast cancer. A 59-year-old woman developed low ACTH and cortisol levels while receiving pembrolizumab in combination with nab-paclitaxel. ICI-related IAD was initially suspected. However, her hormone levels normalized after the discontinuation of dexamethasone mouthwash used for oral mucositis. These findings suggest the transient suppression of the hypothalamic-pituitary-adrenal axis due to exogenous steroid exposure. Clinicians should consider steroid-containing mouthwashes as a potential cause of adrenal axis suppression during ICI therapy.
Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease, with most sporadic cases caused by a single large mitochondrial DNA (mtDNA) deletion. We report the case of a 54-year-old woman with ptosis,...Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease, with most sporadic cases caused by a single large mitochondrial DNA (mtDNA) deletion. We report the case of a 54-year-old woman with ptosis, external ophthalmoplegia, and proximal muscle weakness without any relevant family history. A muscle biopsy supported the diagnosis of sporadic CPEO. However, a muscle DNA analysis revealed multiple mitochondrial DNA (mtDNA) deletions. Whole-exome sequencing identified a heterozygous pathogenic TWNK variant [c.1121G>A (p.Arg374Gln)] absent in her parents, suggesting a de novo origin. Although TWNK pathogenic variants typically cause autosomal dominant CPEO, this case mimicked a sporadic form, thus highlighting the importance of a nuclear gene analysis in such cases.
A 46-year-old man was diagnosed with autoimmune pulmonary alveolar proteinosis (aPAP). Despite repeated segmental bronchoscopic lavage, his symptoms, pulmonary function, and radiological findings gradually worsened, and...A 46-year-old man was diagnosed with autoimmune pulmonary alveolar proteinosis (aPAP). Despite repeated segmental bronchoscopic lavage, his symptoms, pulmonary function, and radiological findings gradually worsened, and he declined whole-lung lavage. Although classified as disease severity score 2 (partial pressure of arterial oxygen 75.2 mmHg), inhaled granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy (sargramostim) was initiated. After 6 months, a marked improvement was observed, and the alveolar-arterial oxygen difference decreased from 21.8 to 1.1 mmHg. Given the limited evidence in milder cases, this report suggests that early intervention with inhaled sargramostim may be effective in relatively mild but progressive aPAP.