Real-world evidence of safety and influence for lung cancer surgery under COVID-19 pandemic in Japan.

Background: The COVID-19 pandemic has affected the clinical practice of lung cancer surgery in Japan, but few studies have revealed the real situation of surgical practice for lung cancer in this country. This latest information will help us to decide the future direction of lung cancer surgery under pandemic circumstances. Methods: We collected data from patients with primary lung cancer who underwent thoracic surgery between 2018 and 2021. To investigate the impact of the COVID-19 pandemic on lung cancer surgery, we compared between 2018-2019 (prepandemic group) and 2020-2021 (pandemic group) in the respect of patient characteristics, pathological findings, and short-term outcome after lung cancer resection by Mann-Whitney and Fisher's exact tests. Moreover, the monthly number of surgeries for lung cancer in our institution during 2020-2021 was compared with the number of newly diagnosed COVID-19 patients in Japan by Spearman correlation analysis. Results: From 2018 through 2021, 936 patients with primary lung cancer underwent surgical intervention in our institute and were included in this study. The number of surgeries did not decrease in the pandemic group (n=443) compared with that in the prepandemic group (n=493). Tumor and invasive size in stage I which was measured by pathologist were significantly larger in the pandemic group than in the prepandemic group (tumor size: P=0.031, invasive size: P<0.001). In terms of postoperative short-term outcome, the median hospital stay was 6 days, 30-day mortality was 2, and morbidity was around 20% in both groups. Only one patient suffered from COVID-19 infection 5 months after right upper lobectomy. An increased ratio of newly diagnosed COVID-19 cases in Japan was negatively correlated with the number of surgeries for lung cancer in our institution in the next month (r=-0.393, P=0.007), although there was no correlation in the present or the month after next. Conclusions: Even during the COVID-19 pandemic period, lung cancer surgery could be performed safely and in a sustainable manner. However, pathological findings of lung cancer tended to be progressive in early-stage lung cancer.

A novel cell-based assay for the high-throughput screening of epithelial-mesenchymal transition inhibitors: Identification of approved and investigational drugs that inhibit epithelial-mesenchymal transition.

OBJECTIVES: Lung cancer with distant metastases is associated with a very poor prognosis, and epithelial-mesenchymal transition (EMT) contributes to cancer metastasis. Therefore, elucidation and inhibition of EMT signaling in lung cancer may be a new therapeutic strategy for improving the prognosis of patients. We constructed a high-throughput screening system for EMT inhibitors. Using this system, we aimed to identify compounds that indeed inhibit EMT. MATERIALS AND METHODS: We generated a luciferase reporter cell line using A549 human lung cancer cells and E-cadherin or vimentin as EMT markers. EMT was induced by transforming growth factor ß1 (TGF-ß1), and candidate EMT inhibitors were screened from a library of 2,350 compounds. The selected compounds were further tested using secondary assays to verify the inhibition of EMT and invasive capacity of cells. RESULTS: Values obtained by the assay were adjusted for the number of viable cells and scored by determining the difference between mean values of the positive and negative control groups. Four compounds were identified as novel candidate drugs. Among those, one (avagacestat) and two compounds (GDC-0879 and levothyroxine) improved the expression of E-cadherin and vimentin, respectively, in epithelial cells. GDC-0879 and levothyroxine also significantly inhibited the invasive capacity of cells. CONCLUSION: We systematically screened approved, investigational, and druggable compounds with inhibitory effects using a reporter assay, and identified candidate drugs for EMT inhibition.

Nrf2/p­Fyn/ABCB1 axis accompanied by p­Fyn nuclear accumulation plays pivotal roles in vinorelbine resistance in non­small cell lung cancer.

Adjuvant cisplatin­vinorelbine is a standard therapy for stage II/III lung cancer. However, a poor survival rate of patients with lung cancer is attributed to vinorelbine resistance arising from ATP­binding cassette (ABC) sub­family B member 1 (ABCB1) and phosphorylated Fyn (p­Fyn) overexpression. However, the underlying mechanisms remain unclear. NF­E2­related factor 2 (Nrf2) regulates the ABC family and activates the nuclear transport of Fyn. The present study evaluated the roles of the Nrf2/p­Fyn/ABCB1 axis in vinorelbine­resistant (VR) cells and clinical samples. To establish VR cells, H1299 cells were exposed to vinorelbine, and the intracellular reactive oxygen species (ROS) level in the H1299 cells was determined using a DCFH­DA assay. The total and subcellular expression of Nrf2, ABCB1 and p­Fyn in VR cells was evaluated. Immunofluorescence was used to detect the subcellular localization of p­Fyn in VR cells. A cell viability assay was used to examine whether the sensitivity of VR cells to vinorelbine is dependent on Nrf2 activity. Immunohistochemistry was performed on 104 tissue samples from patients with lung cancer who underwent surgery followed by cisplatin­vinorelbine treatment. The results revealed that persistent exposure to vinorelbine induced intracellular ROS formation in H1299 cells. p­Fyn was localized in the nucleus, and ABCB1 and Nrf2 were overexpressed in VR cells. ABCB1 expression was dependent on Nrf2 downstream activation. The decreased expression of Nrf2 restored the sensitivity of VR cells to vinorelbine. In the surgical samples, Nrf2 and ABCB1 were associated with disease­free survival, and p­Fyn was associated with overall survival (P<0.05). On the whole, the present study demonstrates that Nrf2 upregulates ABCB1 and, accompanied by the nuclear accumulation of p­Fyn, induces vinorelbine resistance. These findings may facilitate the development of drug resistance prevention strategies or new drug targets against non­small cell lung cancer.

High programmed death ligand 1 expression in carcinomatous components predicts a poor prognosis in pulmonary pleomorphic carcinoma.

PURPOSE: This study reviewed the clinicopathological characteristics and programmed death ligand 1 (PD-L1) expression of 46 patients with pulmonary pleomorphic carcinoma to better understand its clinical behavior and factors affecting the survival. METHODS: Data of patients with pulmonary pleomorphic carcinomas resected in our institution were retrospectively reviewed. The tumors were classified as carcinomatous or sarcomatous according to the tissue components. Pathological characteristics were evaluated on hematoxylin and eosin-stained sections. The percentages of tumor cells with membrane staining for PD-L1 in carcinomatous and sarcomatous components were determined. RESULTS: We reviewed data of 46 patients (41 males, 5 females; median age 70.5 years old, range 36-83 years old). Most patients with pulmonary pleomorphic carcinoma expressed PD-L1 (80.4%), and the proportion of PD-L1 expression in tumor cells was significantly higher in sarcomatous components than in carcinomatous components. In univariable analyses, high p-stage (III), necrosis on pathological findings, and high PD-L1 expression in carcinomatous components (≥ 50%) were poor prognostic factors for the overall survival. In multivariable analyses, high PD-L1 expression in carcinomatous components was significantly associated with a poor prognosis after surgery. CONCLUSIONS: High PD-L1 expression in carcinomatous components was significantly associated with a poor prognosis after surgery.

Expanded indications for lung transplantation for pulmonary complications after hematopoietic stem cell transplantation.

OBJECTIVES: Pulmonary complications after hematopoietic stem cell transplantation (HSCT) are associated with poor survival and can be treated by lung transplantation (LT). However, the indications for LT in patients with pulmonary complications after HSCT remain unclear due to low number of cases. HSCT is frequently conducted for hematologic malignancies, which have different recurrence patterns from solid-organ malignancies. Some patients also experience ABO blood type changes post-HSCT. This study aimed to reassess the indication of LT for pulmonary complications post-HSCT, focusing on disease-free interval (DFI) and ABO-incompatibility. METHODS: Retrospective chart reviews were performed in patients who underwent LT for post-HSCT pulmonary complications. In patients with previous hematologic malignancy, indication was based on estimated recurrence rate instead of DFI. Donors were selected based on the recipient anti-A/B antibody profile rather than ABO type. Post-LT survival and complication rates were examined. RESULTS: Forty consecutive patients undergoing LT after HSCT (including 31 with previous hematologic malignancy) were analyzed. The median DFI between HSCT and LT was 64.5 months. Thirteen patients with previous hematologic malignancy had DFI <5 years but none experienced recurrence. There was no significant difference in 5-year post-LT survival between patients undergoing (74.7%) and not undergoing HSCT (68.4%). There was no significant difference in survival between patients with DFI ≥5 years (63.8%) and patients with DFI <5 years (83.3%). Five patients underwent LTs from major ABO-incompatible donors, but none developed incompatibility-related complications. CONCLUSIONS: Indications based on estimated recurrence rates and recipients' anti-A/B antibody profiles may increase the use of LT for patients after HSCT.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors as a first-line treatment for postoperative recurrent and EGFR-mutated non-small-cell lung cancer.

OBJECTIVES: To clarify survival outcomes and prognostic factors of patients receiving epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitors (TKIs) as first-line treatment for postoperative recurrence. METHODS: A retrospective chart review was performed to identify consecutive patients who received EGFR-TKIs as first-line treatment for postoperative recurrence of non-small-cell lung cancer (NSCLC) harbouring EGFR gene mutations at our institution between August 2002 and October 2020. Therapeutic response, adverse events, progression-free survival (PFS) and overall survival (OS) were investigated. Survival outcomes were assessed using the Kaplan-Meier analysis. The Cox proportional hazards model was used for univariable and multivariable analyses. RESULTS: Sixty-four patients were included in the study. The objective response and disease control rates were 53% and 92%, respectively. Grade 3 or greater adverse events were noted in 4 (6.3%) patients, including 1 patient (1.6%) of interstitial pneumonia. The median follow-up period was 28.5 months (range 3-202 months). The total number of events was 43 for PFS and 23 for OS, respectively. The median PFS was 18 months, and the median OS was 61 months after EGFR-TKI treatment. In multivariable analysis, osimertinib showed a tendency to prolong PFS [hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.12-1.1; P = 0.071], whereas the micropapillary component was significantly associated with shorter OS (HR 2.1, 95% CI 1.02-6.9; P = 0.045). CONCLUSIONS: EGFR-TKIs as first-line treatment appeared to be a reasonable treatment option in selected patients with postoperative recurrent EGFR-mutated NSCLC. Osimertinib and the micropapillary component may be prognostic factors.

Aberrant expression of MYD88 via RNA-controlling CNOT4 and EXOSC3 in colonic mucosa impacts generation of colonic cancer.

In 2020, the worldwide incidence and mortality of colorectal cancer (CRC) were third and second, respectively. As the 5-y survival rate is low when CRC is diagnosed at an advanced stage, a reliable method to predict CRC susceptibility is important for preventing the onset and development and improving the prognosis of CRC. Therefore, we focused on the normal colonic mucosa to investigate changes in gene expression that may induce subsequent genetic alterations that induce malignant transformation. Comprehensive gene expression profiling in the normal mucosa adjacent to colon cancer (CC) compared with tissue from non-colon cancer patients was performed. PCR arrays and qRT-PCR revealed that the expression of 5 genes involved in the immune response, including MYD88, was increased in the normal mucosa of CC patients. The expression levels of MYD88 were strikingly increased in precancerous normal mucosa specimens, which harbored no somatic mutations, as shown by immunohistochemistry. Microarray analysis identified 2 novel RNA-controlling molecules, EXOSC3 and CNOT4, that were significantly upregulated in the normal mucosa of CC patients and were clearly visualized in the nuclei. Forced expression of EXOSC3 and CNOT4 in human colonic epithelial cells increased the expression of IFNGR1, MYD88, NFκBIA, and STAT3 and activated ERK1/2 and JNK in 293T cells. Taken together, these results suggested that, in the inflamed mucosa, EXOSC3- and CNOT4-mediated RNA stabilization, including that of MYD88, may trigger the development of cancer and can serve as a potential predictive marker and innovative treatment to control cancer development.

Prognostic significance of cribriform adenocarcinoma of the lung: validation analysis of 1,057 Japanese patients with resected lung adenocarcinoma and a review of the literature.

BACKGROUND: Cribriform-predominant adenocarcinoma of the lung (Cribri-ADC) is a recently described tumor growth pattern. However, its prognostic impact has not been clearly determined. We analyzed the data of a series of 1,057 Japanese patients with resected lung adenocarcinoma to identify the clinical significance of Cribri-ADC. METHODS: Cribriform pattern (Cribri-p) is defined as invasive back-to-back fused tumor glands with poorly formed glandular spaces or invasive tumor nests comprising tumors cells that produced glandular lumina. We investigated the correlations of Cribri-p and Cribri-ADC with clinicopathological factors as well as disease-free survival (DFS) and overall survival (OS). RESULTS: Cribri-p was present in 217 patients (20.5%) and Cribri-ADC was determined in 25 patients (2.4%). Cribri-p was associated with larger tumor size, pleural invasion, vascular invasion, lymphatic invasion, and spreading through air spaces (STAS) (all, P<0.0001). Cribri-ADC was associated with younger age (P=0.019), vascular invasion (P=0.0025), STAS (P<0.0001), and ALK rearrangement (P=0.012). The DFS curve of patients with Cribri-ADC was identical to that of patients with solid adenocarcinoma; however, the OS curve was located between that of patients with papillary and acinar adenocarcinoma. Of the 10 patients who had tumor recurrences, eight had EGFR mutations or ALK rearrangement, six of whom achieved relatively long survival (median, 64.6, range, 37.4-113 months) following treatment with tyrosine kinase inhibitors (TKIs). In multivariate analysis, Cribri-ADC was not an independent prognostic factor of either recurrence or death. CONCLUSIONS: Cribri-ADC is associated with a higher risk of recurrence; however, most patients can be successfully treated with TKIs.

T-cell chimerism prior to graft-versus-host disease.

Graft-versus-host disease (GVHD), a serious complication of haematopoietic stem cell transplantation, can occur following solid organ transplantation. However, diagnosing solid organ transplantation-associated GVHD is difficult, and its risk factors are not fully understood. Here, we report a GVHD case in a 59-year-old woman with dermatomyositis-associated interstitial pneumonia, who took immunosuppressants including corticosteroids before receiving right lung transplantation from a 13-year-old brain-dead male donor. She developed systemic erythema with desquamation and pancytopenia by day 20. Mixed chimerism with donor- and recipient-type cells in the bone marrow and skin led to the diagnosis of GVHD. Corticosteroid pulse therapy reduced the symptoms and decreased donor-type cell percentage. On day 50, the patient developed donor lung injury and was diagnosed with acute rejection, which was treated using steroid pulse therapy again. Although the granulocytes were recipient type, donor chimerism of peripheral blood T cells exacerbated on day 68. Subsequent deterioration of liver function and pulmonary injury in the patient's own lung led to the diagnosis of relapsing GVHD. The patient died of multiple organ failure despite treatment with anti-thymocyte globulin. Thus, repeated steroid pulse therapy and age difference between donors and recipients may predispose to GVHD and T-cell mixed chimerism can be an important diagnostic indicator of GVHD.

Skin marking with computed tomography at functional residual capacity to predict lung nodule site.

Various marking techniques for lung nodules may be complex and can cause serious complications. In this study, we aimed to describe and evaluate the feasibility of CTFRC marking, a novel preoperative skin marking technique guided by computed tomography (CT) at functional residual capacity (FRC). This simple and non-invasive marking technique only requires a preoperative CT scan without any anaesthesia. We retrospectively reviewed CTFRC markings performed for 109 lung nodules in 108 patients. The mean nodule size was 11.4 ± 5.0 mm. The mean distance from the nodule to the lung marking point was 3.8 ± 7.3 mm. We found no procedure-associated complications. CTFRC marking is a simple, safe and non-invasive method to predict the precise location of lung nodules during thoracoscopic surgery.

Pulmonary vein thrombosis after lobectomy with vein stump closure by ligation.

Objectives Thrombosis in the pulmonary vein stump after a left upper lobectomy is a rare but potentially life-threatening complication, and the pulmonary vein stump length plays an important role here. We assessed the frequency and risk factors for thrombosis in patients undergoing lobectomy with division of the superior pulmonary vein using ligation. Methods We retrospectively reviewed 425 patients with primary lung cancer who underwent lobectomy or bilobectomy in our institution from 2008 to 2016, with contrast-enhanced chest computed tomography within a year after lobectomy. The superior pulmonary vein was divided by thread ligation, while the inferior pulmonary vein was divided using a linear stapler. The pulmonary vein stump length was measured using contrast-enhanced chest computed tomography. Results Four (0.9%) of the 425 patients experienced thrombosis in the pulmonary vein stump within 6 months after lobectomy. All 4 patients had undergone a left upper lobectomy, and 4.1% of this subset developed thrombus. One patient with a thrombus in the pulmonary vein stump experienced renal and cerebral infarction after a left upper lobectomy. The left superior pulmonary vein stump was significantly longer than the other pulmonary vein stumps. Conclusions Thrombosis in the pulmonary vein stump occurred in 4.1% of patients undergoing a left upper lobectomy with pulmonary vein stump closure by thread ligation, which is a relatively low frequency. Superior pulmonary vein stump closure using thread ligation might help prevent pulmonary vein stump thrombus after a left upper lobectomy.

A design for the control of apoptosis in genetically modified Saccharomyces cerevisiae.

We have engineered a system that holds potential for use as a safety switch in genetically modified yeasts. Human apoptotic factor BAX (no homolog in yeast), under the control of the FBP1 (gluconeogenesis enzyme) promoter, was conditionally expressed to induce yeast cell apoptosis after glucose depletion. Such systems might prove useful for the safe use of genetically modified organisms.

Spontaneous whole-lung torsion after massive pleural effusion and atelectasis.

We present a case of whole-lung torsion after massive pleural effusion and atelectasis. A 79-year-old woman with a history of recent pneumonia and pleurisy presented to our hospital and complained of left leg edema and pain that was considered to be vasculitis. A sagittal computed tomography (CT) scan showed that her whole right lung had a 120-degree counterclockwise torsion toward the hilum. We obtained and compared a CT image from the previous doctor. By comparing the CT scans, we determined that lung torsion had progressed gradually. To our knowledge, this is the first report that confirms the progress of whole-lung torsion with CT images.

[Plication of diaphragm for eventration of diaphragm caused by megacolon; report of a case].

A 70-year-old woman with severe respiratory distress was admitted to our hospital by ambulance. Chest X-ray revealed marked elevation of left diaphragm and invagination of megacolon. Colectomy was performed to improve the respiratory distress, but continuous mechanical ventilation was necessary after operation due to hypoxia and hypercapnea. Therefore, plication of diaphragm was additionally performed. With 10 rows of nonabsorbable sutures, 6 to 8 pleats were formed. The following day of operation, she was successfully relieved from the ventilator.

New invagination procedure for pancreaticojejunostomy using only four sutures.

BACKGROUND: Pancreaticoenterostomy remains one of the most stressful parts of pancreatoduodenectomy. We introduce herein a new convenient and secure invagination procedure for pancreaticojejunostomy. METHODS: We performed our new procedure during pancreatoduodenectomy in 15 consecutive patients (7 men, 8 women). The features of the procedure are as follows. First, it is performed using only four sutures. Second, the pancreas stump is invaginated into the jejunum, mainly by two sutures that penetrate the parenchyma and are continuously purse-string sutured to the jejunum. Third, all needle holes on the surface of the pancreas are covered with the jejunal wall. RESULTS: Eight patients were classified as showing no pancreatic fistula, and seven displayed a grade A fistula, according to the International Study Group on Pancreatic Fistula criteria. The median operating time for these 15 patients using the present procedure was about 60 min shorter than that for the previous nine patients who underwent duct-to-mucosa pancreaticogastrostomy in our hospital. CONCLUSIONS: The present method allows pancreaticojejunostomy to be performed swiftly and conveniently.

Inadvertent Ingestion of a Press-Through Package Causing Perforation of the Small Intestine within an Incisional Hernia and Panperitonitis.

A 90-year-old woman was admitted to the emergency department of our hospital with abdominal pain and a fever of up to 39°C. She had a history of hysterectomy about 30 years previously, and redness and swelling were seen at the abdominal median scar. Serum biochemistry showed minor elevation of C-reactive protein and creatine phosphokinase. Abdominal computed tomography (CT) showed an edematous intestinal tract image over the median abdominal wall. Incarcerated incisional hernia and intestinal necrosis were suspected. Therefore, emergency surgery was performed. On laparotomy, abundant purulent ascitic fluid was found. The small intestine was incarcerated about 100 cm orally from the terminal ileum, and a 2-mm perforation was present in the incarcerated small intestine. In addition, some white areas measuring 1 mm were found in the small intestinal wall. A press-through package (PTP) of a tablet was confirmed in the intestinal tract near the perforated area. We removed the PTP through the perforation and performed direct suture. Postoperatively, we retrospectively reviewed the CT image and found a high-density shadow which seemed to represent the PTP.

Long-term survival of resected advanced gastric cancer with hepatic and pancreatic invasion.

A 64-year-old man was transferred to our division with a suspicion of gastric cancer. Computed tomography showed widespread irregular thickening of the stomach walls close to the liver and pancreas. Gastrointestinal fiberscopy showed a type 5 tumor in the upper to lower stomach, histologically diagnosed as tubular adenocarcinoma. Gastric cancer with hepatic and pancreatic invasion was diagnosed. Distant metastasis was not proven and complete resection was planned. At laparotomy, the tumor showed general expanding growth and invasion through the lateral segment of the liver and pancreas. Total gastrectomy and combined resection of the distal pancreas, spleen and left segment of the liver were performed. Hepatic and pancreatic invasion and lymph node metastasis were microscopically proven. Pancreatic fistula occurred postoperatively. On postoperative days 40, he was discharged. He received two cycles of adjuvant tegafur/gimeracil/oteracil chemotherapy. He has had no sign of recurrence for 7 years and 8 months.