Clinical Association Between Immune-related Adverse Events and Treatment Efficacy in Patients With Non-small-cell Lung Cancer Treated With Nivolumab-Ipilimumab-based Therapy.

BACKGROUND/AIM: Nivolumab and ipilimumab combination therapy has been extensively explored for the treatment of advanced non-small-cell lung cancer (NSCLC) through the pivotal phase III trials CheckMate 227 and CheckMate 9LA. However, the relationship between immune-related adverse events (irAEs) and the effectiveness of nivolumab plus ipilimumab-based therapy in a real-world clinical setting remains uncertain. PATIENTS AND METHODS: We performed a retrospective analysis of 28 patients with advanced or recurrent NSCLC who underwent treatment with nivolumab plus ipilimumab, with or without platinum-doublet chemotherapy, from February 2021 to January 2023. The primary objective was to elucidate the clinical association between irAEs and treatment efficacy associated with nivolumab plus ipilimumab-based therapy. RESULTS: Among the 28 patients, 22 (78.6%) experienced irAEs. The median progression-free survival (PFS) was significantly longer for patients with irAEs than for those without (p=0.0158), as was overall survival (OS) (p=0.000394). The severity of irAEs had no significant influence on PFS or OS. The objective response rate tended to be higher in patients with irAEs than in those without (50.0% versus 0.0%, respectively; p=0.0549). Multivariate analysis indicated that irAE occurrence was an independent factor for improved PFS (hazard ratio=0.2084, p=0.01383) and OS (hazard ratio=0.0857, p=0.001588). Interstitial lung disease was inferior to other irAE profiles for both PFS and OS. CONCLUSION: Patients with advanced NSCLC experiencing irAEs demonstrated superior clinical outcomes when treated with nivolumab plus ipilimumab-based therapy compared with those without irAEs. However, immune-related interstitial lung disease may be less linked with PFS and OS than other irAE profiles.

Real-world Efficacy and Safety of Atezolizumab Plus Bevacizumab, Paclitaxel and Carboplatin for First-line Treatment of Japanese Patients With Metastatic Non-squamous Non-small Cell Lung Cancer.

BACKGROUND/AIM: Platinum-doublet chemotherapy plus either programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) checkpoint inhibitors has been reported to improve the survival of patients with advanced non-small cell lung cancer (NSCLC). The IMpower150 study showed significant improvements in progression-free survival and overall survival with atezolizumab in combination with bevacizumab, a humanized anti-VEGF monoclonal antibody, paclitaxel, and carboplatin (ABCP therapy) in chemotherapy-naïve patients with non-squamous NSCLC. We herein report the efficacy and safety of ABCP therapy in Japanese patients with non-squamous NSCLC in clinical practice. PATIENTS AND METHODS: We retrospectively evaluated the efficacy and safety of ABCP therapy in 30 patients treated at our hospital from February 2019 to December 2021. RESULTS: The median age of patients was 69 years, 24 (80.0%) patients were male, 29 (96.7%) patients had a performance status of 0 or 1, 28 (93.3%) patients had adenocarcinoma histology, and 7 (23.3%) patients had epidermal growth factor receptor mutations. Evaluation of the PD-L1 tumor proportion score (TPS) showed that 12 (40.0%), 8 (26.7%), and 6 (20.0%) patients had a TPS of ≥50%, 1% to 49%, and <1%, respectively. The objective response rate of the intention-to-treat wild-type population was 73.9%, and the median progression-free survival was 8.3 months. Immune checkpoint inhibitor (ICI)-induced pneumonitis occurred in one (3.3%) patient. CONCLUSION: ABCP therapy for Japanese non-squamous NSCLC patients in a clinical setting achieved a high response rate with low incidence of ICI-induced pneumonitis equivalent to those observed in IMpower150 study.

A pH-Adjustable Tissue Clearing Solution That Preserves Lipid Ultrastructures: Suitable Tissue Clearing Method for DDS Evaluation.

Visualizing biological events and states to resolve biological questions is challenging. Tissue clearing permits three-dimensional multicolor imaging. Here, we describe a pH-adjustable tissue clearing solution, Seebest (SEE Biological Events and States in Tissues), which preserves lipid ultrastructures at an electron microscopy level. Adoption of polyethylenimine was required for a wide pH range adjustment of the tissue clearing solution. The combination of polyethylenimine and urea had a good tissue clearing ability for multiple tissues within several hours. Blood vessels stained with lipophilic carbocyanine dyes were deeply visible using the solution. Adjusting the pH of the solution was important to maximize the fluorescent intensity and suppress dye leakage during tissue clearing. The spatial distribution of doxorubicin and oxidative stress were observable using the solution. Moreover, spatial distribution of liposomes in the liver was visualized. Hence, the Seebest solution provides pH-adjustable, rapid, sufficient tissue clearing, while preserving lipid ultrastructures, which is suitable for drug delivery system evaluations.

Monitoring method for transgene expression in target tissue by blood sampling.

In this study, we have developed a novel method to monitor transgene expression in tissues by blood sampling. We administered plasmid DNA (pDNA) encoding non-secretory form of firefly luciferase as a reporter gene and pDNA encoding secretable Gaussia princeps luciferase as a monitor gene simultaneously into mice. Good positive correlations were found between log-transgene expression of the reporter gene and the monitor gene in the treated muscle, between the monitor gene in the treated muscle and plasma, and consequently between the reporter gene in the treated muscle and the monitor gene in plasma after naked pDNA transfer into the muscle of mice. Such positive correlations were also found with gastric serosal surface instillation of naked pDNA, intravenous injection of lipoplex, and hydrodynamics-based injection of naked pDNA. We developed monitoring method of transgene expression in tissues by blood sampling, which was named 'Therapeutic transgene monitoring (TTM)', after 'Therapeutic drug monitoring (TDM)'.

trans-2-Pentenal, an Active Compound in Cigarette Smoke, Identified via Its Ability to Form Adducts with Glutathione.

α,ß-Unsaturated carbonyl compounds readily form adducts with SH or NH2 residues, which are nucleophilic agents, by Michael addition. Glutathione (GSH) is a tripeptide that contains an SH residue and functions as an antioxidant. We demonstrated previously that acrolein (ACR), crotonaldehyde (CA), and methyl vinyl ketone (MVK) are present in nicotine- and tar-removed cigarette smoke extract (CSE) and reacted with GSH in B16-BL6 mouse melanoma cells to form GSH-ACR, GSH-CA, and GSH-MVK adducts, suggesting a possible mechanism for CSE-induced cytotoxicity. In this study, we searched for novel α,ß-unsaturated carbonyl compounds other than ACR, CA, and MVK. We selected candidate compounds in CSE based on accurate mass values generated using LC/MS analysis of products formed between CSE and GSH, and identified these using GC/MS analysis and library screening. As a result, we isolated trans-2-methyl-2-butenal, 2-methyl-2-cyclopenten-1-one, 3-methyl-2-cyclopenten-1-one, and furfural, which were poorly reactive with GSH and only very weakly inhibited growth of Colon-26 mouse carcinoma cells and BALB/3T3 clone A31 mouse normal cells. We also isolated 2-cyclopenten-1-one, trans-2-pentenal, 3-methyl-2-butenal and ethyl vinyl ketone, which were highly reactive with GSH and significantly inhibited the growth of both cell lines. Our data suggest that the reactivity of compounds in CSE with GSH may be positively correlated with the effect on inhibiting cell growth. Notably, trans-2-pentenal showed marked inhibition of carcinoma cells growth, whereas this compound exhibited little inhibitory effect on normal cells. trans-2-Pentenal may be a potent candidate or seed for antitumor agents.

Invasion-inhibiting Effects of Gaseous Components in Cigarette Smoke on Mouse Rectal Carcinoma Colon-26 Cells.

We investigated the anti-metastatic action of nicotine- and tar-removed cigarette smoke extract (CSE) on highly metastatic mouse Colon-26 cells using syngeneic BALB/c mice. Colon-26 cells were injected into the spleen of mice, cells were grown in the spleen as the primary lesion, and some metastasized from the spleen to liver and established a metastatic lesion. CSE (10, 30, and 100%) was intraperitoneally administered daily to the mice for 14 days after tumor inoculation. As a result, the relative spleen weights of CSE-administered mice did not differ significantly from those of the control mice. However, the relative liver weights of CSE 30%-administered mice significantly decreased compared to control mice. In order to identify the active component in CSE, we examined the action of methyl vinyl ketone (MVK) on the invasiveness of Colon-26 cells. MVK significantly reduced the invasiveness of cells. MVK may be a candidate active component of CSE.

Thymic lymphoid hyperplasia with multilocular thymic cysts diagnosed before the Sjögren syndrome diagnosis.

BACKGROUND: Thymic lymphoid hyperplasia is often present with myasthenia gravis as well as other autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Of the 4 cases of thymic lymphoid hyperplasia associated with Sjögren syndrome that have been reported, no case with a thymic lesion diagnosis that led to the diagnosis of Sjögren syndrome has been reported. We herein report a case of thymic lymphoid hyperplasia with multilocular thymic cysts, diagnosed before Sjögren syndrome. CASE PRESENTATION: A 37-year-old Japanese woman had an approximate 5-cm anterior mediastinal mass detected by chest imaging. The resected lesion revealed multilocular thymic cysts that were filled with colloid-like material. Histology showed lymph follicular hyperplasia with many epithelial cysts. The epithelium consisted of thymic medullary epithelium, and no epithelial proliferation was seen in the lymphoid tissue. Lymphocytes were composed of an organized mixed population of mature T and B cells without significant atypia. The infiltrated B cells did not reveal light chain restriction or immunoglobulin heavy chain gene rearrangement. After the pathological diagnosis of thymic lesion, tests for the presence of autoantibodies were positive for antinuclear antibodies, rheumatic factor, and anti-SSA/Ro antibodies. The Schirmer's, chewing gum, and Saxon tests showed decreased salivary and lacrimal secretion. Lip biopsy showed focal lymphocytic sialadenitis. The signs and symptoms of Sjögren syndrome had not resolved, without aggravation, 1 year after the thymectomy. CONCLUSION: When a case with thymic lymphoid hyperplasia without myasthenia gravis is encountered, it is essential to consider the presence of another autoimmune disease including Sjögren syndrome.

Catalytic reduction of dinitrogen to ammonia by use of molybdenum-nitride complexes bearing a tridentate triphosphine as catalysts.

Newly designed and prepared molybdenum-nitride complexes bearing a mer-tridentate triphosphine as a ligand have been found to work as the most effective catalysts toward the catalytic reduction of dinitrogen to ammonia under ambient conditions, where up to 63 equiv of ammonia based on the Mo atom of the catalyst were produced.

Localized pigmented villonodular synovitis of the hip: sudden-onset pain caused by torsion of the tumor pedicle.

Pigmented villonodular synovitis is a rare, benign, but potentially locally aggressive disease that should be considered in younger patients who present with monoarticular joint symptoms and pathology. We present the case of a 33-year-old woman with a mass arising from her right hip joint that was examined using a multimodal radiological approach. Because her clinical presentation mimicked that of synovial osteochondromatosis of the hip, surgical dislocation was performed. Histopathological examination of the resected specimen confirmed the diagnosis of localized pigmented villonodular synovitis, with the mass consisting of proliferation of fibrohistiocytic cells, abundant hemosiderin, foamy histiocytes, and occasional giant cells. Because of the presence of tumor necrosis, we hypothesize that torsion of the tumor pedicle was the cause of acute presentation.

Detection of high-risk human papillomavirus subtypes in cervical glandular neoplasia by in situ hybridization.

In situ hybridization (ISH) was performed on paraffin-embedded tissues to detect multiple high-risk human papillomavirus (HPV) subtypes in 27 cases of cervical adenocarcinoma in situ (AIS) and adenocarcinoma (CA) specimens. These results were compared with those of HPV detection by HPV-PCR genotyping and p16 immunohistochemistry in the same specimens. Of the 27 cases, 17 (63%) showed HPV-DNA by HPV-ISH, including 3 metastatic lesions. HPV-DNA was detected in 18 cases (67%) by PCR. The concordance rate between HPV-ISH and HPV-PCR genotyping was 74% with moderate agreement (Kappa value, 0.41). HPV-16 was identified in 5 cases, HPV-18 in 2 cases, and HPV-45 in 1 case. Combining the results of HPV-ISH and HPV-PCR/genotyping, 22 cases (81.5%) were considered HPV positive. Immunohistochemical staining of p16 indicated that 25 (93%) cases were positive; however, 4 of these cases were HPV-negative by both PCR and ISH. Combining HPV-ISH and HPV-PCR/genotyping techniques demonstrated a high sensitivity of HPV detection in FFPE tissues from cervical glandular neoplasias. In contrast, p16 immunohistochemistry seemed to have a low specificity for determining HPV status in cervical glandular neoplasia. HPV-ISH is useful for recognizing the distribution of HPV in AIS and CA tissues and visualizing signal patterns, and may be a useful tool to confirm the cervical origin of neoplasias and metastatic lesions.

Adult-onset renal failure in a family with Alagille syndrome with proteinuria and a novel JAG1 mutation.

Alagille syndrome (AGS) is an autosomal-dominant multi-organ disorder involving the liver, heart, eyes, face and skeleton. In addition, various renal abnormalities have also been reported in several cases. We describe a patient with a novel frameshift mutation in exon 12 of the JAG1 gene who presented with chronic renal failure. In this family, five members of three generations had clinical features implicated in AGS. Three members had adult-onset renal dysfunction with proteinuria, and two of them required haemodialysis therapy. AGS should be considered in the differential diagnosis of proteinuric renal disease, even in adult patients.

[A case of Castleman disease with status epileptics originating from focal cortical dysplasia].

A 55-year-old man was admitted to our hospital because of prolonged consciousness disturbance after generalized convulsions. He had been afflicted with chronic inflammatory symptoms since 43 years of age, while multiple abdominal lymphadenopathy with a high level of serum IL-6 was revealed at the age of 53. FDG-PET/CT showed hypermetabolism in the left medial portion of the frontal lobe. Biopsy specimens of this lesion revealed a pathology of focal cortical dysplasia (FCD). Non-convulsive status epileptics continued despite enhanced treatment with antiepileptic drugs, while cortical T2 hyperintense lesions developed and expanded. Castleman disease was confirmed by pathological findings of abdominal lymph node biopsy specimens. The patient showed a higher level of IL-6 in cerebrospinal fluid (1,400 pg/dl) than in serum (720 pg/dl), thus indicating intrathecal production of this proinflammatory cytokine. We concluded that continuous exposure of FCD tissue to IL-6 may have augmented epileptogenesis of the originally silent congenital lesion.

Solitary intrapulmonary cystic lymphangioma in an infant: a case report with literature review.

Lymphangioma rarely presents as a solitary pulmonary lesion. We encountered a case of solitary cystic lymphangioma and present its clinicopathologic and immunohistochemical findings. A 2-month-old boy was referred to the hospital after developing a persistent cough. Chest X-ray showed a large cyst in the right lung. Under the preoperative diagnosis of bronchogenic cyst, he underwent right lower lobectomy at the age of 11 months. The resected specimen contained a 5.5-cm septate cystic lesion. Microscopically, the lesion consisted of a large cystic space and interconnected slit-like spaces surrounding bronchovascular islands. The cyst was lined by a monolayer of flat cells with focal multinucleated giant cells. Immunohistochemically, the cells lining the cystic lesion were positive for D2-40, Prox1, CD34, and CD31, and weakly positive for VEGFR-3, but were negative for AE1/3, HMB45, VEGF-A, VFGF-C, VEGFR-1. Differential diagnoses included lobar or interstitial emphysema, bronchogenic cyst, congenital pulmonary airway malformation and alveolar adenoma. D2-40 and Prox1 were useful in differentiation and in determining the extent of the lesion. A review of the literature found only 15 cases of solitary pulmonary lymphangioma. In younger patients, the lesions tend to occupy more of the lung. Focal giant cell reaction has not been described in the reported papers.

[Curatively resected case of non-functioning pancreatic neuroendocrine carcinoma with multiple liver metastases after downstaging with S-1 monotherapy].

A 73-year-old man diagnosed as having pancreatic body cancer with multiple liver metastases was referred to our hospital. Since the patient preferred oral agents, S-1 monotherapy (4-week administration followed by 2-week interval) was started. The initial dose of S-1 was 80 mg, and gradually increased to 150 mg/day. There were no significant adverse events. The liver metastases disappeared and the pancreatic tumor was markedly reduced in size at the completion of 4 courses. Distal pancreatectomy was carried out at 7 months since his first visit. Pathological diagnosis was non-functioning well-differentiated neuroendocrine carcinoma (pT4, pN0, pM0, Stage IVa). He is alive without relapse 6 months after operation. S-1 might be a candidate for chemotherapy for this neuroendocrine tumor.

Adenomatoid tumor of the pleura.

A case of adenomatoid tumor of the pleura is reported, and its differential diagnosis from benign and malignant pleural lesions is discussed. A small pleural nodule was incidentally found during a thoracic operation in a 54-year-old woman with esophageal cancer. The patient had no history of exposure to asbestos, and was well with no sign of recurrence 14 months after the operation. A 7 mm, circumscribed tumor had characteristic features of adenomatoid tumor. The tumor was composed of an aggregation of irregularly shaped tubulocystic spaces with fibrous stoma. The spaces were lined by flattened and occasional cuboidal epithelioid cells with cytoplasmic vacuolization, and several spaces contained pale blue mucinous fluid. On immunohistochemistry the tumor cells were positive for AE1/AE3, CAM5.2, vimentin, cytokeratin 5/6, D2-40, calretinin, thrombomodulin, and WT-1, but negative for CEA, Leu M1 (CD15), thyroid transcription factor-1, epithelial membrane antigen, desmin, glucose transporter-1 (GLUT-1), CD31, and CD34. The MIB-1 (Ki-67) labeling index was 1-2%, indicating low proliferative activity. Adenomatoid tumor of the pleura is rare, and the pathogenesis has not been elucidated. Recognition of these benign mesothelial lesions in the pleura is important to avoid misdiagnosis. The immunohistochemistry in the present case supports its mesothelial origin.

Intravascular large B cell lymphoma: proposed of the strategy for early diagnosis and treatment of patients with rapid deteriorating condition.

We summarize our experience and propose methods for early diagnosis and treatment of intravascular large B cell lymphoma (IVL). A total of 16 patients with IVL between 1994 and 2007 were included and analyzed in this study. Predicted survival durations were short until September 2003. However, there have been marked improvement since the introduction of rituximab, and all patients responded to treatment and survived for more than 1 year following diagnosis of IVL. We propose an early clinical diagnostic strategy for starting treatment for IVL patients with quite poor performance status (PS) and in whom time is a limiting factor: (1) age >40 years, (2) fever above 38 degrees C with poor PS (ECOG 2-4), (3) lactate dehydrogenase (LDH) more than twice the upper limit of the normal level and/or sIL2R >5,000 IU/ml in serum, (4) worsening PS and/or elevation of serum LDH on a daily basis, and (5) confirmation of pathological lymphoid cells in peripheral blood or bone marrow smear and/or flow cytometry. Although accurate pathological diagnosis is quite important, time is a limiting factor for most of IVL patients. In such cases, we can start chemotherapy based on early clinical diagnostic strategy with high sensitivity and obtain good clinical outcome.

Insulin responses to selective arterial calcium infusion under hyperinsulinemic euglycemic glucose clamps: case studies in adult nesidioblastosis and childhood insulinoma.

Selective arterial calcium stimulation and hepatic venous sampling (ASVS) for insulin secretion is used as a diagnostic procedure in patients with insulinomas or adult nesidioblastosis. In some of those patients, severe hypoglycemia requiring urgent glucose administration occurs during the procedure. Such glucose administration, however, may affect the results and damage the validity of the test. We report two cases of hyperinsulinemic hypoglycemia, in which ASVS tests were successfully performed under hyperinsulinemic euglycemic glucose clamps. A 40-year-old male with nesidioblastosis developed continual severe hypoglycemia several years after a Billroth II-Braun gastrectomy, and continuous glucose infusion could not be stopped even during ASVS tests. A 9-year-old girl with an insulinoma that showed atypical hypovascularity on imaging examinations had ASVS tests under a glucose clamp for safety. Hyperinsulinemic (approximately 100 microU/ml) euglycemic (approximately 90 mg/dl) clamps were achieved by an artificial endocrine pancreas. The insulin analogue lispro was utilized for clamps and endogenous insulin was measured with an assay that does not cross-react with the analogue. Diagnostically significant responses (more than twofold) of insulin secretion were observed under hyperinsulinemic clamps in both cases. The use of the hyperinsulinemic glucose clamp technique during the ASVS test should be considered for maintaining the safety of some hypoglycemic patients.