Influence of major hepatectomy on gemcitabine-based chemotherapy for recurrent biliary tract cancer after surgery: a subgroup analysis of JCOG1113.

BACKGROUND: Major hepatectomy (MH) can increase the risk of adverse events (AEs) owing to impaired drug metabolism due to decreased liver volume and surgical injury. Thus, we performed this subgroup analysis using data from JCOG1113, a phase III trial comparing gemcitabine plus S-1 (GS) and gemcitabine plus cisplatin (GC) in patients with advanced and recurrent biliary tract cancer (BTC), to evaluate the effect of MH on the safety and efficacy of GC and GS regimens in patients with recurrent BTC. METHODS: Of the 354 patients with advanced BTC enrolled in JCOG1113, 76 patients with postoperative recurrence (30 in the MH group and 46 in the non-MH group) were analyzed. RESULTS: Grade ≥ 3 platelet count decreased in both arms was more frequent in the MH group than in non-MH group (GC, 0.0 vs. 17.6%; GS, 3.9 vs. 15.4%). However, in the MH group, the white blood cell decreased (GC, 55.0 vs. 38.5%; GS, 23.1 vs. 7.7%) and anemia (GC, 15.0 vs. 11.8%; GS, 23.1 vs. 7.7%) were less common than in the non-MH group. The MH and non-MH groups showed no significant difference in overall survival (OS) in both GC [median OS, 23.0 in MH vs. 16.9 months in non-MH (hazard ratio, 0.857; 95% CI 0.387-1.899)], and GS [median OS, 21.5 vs. 14.9 months (hazard ratio, 0.670; 95% CI 0.310-1.447)] arms. CONCLUSIONS: The safety and efficacy of gemcitabine-based chemotherapy were comparable between patients who underwent MH and those who underwent other surgeries.

A case of invasive mucinous adenocarcinoma presenting with massive bronchorrhea.

An 80-year-old non-smoking woman was admitted to hospital due to persistent sputum production and dyspnea. She developed respiratory failure, and chest imaging revealed multifocal consolidation and cavities. Her respiratory status did not respond to antimicrobial treatment and progressively worsened, with massive sputum production of approximately 1 L per day, and she died 19 days after admission. The patient was diagnosed with invasive mucinous adenocarcinoma based on a postmortem needle biopsy of the lung. Clinicians should consider invasive mucinous adenocarcinoma in the differential diagnosis of patients who present with massive bronchorrhea and diffuse pulmonary cavity abnormalities.

Platythorax increases residual volume/total lung capacity in idiopathic pleuroparenchymal fibroelastosis.

Platythorax significantly contributes to the increase in residual volume/total lung capacity ratio in patients with idiopathic pleuroparenchymal fibroelastosis https://bit.ly/3uZ0rmP.

Current status of the cost burden of first-line systemic treatment for patients with advanced hepatocellular carcinoma in Japan, 2021-22.

BACKGROUND: Although recent advances in systemic therapies for hepatocellular carcinoma (HCC) have led to prolonged patient survival, the high costs of the drugs place a heavy burden on both patients and society. The objectives of this study were to examine the treatment regimens used as first-line systemic treatment for patients with advanced HCC in Japan and to estimate the treatment costs per regimen. METHODS: For this study, we aggregated the data of patients who had received first-line systemic treatment for advanced HCC between July 2021 and June 2022. The treatment cost per month of each regimen was estimated based on standard usage, assuming an average weight of 60 kg for male patients. The data were categorized by the treatment regimen, and the treatments were categorized based on the cost into very high-cost (≥1 000 000 Japanese yen [JPY]/month), high-cost (≥500 000 JPY/month) and other (<500 000 JPY/month) treatments. RESULTS: Of the total of 552 patients from 24 institutions whose data were analyzed in this study, 439 (79.5%) received atezolizumab plus bevacizumab, 98 (17.8%) received lenvatinib and 15 (2.7%) received sorafenib as the first-line treatment. The treatment cost per month for each of the above regimens was as follows: atezolizumab plus bevacizumab, 1 176 284 JPY; lenvatinib, 362 295 JPY and sorafenib, 571 644 JPY. In total, 82.2% of patients received high-cost regimens, and the majority of these patients received a very high-cost regimen of atezolizumab plus bevacizumab. CONCLUSIONS: Advances in systemic therapies for HCC have led to prolonged patient survival. However, the treatment costs are also increasing, imposing a burden on both the patients and society.

Prophylactic vaccination inducing anti-Env antibodies can result in protection against HTLV-1 challenge in macaques.

Human T cell leukemia/T-lymphotropic virus type 1 (HTLV-1) infection occurs by cell-to-cell transmission and can induce fatal adult T cell leukemia. Vaccine development is critical for the control of HTLV-1 transmission. However, determining whether vaccine-induced anti-Env antibodies can prevent cell-to-cell HTLV-1 transmission is challenging. Here, we examined the protective efficacy of a vaccine inducing anti-Env antibodies against HTLV-1 challenge in cynomolgus macaques. Eight of 10 vaccinated macaques produced anti-HTLV-1 neutralizing antibodies (NAbs) and were protected from an intravenous challenge with 108 HTLV-1-producing cells. In contrast, the 2 vaccinated macaques without NAb induction and 10 unvaccinated controls showed HTLV-1 infection with detectable proviral load after challenge. Five of the eight protected macaques were administered with an anti-CD8 monoclonal antibody, but proviruses remained undetectable and no increase in anti-HTLV-1 antibodies was observed even after CD8+ cell depletion in three of them. Analysis of Env-specific T cell responses did not suggest involvement of vaccine-induced Env-specific T cell responses in the protection. These results indicate that anti-Env antibody induction by vaccination can result in functionally sterile HTLV-1 protection, implying the rationale for strategies aimed at anti-Env antibody induction in prophylactic HTLV-1 vaccine development.

Target sign of the lung.

A target sign of the lung consists of a ring-like opacity and a central nodular opacity and has been limited to reports associated with SARS-CoV-2 infection or organizing pneumonia. This is the first report of a target sign that was potentially associated with drug-induced lung injury.

Pharmacogenomic study of gemcitabine efficacy in patients with metastatic pancreatic cancer: A multicenter, prospective, observational cohort study (GENESECT study).

BACKGROUND: Genetic polymorphisms of molecules are known to cause individual differences in the therapeutic efficacy of anticancer drugs. However, to date, germline mutations (but not somatic mutations) for anticancer drugs have not been adequately studied. The objective of this study was to investigate the association between germline polymorphisms of gemcitabine metabolic and transporter genes with carbohydrate antigen 19-9 (CA 19-9) response (decrease ≥50% from the pretreatment level at 8 weeks) and overall survival (OS) in patients with metastatic pancreatic cancer who receive gemcitabine-based chemotherapy. METHODS: This multicenter, prospective, observational study enrolled patients with metastatic pancreatic cancer patients who were receiving gemcitabine monotherapy or gemcitabine plus nanoparticle albumin-bound paclitaxel combination chemotherapy. Thirteen polymorphisms that may be involved in gemcitabine responsiveness were genotyped, and univariate and multivariate logistic regression analyses were used to determine the association of these genotypes with CA 19-9 response and OS. The significance level was set at 5%. RESULTS: In total, 180 patients from 11 hospitals in Japan were registered, and 159 patients whose CA 19-9 response could be assessed were included in the final analysis. Patients who had a CA 19-9 response had significantly longer OS (372 vs. 241 days; p = .007). RRM1 2464A>G and RRM2 175T>G polymorphisms suggested a weak association with CA 19-9 response and OS, but it was not statistically significant. COX-2 -765G>C polymorphism did not significantly correlate with CA 19-9 response but was significantly associated with OS (hazard ratio, 2.031; p = .019). CONCLUSIONS: Genetic polymorphisms from the pharmacokinetics of gemcitabine did not indicate a significant association with efficacy, but COX-2 polymorphisms involved in tumor cell proliferation might affect OS.

An 88-Year-Old Woman With Pneumothorax and Black Pleural Effusion.

CASE PRESENTATION: An 88-year-old woman was admitted to our hospital with the sudden onset of dyspnea after eating. The patient had undergone nephrectomy for a left renal tumor 24 years previously. The patient had been prescribed ferrous citrate for iron-deficiency anemia. She complained of appetite loss a few days before admission but had no abdominal pain. CT scan showed no abnormalities in the lungs but a mass in the liver.

Pseudomonas fluorescens pneumonia.

Pseudomonas fluorescens (P. fluorescens) is not generally considered a bacterial pathogen in humans; however, multiple culture-based and culture-independent studies have identified it in the indigenous microbiota of multiple body sites. We herein report a rare case of pneumonia caused by P. fluorescens. A man in his 80 s with chronic obstructive pulmonary disease and diabetes mellitus was diagnosed with stage II rectal cancer. He underwent laparoscopic surgery, and on the 6th postoperative day, he developed a high fever. Chest computed tomography revealed infiltration in the left lower lung. Gram staining of the sputum showed Gram-negative rods phagocytosed by neutrophils, suggesting postoperative nosocomial pneumonia. The patient was started on tazobactam/piperacillin, and his pneumonia quickly improved. Later, only P. fluorescens was detected in a sputum culture. It was susceptible to common antipseudomonal agents. Gram staining of P. fluorescens appears to show a slightly thicker and larger morphology in comparison to Pseudomonas aeruginosa. Although there have been reports of opportunistic infections caused by P. fluorescens in immunosuppressed patients, including those with advanced cancer, most have been bloodstream infections, with very few reports of pneumonia alone. Clinicians should be aware that patients, who are not necessarily immunosuppressed, may develop pneumonia caused by P. fluorescens.

Desquamative Interstitial Pneumonia with Progressive Pulmonary Fibrosis.

A 70-year-old man who smoked was referred to our hospital because of progressive cough and dyspnea. Radiologic images showed ground-glass attenuation predominantly in the lower lung lobes. A surgical lung biopsy was performed, and a diagnosis of desquamative interstitial pneumonia (DIP) was made. The patient's symptoms improved with smoking cessation and steroid treatment, but the ground-glass attenuation did not completely resolve. At 10 years after the diagnosis, the fibrotic lesions deteriorated and treatment with nintedanib was subsequently initiated. Careful observation is needed in patients with DIP whose lung involvement does not completely improve with initial treatment.

Early Tumor Shrinkage and Depth of Response as Predictors of Survival for Advanced Biliary Tract Cancer: An Exploratory Analysis of JCOG1113.

BACKGROUND: Recent studies suggest that early tumor shrinkage (ETS) and depth of response (DpR) reflect outcomes of chemotherapy in various cancers. This study evaluated the association of ETS and DpR with clinical outcomes using data from JCOG1113, which demonstrated the non-inferiority of gemcitabine plus S-1 (GS) to gemcitabine plus cisplatin (GC) for chemotherapy-naïve advanced biliary tract cancer. MATERIAL AND METHODS: In total, 354 (289 with measurable target lesions) patients enrolled in JCOG1113 were divided into ETS-unachieved and ETS-achieved groups (≥20% tumor reduction at week 6) and DpR-low and DpR-high groups (≥40% maximum shrinkage) until 12 weeks after enrollment. The impact of ETS and DpR on survival outcome was evaluated using the multivariable Cox proportional hazard model. RESULTS: The proportions of patients in the ETS-achieved and DpR-high groups were similar between the 2 treatment arms. The hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) for the ETS-achieved group were 0.70 (95% confidence interval (CI), 0.52-0.93) and 0.60 (95%CI, 0.44-0.81), respectively. The HRs of PFS and OS for the DpR-high group were 0.67 (95%CI, 0.48-0.94) and 0.64 (95%CI, 0.46-0.90), respectively. In the subpopulation treatment effect pattern plot analysis, most patients in the ETS-achieved group in the GC arm did not experience disease progression after 12 weeks from the landmark. CONCLUSION: As on-treatment markers, ETS and DpR were effective tools. ETS was clinically useful, because it can be used to evaluate the outcomes of treatment early at a specific time.

Reducing the use of psychotropics in a convalescent rehabilitation ward.

AIMS: Many patients who are transferred to the convalescent rehabilitation ward of Kawasaki Kokoro Hospital (hereinafter, our hospital) are on psychotropics prescribed for delirium by their physicians at acute care hospitals. In this study, psychiatrists and pharmacists collaborated with rehabilitation physicians to reduce the use of psychotropics. METHODS: The basic information and psychotropics prescription statuses of 88 patients discharged from the convalescent rehabilitation ward of our hospital between April 1, 2021 and March 31, 2022 were derived from their medical records. RESULTS: At admission, psychotropics were prescribed to 55 patients and the number of prescribed drugs was 2 (median). At discharge, psychotropics were prescribed to 41 patients and the number of prescribed drugs was 1 (median), showing a significant decrease (p < 0.05). Compared with those at admission, prescribed psychotropic doses at discharge were significantly higher for lemborexant but significantly lower for antipsychotics, benzodiazepine/nonbenzodiazepine hypnotics, antidepressants, suvorexant, ramelteon, and sodium valproate (p < 0.05). CONCLUSIONS: These results suggest that it may be possible to reduce the types and doses of psychotropics prescribed at acute care hospitals in convalescent rehabilitation wards. However, further investigation is needed because the number of patients in this study was limited, and selection bias due to different patient characteristics cannot be ruled out.

A prospective cohort study of periostin as a serum biomarker in patients with idiopathic pulmonary fibrosis treated with nintedanib.

This study investigated the utility of periostin, a matricellular protein, as a prognostic biomarker in patients with idiopathic pulmonary fibrosis (IPF) who received nintedanib. Monomeric and total periostin levels were measured by enzyme-linked immunosorbent assay in 87 eligible patients who participated in a multicenter prospective study. Forty-three antifibrotic drug-naive patients with IPF described in previous studies were set as historical controls. Monomeric and total periostin levels were not significantly associated with the change in forced vital capacity (FVC) or diffusing capacity of the lungs for carbon monoxide (DLCO) during any follow-up period. Higher monomeric and total periostin levels were independent risk factors for overall survival in the Cox proportional hazard model. In the analysis of nintedanib effectiveness, higher binarized monomeric periostin levels were associated with more favorable suppressive effects on decreased vital capacity (VC) and DLCO in the treatment group compared with historical controls. Higher binarized levels of total periostin were associated with more favorable suppressive effects on decreased DLCO but not VC. In conclusion, higher periostin levels were independently associated with survival and better therapeutic effectiveness in patients with IPF treated with nintedanib. Periostin assessments may contribute to determining therapeutic strategies for patients with IPF.

Survival and acute exacerbation for patients with idiopathic pulmonary fibrosis (IPF) or non-IPF idiopathic interstitial pneumonias: 5-year follow-up analysis of a prospective multi-institutional patient registry.

OBJECTIVE: Few prospective cohort studies with relatively large numbers of patients with non-idiopathic pulmonary fibrosis (non-IPF) of idiopathic interstitial pneumonia (IIP) have been described. We aimed to assess disease progression and cause of death for patients with non-IPF IIPs or IPF under real-life conditions. METHODS: Data were analysed for a prospective multi-institutional cohort of 528 IIP patients enrolled in Japan between September 2013 and April 2016. Diagnosis of IPF versus non-IPF IIPs was based on central multidisciplinary discussion, and follow-up surveillance was performed for up to 5 years after patient registration. Survival and acute exacerbation (AE) were assessed. RESULTS: IPF was the most common diagnosis (58.0%), followed by unclassifiable IIPs (35.8%) and others (6.2%). The 5-year survival rate for non-IPF IIP and IPF groups was 72.8% and 53.7%, respectively, with chronic respiratory failure being the primary cause of death in both groups. AE was the second most common cause of death for both non-IPF IIP (24.1%) and IPF (23.5%) patients. The cumulative incidence of AE did not differ significantly between the two groups (p=0.36), with a 1-year incidence rate of 7.4% and 9.0% in non-IPF IIP and IPF patients, respectively. We found that 30.2% and 39.4% of non-IPF IIP and IPF patients, respectively, who experienced AE died within 3 months after an AE event, whereas 55.8% and 66.7% of such patients, respectively, died within 5 years after registration. CONCLUSION: Closer monitoring of disease progression and palliative care interventions after AE are important for non-IPF IIP patients as well as for IPF patients.

Cohort study to evaluate prognostic factors in idiopathic pulmonary fibrosis patients introduced to oxygen therapy.

While high-level evidence is lacking, numerous retrospective studies have depicted the value of supplemental oxygen in idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases, and its use should be encouraged where necessary. The clinical course and survival of patients with IPF who have been introduced to oxygen therapy is still not fully understood. The objective of this study was to clarify overall survival, factors associated with prognosis, and causes of death in IPF patients after the start of oxygen therapy. This is a prospective cohort multicenter study, enrolling patients with IPF who started oxygen therapy at 19 hospitals with expertise in interstitial lung disease. Baseline clinical data at the start of oxygen therapy and 3-year follow-up data including death and cause of death were assessed. Factors associated with prognosis were analyzed using univariable and multivariable analyses. One hundred forty-seven eligible patients, of whom 86 (59%) were prescribed ambulatory oxygen therapy and 61 (41%) were prescribed long-term oxygen therapy, were recruited. Of them, 111 died (76%) during a median follow-up of 479 days. The median survival from the start of oxygen therapy was 537 ± 74 days. In the univariable analysis, low body mass index (BMI), low forced vital capacity (FVC), low diffusion capacity (DLCO), resting hypoxemia, short 6 min-walk distance, and high COPD assessment test (CAT) score were significantly associated with poor prognosis. Multivariable analysis revealed low BMI, low FVC, low DLCO, low minimum SpO2 on 6MWT, and high CAT score were independent factors for poor prognosis. The overall survival of IPF patients after starting oxygen therapy is about 1.5 years. In addition to pulmonary function tests, 6MWT and patient reported outcomes can be used to predict prognosis more accurately.Clinical Trial Registration: UMIN000009322.

HTLV-1 Proliferation after CD8+ Cell Depletion by Monoclonal Anti-CD8 Antibody Administration in Latently HTLV-1-Infected Cynomolgus Macaques.

Human T-cell leukemia virus type 1 (HTLV-1) induces chronic asymptomatic latent infection with a substantial proviral load but without significant viral replication in vivo. Cumulative studies have indicated involvement of CD8-positive (CD8+) cells, including virus-specific CD8+ T cells in the control of HTLV-1 replication. However, whether HTLV-1 expression from latently infected cells in vivo occurs in the absence of CD8+ cells remains unclear. Here, we examined the impact of CD8+ cell depletion by monoclonal anti-CD8 antibody administration on proviral load in HTLV-1-infected cynomolgus macaques. Five cynomolgus macaques were infected with HTLV-1 by inoculation with HTLV-1-producing cells. Administration of monoclonal anti-CD8 antibody in the chronic phase resulted in complete depletion of peripheral CD8+ T cells for approximately 2 months. All five macaques showed an increase in proviral load following CD8+ cell depletion, which peaked just before the reappearance of peripheral CD8+ T cells. Tax-specific CD8+ T-cell responses were detected in these recovered CD8+ T cells. Importantly, anti-HTLV-1 antibodies also increased after CD8+ cell depletion, indicating HTLV-1 antigen expression. These results provide evidence indicating that HTLV-1 can proliferate from the latent phase in the absence of CD8+ cells and suggest that CD8+ cells are responsible for the control of HTLV-1 replication. IMPORTANCE HTLV-1 can cause serious diseases such as adult T-cell leukemia (ATL) in humans after chronic asymptomatic latent infection with substantial proviral load. Proviruses are detectable in peripheral lymphocytes in HTLV-1 carriers, and the association of a higher proviral load with a higher risk of disease progression has been observed. However, neither substantial viral structural protein expression nor viral replication was detectable in vivo. Cumulative studies have indicated involvement of CD8+ cells, including virus-specific CD8+ T cells in the control of HTLV-1 replication. In the present study, we showed that CD8+ cell depletion by monoclonal anti-CD8 antibody administration results in HTLV-1 expression and an increase in proviral load in HTLV-1-infected cynomolgus macaques. Our results indicate that HTLV-1 can proliferate in the absence of CD8+ cells, suggesting that CD8+ cells are responsible for the control of HTLV-1 replication. This study provides insights into the mechanism of virus-host immune interaction in latent HTLV-1 infection.

Neuroprotective role of calreticulin after spinal cord injury in mice.

Accumulating evidence suggests that endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are involved in the pathology of spinal cord injury (SCI). To determine the role of the UPR-target molecule in the pathophysiology of SCI, we analyzed the expression and the possible function of calreticulin (CRT), a molecular chaperone in the ER with high Ca2+ binding capacity, in a mouse SCI model. Spinal cord contusion was induced in T9 by using the Infinite Horizon impactor. Quantitative real-time polymerase chain reaction confirmed increase of Calr mRNA after SCI. Immunohistochemistry revealed that CRT expression was observed mainly in neurons in the control (sham operated) condition, while it was strongly observed in microglia/macrophages after SCI. Comparative analysis between wild-type (WT) and Calr+/- mice revealed that the recovery of hindlimb locomotion was reduced in Calr+/- mice, based on the evaluation using the Basso Mouse Scale and inclined-plane test. Immunohistochemistry also revealed more accumulation of immune cells in Calr+/- mice than in WT mice, at the epicenter 3 days and at the caudal region 7 days after SCI. Consistently, the number of damaged neuron was higher in Calr+/- mice at the caudal region 7 days after SCI. These results suggest a regulatory role of CRT in the neuroinflammation and neurodegeneration after SCI.

Postnatal expression of CD38 in astrocytes regulates synapse formation and adult social memory.

Social behavior is essential for health, survival, and reproduction of animals; however, the role of astrocytes in social behavior remains largely unknown. The transmembrane protein CD38, which acts both as a receptor and ADP-ribosyl cyclase to produce cyclic ADP-ribose (cADPR) regulates social behaviors by promoting oxytocin release from hypothalamic neurons. CD38 is also abundantly expressed in astrocytes in the postnatal brain and is important for astroglial development. Here, we demonstrate that the astroglial-expressed CD38 plays an important role in social behavior during development. Selective deletion of CD38 in postnatal astrocytes, but not in adult astrocytes, impairs social memory without any other behavioral abnormalities. Morphological analysis shows that depletion of astroglial CD38 in the postnatal brain interferes with synapse formation in the medial prefrontal cortex (mPFC) and hippocampus. Moreover, astroglial CD38 expression promotes synaptogenesis of excitatory neurons by increasing the level of extracellular SPARCL1 (also known as Hevin), a synaptogenic protein. The release of SPARCL1 from astrocytes is regulated by CD38/cADPR/calcium signaling. These data demonstrate a novel developmental role of astrocytes in neural circuit formation and regulation of social behavior in adults.

Effect of systemic inflammatory response on induction chemotherapy followed by chemoradiotherapy for locally advanced pancreatic cancer: an exploratory subgroup analysis on systemic inflammatory response in JCOG1106.

OBJECTIVE: JCOG1106, a randomized phase II trial conducted to compare chemoradiotherapy (S-1 concurrent radiotherapy) with (Arm B) or without (Arm A) induction chemotherapy using gemcitabine in patients with locally advanced pancreatic cancer, showed a more favorable long-term survival in Arm A. This study was aimed at exploring whether some subgroups classified by the systemic inflammatory response might derive greater benefit from either treatment. METHODS: All subjects eligible for JCOG1106 were included in this analysis (n = 51/49 in Arm A/B). This exploratory subgroup analysis was performed by Cox regression analysis to investigate the impact of the systemic inflammatory response, as assessed based on the serum C-reactive protein, serum albumin (albumin), Glasgow Prognostic Score and derived neutrophil-lymphocyte ratio, at the baseline on overall survival. P values <0.1 for the interaction were regarded as denoting significant association. RESULTS: Glasgow prognostic score showed significant treatment interactions for overall survival. Hazard ratios of Arm B to Arm A were 1.35 (95% confidence interval, 0.82-2.23) in the Glasgow Prognostic Score 0 (C-reactive protein ≤10 mg/L and albumin ≥35 g/L) (n = 44/34 in Arm A/B) and 0.59 (95% confidence interval, 0.24-1.50) in the Glasgow Prognostic Score 1/2 (C-reactive protein >10 mg/L and/or albumin <35 g/L) (n = 7/15) (P-interaction = 0.06). C-reactive protein alone and albumin alone also showed significant treatment interactions for overall survival. CONCLUSIONS: Survival benefits of induction chemotherapy in chemoradiotherapy for locally advanced pancreatic cancer were observed in patients with elevated Glasgow Prognostic Score, high C-reactive protein and low albumin. These results suggest that systemic inflammatory response might be considered to apply induction chemotherapy preceding chemoradiotherapy.