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Background Since 2020, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has become prevalent worldwide. In severe cases, the case fatality rate is high, and vaccine prevention is important. This study evaluated the safety of receiving SARS‐CoV‐2 vaccine in patients with advanced lung cancer receiving anticancer therapy. Methods We prospectively enrolled patients receiving anticancer drugs for advanced lung cancer who planned to receive SARS‐CoV‐2 vaccination. Early adverse events within 7 days of vaccine injection were evaluated using patient‐reported surveys. The chi‐square test and multivariate logistic regression analyses were used. Results Among 120 patients receiving lung cancer treatment, 73 were men; the mean age of the patients was 73.5 years. The treatments received for lung cancer at the time of the first vaccine injection were chemotherapy, ICIs, combined chemotherapy and ICIs, and targeted therapies, including tyrosine kinase inhibitors, in 30, 28, 17, and 45 patients, respectively. All patients received SARS‐CoV‐2 messenger RNA (mRNA) vaccine. After the second mRNA vaccine dose, 15.4% of patients had fever of 38°C (95% confidence interval: 9.34%–23.2%); this rate was slightly higher than that for healthy participants at the time of the BNT162b2 trial. Patients treated with cytotoxic anticancer drugs tended to have high fever. In the multivariate analyses, male sex was associated with higher fever frequencies. However, there were no serious early adverse events due to vaccination. Conclusions Anti‐SARS‐CoV‐2 mRNA vaccination tends to be safe, but fever following vaccination tends to be more common among patients undergoing lung cancer treatment than among healthy individuals., Anti‐SARS‐CoV‐2 messenger RNA vaccination itself tends to be safe.Vaccine‐related AEs tend to increase in lung cancer patients with chemotherapy.Serious adverse events are comparable to those in healthy individuals.

COVID-19 incidence is high in patients with cancer. The fatality rate was high for the Delta variant, necessitating infection prevention by vaccination. This study evaluated the safety of a SARS-CoV-2 vaccine in patients with advanced lung cancer receiving anticancer therapy.We prospectively enrolled patients receiving anticancer drugs for advanced lung cancer and planning SARS-CoV-2 vaccination. Early side effects within 7 days of vaccination were evaluated using patient-reported outcome (PRO) surveys. Chi-square test and multivariate logistic regression analyses were used.Post-vaccination PROs were collected from 406 patients (252 were males). The mean age was 72 years. Treatment at the time of initial vaccination included chemotherapy, immune checkpoint inhibitors (ICI), a combination of chemotherapy and ICI, targeted therapy including tyrosine kinase inhibitors, and others in 115, 93, 45, 147, and six cases, respectively. The vaccines administered were BNT162b2 and mRNA273 in 361 and three cases, respectively and unknown in 42 cases. A total of 16.1% of patients developed fever (38°C) after the second mRNA vaccination (95% confidence interval: 12.6%-20.1%). This rate is comparable to data previously reported in 120 patients and slightly higher than that of healthy participants of the BNT162b2 study. Patients receiving treatment with cytotoxic anticancer agents were more likely to have high fever. Multivariate analysis showed no correlation between fever frequency and patient background. No serious initial adverse events due to vaccination were observed.Anti-SARS-CoV-2 mRNA vaccination is safe; however, post-vaccination fever is more common in patients undergoing lung cancer treatment than in healthy individuals.

Primary salivary gland‐type tumors of the lung are rare, accounting for, Lung adenocarcinoma was diagnosed in this patient who subsequently received carboplatin, pemetrexed and pembrolizumab. The carcinomatous lymphangiomatosis improved. Autopsy revealed the tumor was primary salivary gland‐type lung adenocarcinoma.

A 70-year-old woman, who was taking prednisolone to treat Takayasu arteritis, underwent surgery for aortic regurgitation and aneurysm of the ascending aorta. The probe of the transesophageal echocardiography (TEE) could not be inserted due to resistance during anesthesia induction and was inserted after starting cardiopulmonary bypass. The right pneumothorax was observed during surgery. After surgery, fever and a high C-reactive protein level continued, and a computed tomography (CT) examination revealed right thoracic empyema together with free air around the esophagus. The esophageal perforation diagnosis was confirmed by upper endoscopy. Esophageal leakage continued despite emergency esophageal repair and enterostomy. Although esophagectomy was performed 2 months later, the patient died 6 months after cardiac surgery due to sepsis. Thus, esophageal perforation related to TEE in open-heart surgery was considered to be associated with a poor prognosis.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are non-epithelial neuroendocrine neoplasms originating from the adrenal medulla and paraganglion of the sympathetic and parasympathetic nervous system, respectively. PCCs and PGLs show histological similarities with other epithelial neuroendocrine neoplasms and olfactory neuroblastomas (ONBs), and the differential diagnosis of PGLs is particularly difficult. Therefore, we compared the sensitivity of PHOX2A, PHOX2B, and tyrosine hydroxylase (TH) in the histopathological diagnosis of PCCs and PGLs immunohistochemically using the tissue microarrays of 297 neoplasms including PCCs, PGLs, neuroblastomas, ganglioneuromas, epithelial neuroendocrine neoplasms, and ONBs. Using cutoff values of 25%, 5%, and 5% of tumor cells expressing PHOX2A, PHOX2B, and TH, respectively, as positive, 40 of 51 PCCs, 32 of 33 parasympathetic/head and neck PGLs (HNPGLs), 17 of 19 sympathetic/thoracoabdominal PGLs (TAPGLs), and 12 of 152 epithelial neuroendocrine neoplasms, including 123 well-differentiated and 29 poorly differentiated neuroendocrine neoplasms, were PHOX2A-positive. All 51 PCCs, 33 HNPGLs, and 19 TAPGLs were PHOX2B-positive, while all 152 epithelial neuroendocrine neoplasms were PHOX2B-negative. Moreover, 50 of 51 PCCs, 13 of 33 HNPGLs, all TAPGLs, and 12 of 152 epithelial neuroendocrine neoplasms were TH-positive. All ONBs were negative for PHOX2A, PHOX2B, and TH. PHOX2B was the most sensitive and specific diagnostic marker for PCCs and PGLs among PHOX2A, PHOX2B, and TH. PHOX2B can facilitate identification of PCCs and PGLs from epithelial neuroendocrine neoplasms and ONBs, especially in the case of HNPGLs, in which TH is often negative.

Combination therapy with immune checkpoint inhibitors (ICIs) and chemotherapy (ICI + chemotherapy) has become the standard first line treatment for driver oncogene-negative advanced non-small-cell lung cancer (NSCLC). However, it may be more toxic compared to monotherapy, which limits its use. Moreover, the feasibility of the combination therapy in clinical practice remains unknown.We conducted a cohort study to determine the implementation rate of ICI + chemotherapy in clinical practice. We retrospectively reviewed clinical data from advanced NSCLC patients who received systemic therapy at 13 institutions between December 2018 and December 2020.After excluding 154 patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene alterations, a total of 919 NSCLC patients were included. Among them, 442 were treated with ICI + chemotherapy (48%), whereas 477 were treated with other therapies (52%). Among these 477 patients, 340 did not receive ICI + chemotherapy because of intolerance (71%); thus, more than one-third of the advanced NSCLC patients do not benefit from the combination therapy due to intolerance. Among the 659 NSCLC patients for whom PD-L1 was 50% or unknown, only 342 received the ICI + chemotherapy combination (52%) even though it is considered preferable to either therapy alone; the remaining 318 patients were treated with other therapies (48%). Among the 318 patients who did not receive ICI + chemotherapy, 274 were intolerant to it (86%).Our results revealed that a substantial proportion of advanced NSCLC patients did not benefit from ICI + chemotherapy due to intolerance. As treatments for NSCLC are moving toward combinations for greater efficacy, their feasibility in clinical practice must be taken into consideration.

Pembrolizumab is a monoclonal antibody with anti-tumor effects. Only a few reports have previously described retrobulbar optic neuritis induced by pembrolizumab. We herein report the case of a 64 -year-old man with advanced lung adenocarcinoma who received cisplatin, pemetrexed, and pembrolizumab combination therapy for six months. Following treatment, a visual field test showed a left central scotoma. Imaging studies showed left optic neuritis without brain metastasis. Blood tests showed an elevated serum creatinine level. He was diagnosed with retrobulbar optic neuritis and pembrolizumab-induced renal failure. After receiving corticosteroid treatment, his renal function rapidly improved. The optic neuritis improved somewhat, but it was not adequately resolved.

Epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) are key drugs in the treatment of non‐small cell lung cancer (NSCLC) patients with EGFR mutations; however, first‐generation EGFR‐TKIs, such as gefitinib and erlotinib, are not effective in patients with uncommon EGFR mutations. In contrast, efficacy of afatinib has been reported in some types of uncommon EGFR mutation such as G710X, L861Q. The effect of afatinib in NSCLC patients with the EGFR K860I mutation has been shown in vitro, but its clinical efficacy has not been demonstrated. Here, we report the experience of afatinib administration in an NSCLC patient with an EGFR K860I mutation. A 69‐year‐old woman presented with right hemiplegia and dysarthria. Multiple brain and lung tumors were observed. She underwent craniotomy and was diagnosed with lung adenocarcinoma. After stereotactic brain radiation therapy, cisplatin, pemetrexed, and bevacizumab combination therapy was initiated. Unfortunately, she was unable to continue chemotherapy as she had an intestinal perforation after two cycles. After five months, recurrence of multiple brain metastases and an increase in primary lung cancer were confirmed. Next‐generation sequencing (NGS) was performed in a clinical trial, and an EGFR K860I mutation was detected in her tumor. Afatinib was administered and the primary lung tumor shrank, but multiple brain metastases were exacerbated. After irradiation of the brain, afatinib administration was continued. In conclusion, afatinib may show an effect in NSCLC patients with the EGFR K860I mutation, but its efficacy is limited., The role of EGFR K860I mutation in lung carcinogenesis is unclear, and this case reports a patient with lung adenocarcinoma harboring a rare uncommon EGFR mutation. Afatinib, a second‐generation EGFR‐TKI, does not show a significant antitumor effect in non‐small cell lung carcinoma patients with the EGFR K860I mutation.

Alectinib is a key drug for treating anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). Alectinib-induced hepatotoxicity is less common than that through other ALK inhibitors, such as crizotinib or ceritinib. Herein, we describe a case of ALK-positive adenocarcinoma successfully treated with lorlatinib after developing alectinib-induced hepatotoxicity. A 57-year-old Japanese man received alectinib as first-line therapy for ALK-positive NSCLC. After 79 days, alectinib was discontinued because of hepatotoxicity and later restarted at 150 mg/day, inducing hepatotoxicity again after 64 days. Switching to lorlatinib treatment (continued for >4 months) caused no severe adverse effects. Hence, lorlatinib may be useful for patients experiencing alectinib-induced hepatotoxicity.

The first total syntheses of hericenones C-H and "putative 3-hydroxyhericenone F" were achieved. Highlights of the synthesis include the straightforward construction of the resorcinol core and geranyl side chain, assembly of the natural product skeleton by sequential O-geranylation and a clay/zeolite-mediated O → C rearrangement reaction, and a biomimetic cyclization to form a variety of bicyclic natural hericenones and their congeners. The structure of the "putative 3-hydroxyhericenone F" was revised as the 5-exo cyclization product (named: hericenone Z) of epoxyhericenone C through in-depth analyses of the cyclization modes in addition to NMR spectroscopic studies. To gain insights into the biological functions of geranyl-resorcinols in Hericium erinaceus, potential neuroprotective effects against endoplasmic reticulum (ER) stress-dependent cell death were evaluated systematically to clarify a fundamental structure-activity relationship. Among the compounds assayed, the linoleate-containing hericenone analogue, i.e., the regioisomer of hericene D, was found to possess the most potent neuroprotective effect against tunicamycin and thapsigargin-induced ER stress-dependent cell death.

Background The guidelines on pharmacotherapy for cancer-related pain advocate active measures against the adverse effects of opioids to increase adherence to medication. However, preventative therapy for the management of nausea and vomiting has not been specified. This study aimed to verify the effects of prophylactic anti-emetics in preventing opioid-induced nausea and vomiting. Patients and methods We conducted a retrospective analysis of cases at our hospital in which oral opioids or patches were initiated for the management of pain due to malignant tumours from January 2017 to September 2019. Results Strong opioids were initiated for 349 patients; of these, data for 298 patients were analysed. A total of 193 patients were on anti-emetic prophylaxis. We found that the group that did not receive anti-emetic prophylaxis was significantly more likely to be prescribed an additional anti-emetic. Conclusion Prophylactic administration of anti-emetics at the time of initiating opioid analgesics may reduce gastrointestinal toxicity.

Heerfordt's syndrome is a rare subtype of sarcoidosis and features a combination of facial palsy, parotid swelling, and uveitis, associated with a low-grade fever. Cases with two of three symptoms are called "incomplete Heerfordt's syndrome." Heerfordt's syndrome involving other cranial nerve symptoms is relatively rare. We herein report a case of incomplete Heerfordt's syndrome presenting with trigeminal nerve palsy and a reversed halo sign, a rare manifestation of pulmonary sarcoidosis. The histological diagnosis following a biopsy of the parotid gland and endobronchial ultrasound-guided trans-bronchial needle aspiration of the mediastinal lymph nodes was sarcoidosis. The symptoms and lung lesions improved after corticosteroid therapy.

Some patients discontinue receiving osimertinib for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) Thr790Met (T790M) mutation due to adverse its effects. We report a case of successful desensitization therapy after osimertinib-induced urticaria. An 85-year-old Japanese woman received osimertinib as third-line therapy for NSCLC with the EGFR T790M mutation. After two days, she developed urticaria of the lower extremities. We started osimertinib desensitization therapy at 0.1 mg/day, which was gradually increased to 40 mg/day. She continued osimertinib for >12 months without adverse effects. Desensitization therapy with osimertinib could be useful for patients experiencing osimertinib-induced urticaria.

The role of pembrolizumab in the treatment of poor performance status (PS) patients remains unclear.We conducted a phase II trial to investigate the efficacy and safety of pembrolizumab as first-line therapy for non-small-cell lung cancer (NSCLC) patients with PSs of 2-3 and programmed cell death ligand 1 (PD-L1) expression ≥ 50%. The primary endpoint of this study was the objective response rate (ORR).Fourteen patients treated at eight institutions were enrolled. Most patients had PS 2 (12/14; 86%) and others had PS 3 (2/14; 14%). The ORR was 57.1% (95% confidence interval 28.9-82.3%), which met the primary endpoint. The median progression-free survival (PFS) and 1-year PFS rates were 5.8 months and 20.0%, respectively. At the time of data cut-off, one patient had received treatment for more than 1 year; another patient had received treatment for more than 2 years. Nine patients had improved PS with treatment (Wilcoxon signed-rank test, p = 0.003). Two patients had immune-related adverse events ≥ grade 3: grades 5 and 3 elevation in alanine and aspartate aminotransferases. Two PS 3-stage patients were diagnosed with clinically progressive disease prior to initial computed tomography; both died within 2 months.Pembrolizumab was effective for the treatment of NSCLC patients with a poor PS and PD-L1 level ≥ 50%. However, given the poor outcomes of the PS 3 patients, the drug is not indicated for such patients. Adverse events, including liver dysfunction, should be carefully monitored.UMIN000030955.

Simple Summary Minimal data exists on pleural effusion (PE) for non-small cell lung cancer (NSCLC) patients undergoing combined ICI and chemotherapy. We retrospectively investigated how PE affects survival outcomes in patients with NSCLC undergoing this combined therapy. We identified 478 patients who underwent combined ICI therapy and chemotherapy; 357 patients did not have PE, and 121 patients did have PE. Patients with PE had significantly shorter progression-free survival and overall survival than those without PE. In addition, bevacizumab-containing regimens did not improve the survival outcomes for patients with PE. In conclusion, PE was associated with poor outcomes among patients with NSCLC undergoing combined ICI therapy and chemotherapy. Objectives: Combined immune checkpoint inhibitor (ICI) therapy and chemotherapy has become the standard treatment for advanced non-small-cell lung cancer (NSCLC). Pleural effusion (PE) is associated with poor outcomes among patients with NSCLC undergoing chemotherapy. However, minimal data exists on PE for patients undergoing combined ICI and chemotherapy. Therefore, we investigated how PE affects survival outcomes in patients with NSCLC undergoing this combined therapy. Methods: We identified patients with advanced NSCLC undergoing chemotherapy and ICI therapy from the Okayama Lung Cancer Study Group-Immune Chemotherapy Database (OLCSG-ICD) between December 2018 and December 2020; the OLCSG-ICD includes the clinical data of patients with advanced NSCLC from 13 institutions. Then, we analyzed the treatment outcomes based on the presence of PE. Results: We identified 478 patients who underwent combined ICI therapy and chemotherapy; 357 patients did not have PE, and 121 patients did have PE. Patients with PE had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without PE (median PFS: 6.2 months versus 9.1 months; p < 0.001; median OS: 16.4 months versus 27.7 months; p < 0.001). The negative effect of PE differed based on the patient's programmed cell death-ligand 1 (PD-L1) expression status; with the effect being more evident in patients with high PD-L1 expression. In addition, PFS and OS did not differ between patients who did and did not undergo bevacizumab treatment; thus, bevacizumab-containing regimens did not improve the survival outcomes for patients with PE. Conclusion: PE is associated with poor outcomes among patients with NSCLC undergoing combined ICI therapy and chemotherapy.

4‐Methyltetrahydropyran (4‐MeTHP) is a hydrophobic cyclic ether with potential for industrial applications. We herein report, for the first time, a comprehensive study on the performance of 4‐MeTHP as an organic reaction solvent. Its broad application to organic reactions includes radical, Grignard, Wittig, organometallic, halogen‐metal exchange, reduction, oxidation, epoxidation, amidation, esterification, metathesis, and other miscellaneous organic reactions. This breadth suggests 4‐MeTHP can serve as a substitute for conventional ethers and harmful halogenated solvents. However, 4‐MeTHP was found incompatible with strong Lewis acids, and the C−O bond was readily cleaved by treatment with BBr3. Moreover, the radical‐based degradation pathways of 4‐MeTHP, THP and 2‐MeTHF were elucidated on the basis of GC‐MS analyses. The data reported herein is anticipated to be useful for a broad range of synthetic chemists, especially industrial process chemists, when selecting the reaction solvent with green chemistry perspectives., Organic pastures greener: A comprehensive study on the performance of 4‐methyltetrahydropyran (4‐MeTHP) as a reaction solvent is described. The broad applications and higher stability under free‐radical conditions make this solvent a promising alternative to common organic solvents. This study provides key data for process chemists in choosing a reaction solvent under green chemistry perspectives.

Bacterial catalase is important for intracellular survival of the bacteria. This protein of Propionibacterium acnes, one of possible causes of sarcoidosis, induces hypersensitive Th1 immune responses in sarcoidosis patients. We examined catalase expression in cultured P. acnes isolated from 19 sarcoid and 18 control lymph nodes and immunohistochemical localization of the protein in lymph nodes from 43 sarcoidosis and 102 control patients using a novel P. acnes-specific antibody (PAC) that reacts with the catalase protein, together with the previously reported P. acnes-specific PAB and TIG antibodies. High catalase expression of P. acnes cells was found during stationary phase in more isolates from sarcoid than from non-sarcoid lymph nodes and was associated with bacterial survival under H2O2-induced oxidative stress. In many sarcoid and some control lymph nodes, catalase expression was detected at the outer margins of PAB-reactive Hamazaki-Wesenberg (HW) bodies in sinus macrophages, the same location as catalase expression on the surface of cultured P. acnes and the same distribution as bacterial cell membrane-bound lipoteichoic acid in HW bodies. Some or no catalase expression was detected in sarcoid granulomas with PAB reactivity or in clustered paracortical macrophages packed with many PAB-reactive small-round bodies. HW bodies expressing catalase may be persistent P. acnes in sinus macrophages whereas PAB-reactive small-round bodies with undetectable catalase may be activated P. acnes proliferating in paracortical macrophages. Intracellular proliferation of P. acnes in paracortical macrophages may lead to granuloma formation by this commensal bacterium in sarcoidosis patients with Th1 hypersensitivity to certain P. acnes antigens, including catalase.

Key Clinical Message The natural history of idiopathic peripheral pulmonary arterial aneurysms (PAAs) is unclear; however, they can cause sudden death by rupture. Our case illustrates the utility and low invasiveness of transcatheter embolization using an AMPLATZER™ Vascular Plug 4 and hydrogel‐coated metallic coils in patients with idiopathic peripheral PAAs.

Cases of inferior phrenic artery-to-pulmonary artery fistulas and those complicated by massive hemoptysis have been rarely reported. A 38-year-old man presented to our hospital with a chief complaint of coughing. Computed tomography (CT) revealed a nodule in the left lower lobe, and contrast-enhanced CT showed inflow of contrast medium into the nodule. CT angiography detected an aneurysm associated with a left inferior phrenic artery-to-left pulmonary artery fistula. Transcatheter arterial embolization (TAE) was performed to prevent hemoptysis. Hemoptysis did not occur during the 2-year follow-up. We report a rare case of asymptomatic aneurysm associated with a left inferior phrenic artery-to-left pulmonary artery fistula, which was successfully treated using TAE to prevent hemoptysis.

Necrotizing sarcoid granulomatosis (NSG) is a rare disease that presents with nodular lung lesions and necrosis. The pathology is consistent with sarcoidosis, but the necrosis can lead to a diagnosis of tuberculosis. Herein, we report a rare case of NSG that recurred four years after the initial diagnosis was made by surgical lung biopsy. A 51-year-old woman was initially referred to our hospital for the evaluation of multiple lung nodules. The pathological evaluation of a lung biopsy showed granulomas with necrosis and the infiltration of lymphocytes; thus, she was diagnosed with NSG. The lung nodules gradually improved after the diagnosis and we continued to follow her even though she did not require treatment. Four years after her initial diagnosis, she complained of back pain. Upon evaluation, we found that multiple lung nodules had recurred. Bronchoscopy also revealed a tracheal polypoid lesion, which showed granulomas with necrosis pathologically. Therefore, we diagnosed her with the recurrence of NSG. After the corticosteroid therapy, multiple lung nodules drastically improved. NSG patients should be carefully followed-up over several years, even if they do not require treatment.

Crohn’s disease (CD) is a gastrointestinal disorder of unknown etiology. CD-specific longitudinal ulcers show an association between disease pathogenesis and vasculature dysfunction. Granulomatous lymphangitis may also contribute to CD pathogenesis; meanwhile, vasculitis is the primary CD lesion. We investigated the association between granulomas and lymphatic and blood vessels to assess the role of vasculature in CD pathogenesis. Two small and large intestine specimens were obtained from four CD patients. From each specimen, 160 sequential sections were obtained and double immunohistochemical stained to label lymphatic and blood vessels in association with granulomas. We found that 289 of 342 granulomas (85%) were associated with a lymphatic vessel and 313 of 364 granulomas (86%) were associated with a blood vessel. Although intrablood vessel granulomas were not detected, intralymphatic vessel granulomas were. In the internal region of the granuloma, we found more blood vessels than lymphatic vessels. Hence, these results cumulatively demonstrate that CD epithelioid cell granulomas are differentially associated with lymphatic and blood vessels, suggesting both as essential for the formation and maintenance of these granulomas. Moreover, both lymphatic and blood vessels may participate in granulomatous inflammation in the primary CD lesions; however, additional studies with larger numbers of participants are required to validate our findings.

Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a key therapy used for patients with EGFR-mutant non-small cell lung cancer (NSCLC), some of whom do not respond well to its therapy. Cytokine including IL-6 secreted by tumour cells is postulated as a potential mechanism for the primary resistance or low sensitivity to EGFR-TKIs. Fifty-two patients with advanced EGFR-mutant NSCLC who had received gefitinib were assessed retrospectively. The protein expression of IL-6 in the tumour cells was assessed by immunostaining and judged as positive if ≥ 50 of 100 tumour cells stained positively. Of the 52 patients, 24 (46%) and 28 (54%) were defined as IL-6-postitive (group P) and IL-6-negative (group N), respectively. Group P had worse progression-free survival (PFS) than that of group N, which was retained in the multivariate analysis (hazard ratio: 2.39; 95 %CI: 1.00-5.68; p 0.05). By contrast, the PFS after platinum-based chemotherapy did not differ between groups P and N (p = 0.47). In cell line-based model, the impact of IL-6 on the effect of EGFR-TKIs was assessed. The combination of EGFR-TKI and anti-IL-6 antibody moderately improved the sensitivity of EGFR-TKI in lung cancer cell with EGFR mutation. Interestingly, suppression of EGFR with EGFR-TKI accelerated the activation of STAT3 induced by IL-6. Taken together, tumour IL-6 levels might indicate a subpopulation of EGFR-mutant NSCLC that benefits less from gefitinib monotherapy.

The practical application of biosensors can be determined by evaluating the sensing ability of fluorophore-modified derivatives of a receptor with appropriate recognition characteristics for target molecules. One of the key determinants for successfully obtaining a useful biosensor is wide variation in the fluorophores attached to a given receptor. Thus, using a larger fluorophore-modified receptor library provides a higher probability of obtaining a practically useful biosensor. However, no effective method has yet been developed for constructing such a diverse library of fluorophore-modified receptors. Herein, we report a method for constructing fluorophore-modified receptors by using a chemical library of synthetic fluorophores with a thiol-reactive group. This library was converted into a library of fluorophore-modified adenosine-binding ribonucleopeptide (RNP) receptors by introducing the fluorophores to the Rev peptide of the RNP complex by alkylation of the thiol group. This method enabled the construction of 263 fluorophore-modified ATP-binding RNP receptors and allowed the selection of suitable receptor-based fluorescent sensors that target ATP.

The central nervous system efficacy of dacomitinib, a key agent used in the treatment of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), is unclear. We herein present our experience in the use of dacomitinib for the treatment of multiple brain metastatic lesions from EGFR-mutation-positive NSCLC in an elderly patient. This case report demonstrates that dacomitinib can be an essential treatment option for patients with brain metastases.

We report the first total syntheses of (+)-isolaurenidificin (1) and (-)-bromlaurenidificin (2), the latest acetogenins of the 2,6-dioxabicyclo[3.3.0]octane class. The synthesis features a completely stereoselective one-pot epimerization-ring contraction to establish the cis configuration with respect to C10-H and C12-H of the tetrahydrofuran ring. Six stereogenic centers and an olefin geometry were constructed in a highly stereoselective manner. Absolute configurations of the natural products were deduced by the comparison of NMR data and specific rotations.

Background Cation transport regulator 1 (CHAC1), a newly discovered enzyme that degrades glutathione, is induced in Helicobacter pylori (H. pylori)‐infected gastric epithelial cells in culture. The CHAC1‐induced decrease in glutathione leads to an accumulation of reactive oxygen species and somatic mutations in TP53. We evaluated the possible correlation between H. pylori infection and CHAC1 expression in human gastric mucosa. Materials and Methods Both fresh‐frozen and formalin‐fixed paraffin‐embedded tissue samples of gastric mucosa with or without H. pylori infection were obtained from 41 esophageal cancer patients that underwent esophago‐gastrectomy. Fresh samples were used for real‐time polymerase chain reaction for H. pylori DNA and CHAC1 mRNA, and formalin‐fixed samples were used for immunohistochemistry with anti‐CHAC1 and anti‐H. pylori monoclonal antibodies. Double‐enzyme or fluorescence immunohistochemistry and immuno‐electron microscopy were used for further analysis. Results Significant CHAC1 overexpression was detected in H. pylori‐infected parietal cells that expressed the human proton pump/H,K‐ATPase α subunit, whereas a constitutively low level of CHAC1 mRNA expression was observed in the other samples regardless of the H. pylori infection status, reflecting the weak CHAC1 expression detected by immunohistochemistry in the fundic‐gland areas. Immuno‐electron microscopy revealed intact H. pylori cells in the secretory canaliculi of infected parietal cells. Some parietal cells exhibited positive nuclear signals for Ki67 in the neck zone of the gastric fundic‐gland mucosa with H. pylori infection. Conclusion Cation transport regulator 1 overexpression in H. pylori‐infected parietal cells may cause the H. pylori‐induced somatic mutations that contribute to the development of gastric cancer.

Objectives: Cortical actin is a thin layer of filamentous (F-)actin that lies beneath the plasma membrane, and its role in pathophysiology remains unclear. We investigated the subcellular localization of cortical actin by the histopathological and experimental studies of lung adenocarcinomas. Materials and Methods: The subcellular localization of cortical actin was studied in surgically resected lung adenocarcinomas tissues and in 3-dimensionally cultured lung adenocarcinoma A549 cells. Results: In normal type II alveolar cells and the bronchiolar epithelium, cortical actin was localized to the apical-side cytoplasm. In invasive adenocarcinoma cells, cortical actin was frequently localized to the matrix side. The degree of cortical actin localized to the matrix side was associated with the loss of basement membrane and a poor prognosis. In A549 cell spheroids cultured in a type I collagen and basement membrane extract Matrigel™ mixed gel, cortical F-actin was localized to the matrix side with phosphorylated myosin light chain. Super-resolution and electron microscopy results suggest that compact wrinkling of the plasma membrane by myosin-mediated F-actin contraction is an explanation for cortical actin accumulation at the matrix side. The myosin II inhibitor blebbistatin suppressed the 3-dimensional collective migration of A549 cells induced by constitutively active Cdc42 and MT1-MMP. Conclusion: Cortical actin accumulation at the matrix-side cytoplasm of cancer cells occurs in invasive lung adenocarcinomas and it possibly participates in the migration of cancer cells through myosin-mediated contraction.

For lung cancer patients with epidermal growth factor receptor (EGFR) mutations, the advent of EGFR tyrosine kinase inhibitors (TKIs) has prolonged survival rates. Even though disease sites have been well controlled by EGFR-TKIs, some patients develop carcinomatous meningitis, which reduces their quality of life drastically. Although multidisciplinary approaches have improved patient survival and quality of life, the outcomes are not yet satisfactory. We report the case of a 54-year-old Japanese woman diagnosed with leptomeningeal metastases (LM) from a lung adenocarcinoma harboring an EGFR exon 21 L858R point mutation. She was treated with gefitinib for 2 months, and symptoms of LM emerged during the treatment period. Although the treatment was switched to erlotinib, disturbance of consciousness worsened because of progressive hydrocephalus. Because all extracranial lesions remained responsive to treatment, and the exon 20 T790M point mutation was not detected in cerebrospinal fluid, we placed a ventriculoperitoneal shunt. The patient's disturbed consciousness improved dramatically after the shunt was placed; however, the optic and auditory nerve impairments due to direct invasion of LM lesions into nerve canals persisted. Administration of bevacizumab subsequent to whole-brain radiotherapy reduced the cranial nerve impairment, and the patient survived for 10 months. In conclusion, a combination of erlotinib and ventriculoperitoneal shunt was effective for hydrocephalus, and the immediate administration of additional therapies, including bevacizumab and radiation therapy, was useful in a patient suffering from LM.

The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non‑small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC‑ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54‑81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post‑operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC‑ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC‑ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC‑ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult.

Adenocarcinoma within anorectal fistulae is rare and is sometimes associated with Crohn’s disease. Crohn’s disease-associated adenocarcinoma within anorectal fistulae has a poor prognosis; however, little is known about the clinicopathological differences between Crohn’s disease-associated adenocarcinoma within anorectal fistulae and usual adenocarcinoma within anorectal fistulae. We retrospectively searched patients’ charts and pathology archives at Tokyo Yamate Medical Center and Tokyo Medical and Dental University Hospital for adenocarcinoma within anorectal fistulae. Clinical and pathological data were collected and immunohistochemical examinations were conducted. Overall survival rate was estimated using the Kaplan–Meier method. Prognostic factors of overall survival were assessed using univariate and multivariate Cox regression analyses. We examined 82 cases of adenocarcinoma within anorectal fistulae. Fifty-nine of 82 cases (72%) had usual adenocarcinoma within anorectal fistulae, while the remaining 23 cases (28%) had Crohn’s disease-associated adenocarcinoma within anorectal fistulae. Patients with Crohn’s disease-associated adenocarcinoma within anorectal fistulae were diagnosed at a younger age and at a more advanced stage than those with usual adenocarcinoma within anorectal fistulae. Macroscopic and histological types were also different between usual adenocarcinoma within anorectal fistulae and Crohn’s disease-associated adenocarcinoma within anorectal fistulae. Crohn’s disease-associated adenocarcinoma within anorectal fistulae included more ulcerative types and high-grade adenocarcinomas. The rate of lymphovascular invasion was higher in Crohn’s disease-associated adenocarcinoma within anorectal fistulae. Immunohistochemically, the expression of E-cadherin, p53, and MUC5AC differed between usual adenocarcinoma within anorectal fistulae and Crohn’s disease-associated adenocarcinoma within anorectal fistulae. Patients with Crohn’s disease-associated adenocarcinoma within anorectal fistulae exhibited worse overall survival than those with usual adenocarcinoma within anorectal fistulae, and vascular invasion was the strongest significant independent predictor of overall survival in patients with adenocarcinoma within anorectal fistulae. In conclusion, usual adenocarcinoma within anorectal fistulae and Crohn’s disease-associated adenocarcinoma within anorectal fistulae have different clinicopathological characteristics and should be considered separate clinical entities.

Purpose To evaluate associations of Ki-67 expression with oncologic outcomes in muscle-invasive bladder cancer (MIBC) patients treated with chemoradiotherapy (CRT)-based bladder-sparing protocol. Materials and Methods Between 1998 and 2011, 190 consecutive MIBC patients were treated with CRT-based bladder-sparing protocol. After transurethral resection of the bladder tumor, the patients underwent induction CRT (40 Gy with concurrent cisplatin) followed by partial cystectomy for bladder preservation or radical cystectomy (RC). Included in this study were 94 patients who were histologically diagnosed with urothelial carcinoma and whose tumor tissues before CRT were available for immunohistochemical evaluation of Ki-67 expression status. Results After induction CRT, 16 (17%) and 53 (56%) patients underwent partial cystectomy and RC, respectively, while the remaining 25 (27%) did not undergo cystectomy. Successful bladder preservation was achieved in 34 patients (36%). Higher Ki-67 labeling index (LI) independently predicted CRT response clinically and pathologically. Among the clinicopathologic variables available before CRT and cystectomy, high Ki-67 LI (≥ 20%) was independently associated with better cancer-specific survival (CSS) (5-year CSS rate, 78% vs. 46% for low Ki-67 LI; P = .019). The difference in CSS according to Ki-67 expression status was more remarkable in patients with cT3 disease (5-year CSS rate, 72% vs. 29%; P = .0098). Conclusion High Ki-67 expression predicts favorable CSS in MIBC patients treated with CRT-based bladder-sparing protocol. MIBC patients with high Ki-67 expression status might benefit from CRT-based multimodal approaches in terms of prognosis and quality of life as a result of bladder preservation.

In the present study, we demonstrate a novel use for a commercially available glutaminase that can be used as a γ-glutamyltranspeptidase in kokumi seasoning production. Soy protein and gluten were hydrolyzed using a protease isolated from Bacillus licheniformis. The resulting protein hydrolysates were γ-glutamylated with a γ-glutamyltranspeptidase, which is sold as a glutaminase from Bacillus amyloliquefaciens, to produce kokumi seasonings. For γ-glutamylation of soy protein hydrolysate, glutamine was added to the reaction mixture. On the other hand, reaction conditions for enzymatic proteolysis were optimized to liberate glutamine from gluten in large amounts, and the addition of glutamine was not required for γ-glutamylation of gluten hydrolysate. The soy protein and gluten hydrolysates as well as their γ-glutamylated products were subjected to taste evaluation. Soy protein hydrolysates were bitter. Although γ-glutamylation significantly reduced bitterness, the taste was still considered unfavorable. γ-Glutamylated gluten hydrolysate is the most preferable sample and had significantly enhanced thickness, kokumi, and umami tastes, with a moderate increase in saltiness.

Functional screening of structurally diverse libraries consisting of proteins or nucleic acids is an effective method to obtain receptors or aptamers with unique molecular recognition characteristics. However, further modification of these selected receptors to exert a newly desired function is still a challenging task. We have constructed a library of structurally diverse ribonucleopeptides (RNPs) that are modified with a catalytic group, in which the catalytic group aligns with various orientations against the ATP binding pocket of RNA subunit. As a proof-of-principle, the screening of the constructed RNP library for the catalytic reaction of ester hydrolysis was successfully carried out. The size of both the substrate-binding RNA library and the catalytic group modified peptide library are independently expandable, and thus, the size of RNPs library could be enlarged by a combination of these two subunits. We anticipate that the library of functionalized and structurally diverse RNPs would be expanded for various other catalytic reactions.