Upfront Multiplex Gene Test Helps Prolong Survival in Advanced Non-small Cell Lung Cancer.

BACKGROUND/AIM: Detection of genetic abnormalities is crucial for selecting an appropriate therapy to effectively treat advanced non-small cell lung cancer (NSCLC). Multiplex genetic testing aids the selection of appropriate therapy and tailored treatments; however, its impact on survival remains unexplored. PATIENTS AND METHODS: Using data from 112 patients with advanced or recurrent NSCLC between February 2020 and April 2023, we investigated the impact of multiplex genetic tests, conducted before the initiation of systemic therapy, on survival. RESULTS: Multiplex genetic test was performed on 72 patients (MPL group). Among the remaining 40 patients (non-MPL group), 18 underwent ≥1 single-plex genetic test, including tests for EGFR (18), ALK (14), and ROS1 (8). The frequency of EGFR mutations in the MPL and non-MPL groups was similar (28% and 25%, respectively), whereas alterations in KRAS, ALK, MET, HER2, and RET levels (5, 4, 4, 4, and 1, respectively) were exclusively detected in the MPL group. The MPL group exhibited a significantly improved survival rate compared to the non-MPL group (median survival time 20.6 vs. 9.3 months, p=0.009). CONCLUSION: Multiplex genetic testing, before the initiation of systemic treatment, could potentially enhance prognosis by uncovering a wide range of non-EGFR gene abnormalities. Multiplex genetic tests could be crucial for the effective application of modern anticancer therapeutic strategies.

The effect of 1-hydroxy-vitamin D treatment in hospitalized patients with COVID-19: A retrospective study.

BACKGROUND & AIMS: The efficacy of vitamin D supplementation in coronavirus disease 2019 (COVID-19) remains unclear. This study aimed to evaluate the effect of 1-hydroxy-vitamin D on the prevention of severe disease and mortality in patients hospitalized for COVID-19. METHODS: This retrospective study included 312 patients with COVID-19 who were admitted to our hospital between April 2021 and October 2021 (primarily the Delta variant) and between July 2022 and September 2022 (primarily Omicron variant). Serum 25-hydroxyvitamin D (25(OH)D) levels were measured at the time of admission and 1-hydroxy-vitamin D was prescribed by the treating physicians. The patients were divided into two groups: those administered 1-hydroxy-vitamin D (Vit D group) and those who were not (control group). The composite primary endpoint was the need for additional respiratory support, including high-flow oxygen therapy or invasive mechanical ventilation, and in-hospital mortality rate. RESULTS: Of 312 patients, 122 (39%) received 1-hydroxy-vitamin D treatment. Although the median age was not significantly higher in the Vit D group than in the control group (66 vs. 58 years old, P = 0.06) and there was no significant difference in the proportion of vitamin D deficiency (defined as serum 25(OH)D level less than 20 ng/mL, 77% vs. 65%, P = 0.07), patients in the control group had a more severe baseline profile compared to the Vit D group according to the Japanese disease severity definition for COVID-19 (P = 0.01). The proportion of those requiring more respiratory support and in-hospital mortality was significantly lower in the Vit D group than in the control group (6% vs. 14%, P = 0.01 log-rank test). After propensity score matching, a statistically significant difference in the primary endpoint was observed (P = 0.03 log-rank test). CONCLUSIONS: 1-hydroxy-vitamin treatment may improve outcomes in hospitalized patients with COVID-19, reducing composite outcomes including the need for additional respiratory support and in-hospital mortality.

[Re-operation for Recurrent Constrictive Pericarditis with Multiple Organ Dysfunction].

The patient was a 64-year-old man with recurrent constrictive pericarditis which developed 12 years after the initial pericardiectomy. He had bilateral heart failure with severe left ventricular diastolic dysfunction, massive ascites, renal failure, and coagulopathy. Computed tomography showed a heavily calcified pericardium around the right atrium, the phrenic side of the right ventricle, and the left ventricle. He underwent pericardiectomy via median sternal re-entry. The calcified pericardium was safely decorticated with an ultrasonic surgical knife. The pericardium around the left ventricular side was safely decorticated under cardiopulmonary bypass and use of a heart positioner. Although permanent hemodialysis was necessary after the operation, he has been well for 6 years since the operation.

Effect of eicosapentaenoic acid on prevention of lean body mass depletion in patients with exacerbation of chronic obstructive pulmonary disease: A prospective randomized controlled trial.

BACKGROUND & AIMS: Systemic inflammation plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD), resulting in depletion of lean body mass (LBM) and muscle mass. Both frequent exacerbation of COPD and low LBM are associated with poor prognosis. This study aimed to evaluate whether supplementation of eicosapentaenoic acid (EPA) prevents depletion of LBM and muscle mass in hospitalized patients with exacerbation of COPD. METHODS: This was a prospective randomized controlled trial, conducted between November 2014 and October 2017. Fifty patients were randomly assigned to receive 1 g/day of EPA-enriched oral nutrition supplementation (ONS) (EPA group) or EPA-free ONS of similar energy (control group) during hospitalization. The LBM index (LBMI) and the skeletal muscle mass index (SMI) were measured using a bioelectrical impedance analyzer at the time of admission and at the time of discharge. Patients underwent pulmonary rehabilitation and wore a pedometer to measure step counts and physical activity. RESULTS: Forty-five patients that completed the experiment were analyzed. Baseline characteristics were similar between the EPA (n = 24) and control groups (n = 21). There were no significant differences in energy intake, step counts, physical activity, or length of hospitalization between the two groups. Although the plasma levels of EPA significantly increased only in the EPA group, we found an insignificant increase in LBMI and SMI in the EPA group compared with the control group (LBMI: +0.35 vs. +0.19 kg/m2, P = 0.60, and SMI: +0.2 vs. -0.3 kg/m2, P = 0.17, respectively). The change in the SMI was significantly correlated with the length of hospitalization in the EPA group, but not in the control group (r = 0.53, P = 0.008, and r = -0.09, P = 0.70, respectively). CONCLUSIONS: EPA-enriched ONS in patients with exacerbation of COPD during short-time hospitalization had no significant advantage in preservation of LBM and muscle mass compared with EPA-free ONS. EPA supplementation for a longer duration might play an important role in the recovery of skeletal muscle mass after exacerbation of COPD.

Overexpression of IGF2 and IGF2 receptor in malignant solitary fibrous tumor with hypoglycemia: a case report.

BACKGROUND: Solitary fibrous tumor (SFT) is a prototypical mesenchymal neoplasm that induces non-islet cell tumor hypoglycemia (NICTH) due to overproduction of insulin-like growth factor 2 (IGF2). We here report the case of a malignant SFT associated with a hypoglycemia attack. CASE PRESENTATION: An 81-year-old man with a large subphrenic mass presented with hypoglycemia and loss of consciousness. His serum insulin and IGF1 levels were relatively low, suggesting an excessively high serum IGF2 levels. Preoperative Western blotting of serum confirmed the overproduction of high-molecular-weight IGF2. After total tumor resection, the patient recovered from hypoglycemia without the need for further treatment. Histological examination revealed proliferation of spindle cells and frequent nuclear mitoses with STAT6 and CD34 immunoreactivity, which led to the diagnosis of malignant SFT. IGF2 was strongly upregulated in the tumor upon immunohistochemistry, consistent with the report of NICTH. In addition, the tumor expressed IGF2 receptor (IGF2R) but not IGF1R. CONCLUSIONS: The present results indicate that the tumor co-expressed IGF2 and IGF2R. IGF2R has not previously been recognized as a tyrosine kinase receptor participating in cell signal transduction. Thus, further case series are required to determine whether IGF2R overexpression reflects the action of an unknown autocrine/paracrine system involving IGF2 for cell proliferation or for the scavenging and degradation of IGF2.

Allergic TH2 Response Governed by B-Cell Lymphoma 6 Function in Naturally Occurring Memory Phenotype CD4+ T Cells.

Transcriptional repressor B-cell lymphoma 6 (Bcl6) appears to regulate TH2 immune responses in allergies, but its precise role is unclear. We previously reported that Bcl6 suppressed IL-4 production in naïve CD4+ T cell-derived memory TH2 cells. To investigate Bcl6 function in allergic responses in naturally occurring memory phenotype CD4+ T (MPT) cells and their derived TH2 (MPTH2) cells, Bcl6-manipulated mice, highly conserved intron enhancer (hcIE)-deficient mice, and reporter mice for conserved noncoding sequence 2 (CNS2) 3' distal enhancer region were used to elucidate Bcl6 function in MPT cells. The molecular mechanisms of Bcl6-mediated TH2 cytokine gene regulation were elucidated using cellular and molecular approaches. Bcl6 function in MPT cells was determined using adoptive transfer to naïve mice, which were assessed for allergic airway inflammation. Bcl6 suppressed IL-4 production in MPT and MPTH2 cells by suppressing CNS2 enhancer activity. Bcl6 downregulated Il4 expression in MPTH2 cells, but not MPT cells, by suppressing hcIE activity. The inhibitory functions of Bcl6 in MPT and MPTH2 cells attenuated allergic responses. Bcl6 is a critical regulator of IL-4 production by MPT and MPTH2 cells in TH2 immune responses related to the pathogenesis of allergies.

Aortic Valve Replacement for Patients with Functioning Internal Mammalian Artery Grafts.

Aortic valve replacement (AVR) for patients with functioning internal mammalian artery (ITA) grafts is technically challenging, and the optimal treatment strategy for these situations remains controversial. Here, we report five cases of AVR with ITA graft using continuous retrograde cardioplegia in addition to moderate hypothermia without the clamping of ITA and discuss the management of these cases.

Bronchodilator Effect of Tiotropium via Respimat®Administered with a Spacer in Patients with Chronic Obstructive Pulmonary Disease (COPD).

Objective Among elderly patients with chronic obstructive pulmonary disease (COPD), there are some patients who cannot inhale tiotropium via Respimat® due to poor hand-lung coordination. This study aimed to examine whether or not tiotropium inhalation therapy using Respimat® with a spacer increased the forced expiratory volume in 1 s (FEV1) in patients with COPD. Methods A randomized, crossover, single-center study was conducted in 18 patients with stable COPD. Tiotropium (5 µg) via Respimat® with or without a spacer (AeroChamber®) was administered for 2 weeks. Following a 2-week washout period using a transdermal tulobuterol patch (2 mg per day), participants were then crossed over to the other inhalation therapy with respect to spacer use. The trough FEV1 was measured at every visit using a spirometer. A questionnaire regarding inhalation therapy was administered to patients at the final visit. Results The administration of tiotropium via Respimat® both with and without a spacer significantly increased the trough FEV1 from baseline during each treatment period, with mean differences of 115.0±169.6 mL and 92.8±128.1 mL, respectively. There was no significant difference in the change in the trough FEV1 between the 2 procedures (p=0.66). A total of 86% of patients reported that inhalation using a spacer was not difficult, and more than half also rated both the usage and maintenance of the AeroChamber® as easy. Conclusion Tiotropium inhalation therapy administered via Respimat® using a spacer exerted a bronchodilatory effect similar to that observed with tiotropium Respimat® alone.

Adventitial Cystic Disease Communicating with the Knee Joint: A Case Report with Histopathological Study of the Connection.

Adventitial cystic disease is a rare nonatheromatous cause of popliteal artery disease. Here, we present a case of a 51-year-old male patient who presented with right calf claudication caused by adventitial cystic disease. Preoperative magnetic resonance imaging and intraoperative findings revealed the presence of a connection between the cyst and adjacent knee joint. In addition, histopathological examination revealed that the tissue structure of the connection was similar to that of adventitial cysts. The tissue composed of 2 types of cells, namely macrophages and fibroblast-like cells, and lesional cells expressed D2-40. These findings supported the ganglion theory as the underlying physiopathology of this disease and were helpful in deciding the management of this case.

Native aortic valve thrombosis in patient with protein S deficiency.

Native aortic valve thrombosis is an extremely rare condition, the causes of which include previous aortic valve diseases, endocarditis, valvular injury by a catheter intervention and an underlying hypercoagulative state. Its diagnosis is important for preventing life-threatening embolic complications. Here, we report a case of native aortic valve thrombosis and recurrent systemic embolism in a patient with protein S deficiency, a disorder associated with a hypercoagulative state.

Development of chronic allergic responses by dampening Bcl6-mediated suppressor activity in memory T helper 2 cells.

Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (TH2) immune responses as patients with allergic diseases. However, the molecular mechanisms underlying Bcl6-directed regulation of TH2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in TH2 cytokine gene loci. We found that Bcl6 is modestly associated with the BSs, and it had no significant effect on cytokine production in newly differentiated TH2 cells. Contrarily, in memory TH2 (mTH2) cells derived from adaptively transferred TH2 effectors, Bcl6 outcompeted STAT5 for binding to TH2 cytokine gene loci, particularly Interleukin4 (Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mTH2 cells. Bcl6 suppressed cytokine production epigenetically in mTH2 cells to negatively tune histone acetylation at TH2 cytokine gene loci, including Il4 loci. In addition, IL-33, a pro-TH2 cytokine, diminished Bcl6's association with loci to which GATA3 recruitment was inversely augmented, resulting in altered IL-4, but not IL-5 and IL-13, production in mTH2 cells but no altered production in newly differentiated TH2 cells. Use of a murine asthma model that generates high levels of pro-TH2 cytokines, such as IL-33, suggested that the suppressive function of Bcl6 in mTH2 cells is abolished in severe asthma. These findings indicate a role of the interaction between TH2-promoting factors and Bcl6 in promoting appropriate IL-4 production in mTH2 cells and suggest that chronic allergic diseases involve the TH2-promoting factor-mediated functional breakdown of Bcl6, resulting in allergy exacerbation.

Prospective open-label randomized comparative, non-inferiority study of two initial antibiotic strategies for patients with nursing- and healthcare-associated pneumonia: Guideline-concordant therapy versus empiric therapy.

BACKGROUND AND OBJECTIVE: The nursing- and healthcare-associated pneumonia guideline, proposed by the Japan Respiratory Society, recommends that patients at risk of exposure to drug-resistant pathogens, classified as treatment category C, be treated with antipseudomonal antibiotics. This study aimed to prove the non-inferiority of empirical therapy in our hospital compared with guideline-concordant therapy. METHODS: This was a randomized controlled trial conducted from December 2011 to December 2012. Patients were randomized to the Guideline group receiving guideline-concordant therapy, and the Empiric group treated with sulbactam/ampicillin or ceftriaxone. The primary endpoint was in-hospital relapse of pneumonia and mortality within 30 days, with a predefined non-inferiority margin of 10%. The secondary endpoints included duration, adverse effects, and cost of antibiotic therapy. RESULTS: One hundred and eleven patients were assigned to the Guideline group (n = 55) and the Empiric group (n = 56; 3 of which were excluded). The incidence of relapse and death within 30 days was similar in the Guideline and the Empiric groups (31% vs. 26%, risk difference -4.5%, 95% CI -21.5% to 12.5%). While the duration of antibiotic therapy was slightly shorter in the Guideline group than in the Empiric group (7 vs. 8 days), there were no significant differences in adverse effects or cost. CONCLUSIONS: The efficacy of empiric therapy was comparable to guideline-concordant therapy, although non-inferiority was not proven. The administration of broad-spectrum antibiotics to patients at risk of exposure to drug-resistant pathogens may not necessarily improve the prognosis. TRIAL REGISTRATION: UMIN000006792.

[The McGRATH MAC Video Laryngoscope Facilitates Probe Insertion during Transesophageal Echocardiography].

BACKGROUND: A transesophageal echocardiography (TEE) probe is often inserted blindly. However, it is desirable to insert it under visual guidance because the blind technique sometimes causes difficulty and may contribute to serious, but rare, complications. This prospective study compared the usefulness of TEE insertion between a brand-new McGRATH MAC video laryngoscope (McGRATH) and a Macintosh laryngoscope (Macintosh). METHODS: We randomly assigned 80 adult patients undergoing cardiovascular surgery into two groups according to the laryngoscope used for TEE probe insertion: the McGRATH (McG Group; n = 40) and Macintosh (MC Group; n = 40) groups. End points included patient demographics, procedure duration, and resistance during insertion (grades 1-5). RESULTS: No differences were found in patient demographics between the groups. There was no significant difference in procedure duration between the groups (P = 0.116). Resistance during insertion was significantly lower in the McG Group than in the MC Group (P < 0.001). There were no failures of insertion in the McG Group. CONCLUSIONS: There were no failures of insertion in the McG Group. Resistance during insertion was lower with the McGRATH than Macintosh. The McGRATH was shown to be very useful when inserting TEE probes.

Idiopathic bronchocentric granulomatosis in an asthmatic adolescent.

Bronchocentric granulomatosis in asthmatic patients has been generally considered to be associated with allergic bronchopulmonary aspergillosis and represent a histopathologic manifestation of fungal hypersensitivity. Here we report a case of an idiopathic bronchocentric granulomatosis in a 17-year-old man with a history of asthma. He was admitted to the hospital with a fever and cough, and a chest CT scan showed peribronchial consolidation in the pulmonary parenchyma, which was unresponsive to antibiotic therapy. The pathological findings obtained by video-assisted thoracoscopic lung biopsy revealed necrotizing granulomatous inflammation centered on bronchi and bronchioles and there was no evidence of fungal colonization, resulting in a diagnosis of idiopathic bronchocentric granulomatosis. Systemic corticosteroid therapy led to clinical and radiological recovery. Physicians should take into account the possibility of the idiopathic process in bronchocentric granulomatosis of asthmatic patients.

Procalcitonin-guided antibiotic therapy in aspiration pneumonia and an assessment of the continuation of oral intake.

BACKGROUND: Procalcitonin-guided antibiotic therapy for community-acquired pneumonia is effective and safe. However, the usefulness of procalcitonin for aspiration pneumonia and its nutrition-related outcomes are unknown. METHODS: We conducted a noninferiority randomized controlled study in patients with aspiration pneumonia who were admitted to our hospital between September 2010 and January 2012. We randomly assigned 105 patients to groups with different durations of antibiotic therapy based on the procalcitonin levels upon admission (procalcitonin group) or according to the standard guidelines (control group). The primary endpoints were relapse of aspiration pneumonia and death within 30 days, with a predefined noninferiority boundary of 10%. Secondary endpoints included duration of antibiotic exposure. Furthermore, we conducted a retrospective analysis of the prognostic factors that determined continuation of oral nutritional intake, relapse of pneumonia, and in-hospital death. RESULTS: The rate of relapse and death within 30 days were similar in the procalcitonin and control groups (25% versus 37.5%; difference, -12.5%; 95% confidence interval, -30.9% to 5.9%). Procalcitonin-guided antibiotic therapy significantly shortened the median duration of antibiotic exposure (5 versus 8 days; p<0.0001); however, the continuation of oral intake was not increased (56% versus 50%; p=0.54). A multivariable analysis showed a significant association between the continuation of oral nutritional intake and the body mass index upon admission. CONCLUSIONS: Procalcitonin-guided antibiotic therapy for aspiration pneumonia can shorten the duration of antibiotic exposure, but it does not increase the continuation of oral intake (UMIN000004800).

Intrathoracic administration of OK-432 elevates the serum procalcitonin levels.

OBJECTIVE: The intrathoracic administration of OK-432, a lyophilized preparation of the heat- and penicillin-treated Su-strain of type 3, group A Streptococcus pyogenes, is performed in Japan for pleurodesis of malignant pleural effusion or pneumothorax. Persistent fever is often observed after pleurodesis. To elucidate whether procalcitonin (PCT) is useful for distinguishing between the side effects of OK-432 and infection, we measured the serum PCT levels before and after pleurodesis. METHODS: We performed a prospective study of 12 patients with refractory pleural effusion or pneumothorax who required pleurodesis using OK-432 between August 2011 and February 2012. The serum PCT and C-reactive protein (CRP) levels were measured on days 1 and 3. RESULTS: Of the 12 patients, five had pneumothorax and seven had uncontrolled pleural effusion with carcinomatous pleurisy. The median serum levels of PCT and CRP increased from 0.055 to 1.59 ng/mL (p=0.0022) and from 1.52 to 16.82 mg/dL (p=0.0022), respectively. The fevers subsided without antibiotic administration. CONCLUSION: The serum PCT level may not be useful for distinguishing fever caused by side effects of OK-432 from that caused by bacterial infection. The intrathoracic administration of OK-432 increased the serum levels of both PCT and CRP in the absence of any bacterial infection.

Chyloptysis after ligation of the thoracic duct.

Chyloptysis is a very rare clinical finding. We describe a 44-year-old man who presented with cough and milky-white sputum. Fiberoptic bronchoscopy revealed white sputum, which originated from the right B(6) bronchus. The finding of elevated triglyceride levels in his sputum led to the diagnosis of chyloptysis. He had a surgical history of ligation of the thoracic duct for idiopathic chylopericarditis 7 years-previously. He also suffered from postoperative bilateral empyema. Since then, his pleural cavity has been adhered bilaterally. It is thought that his abnormal postoperative lymphatic flow caused the chyloptysis.

[Retrospective analysis of pemetrexed plus cisplatin chemotherapy for elderly advanced non-small-cell lung cancer].

BACKGROUND: The efficacy of pemetrexed(PEM)plus cisplatin(CDDP)therapy for chemotherapy-naive non-squamous cell lung cancer has been reported, but the effectiveness of such a regimen for elderly patients is unknown. PURPOSE: The aim of this study is to examine the efficacy and toxicity of CDDP plus PEM therapy for elderly patients, retrospectively. METHODS: We performed a retrospective analysis of six patients 75 years old or older with non-squamous lung cancer, who underwent CDDP plus PEM therapy from June 2009 to May 2010. RESULTS: The mean age was 79. 2 years old(range, 76-82), gender: 3 males/3 females; stage: III B/IV; 1/5, pathology: all patients had adenocarcinoma without epidermal growth factor receptor (EGFR)mutation, line: first/third; 5/1. The scheduled chemotherapy of four courses was completed in four patients. The overall response rate was 50%, and the disease control rate was 83%. Grade 3/4 neutropenia and thrombocytopenia were observed in 1/2 and 1/1 patients, respectively, but no blood transfusions were needed. Severe myelosuppression was shown in patients who were impaired in renal function. Grade 3 nausea or anorexia was also observed in 50%of patients. Therefore, two patients were terminated in one courses of therapy and long-term hospitalization for them was needed. CONCLUSION: Although CDDP plus PEM therapy for elderly patients has sufficient patients compliance because of its tolerable myelosuppression, it is necessary to pay attention to deterioration in renal function and to care for nausea during chemotherapy.