Differential treatment responses to immune checkpoint inhibitor (ICI) therapy in a case of multiple primary malignancies: the programmed death ligand-1 (PD-L1) negative ureteral and lung metastasis from a clear cell renal cell carcinoma appearing after robotic-assisted partial nephrectomy progressed after ICI therapy, while synchronous PD-L1-positive primary lung squamous cell carcinoma responded very well to ICI therapy: a case report.

BACKGROUND: Renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC) are representative malignancies that respond well to immune checkpoint inhibitors (ICIs). Research has been conducted to identify biomarkers, such as programmed death ligand-1 (PD-L1), that would allow the response to ICI therapy to be predicted; however, the complex tumor immune system consisting of both host and tumor factors may also exert an influence. CASE PRESENTATION: Computed tomographic imaging (CT) incidentally revealed a left renal mass, and a left pulmonary nodule with multiple lymph node metastases (LNMs). Firstly, video-assisted thoracic surgery revealed a lung tumor invading the chest wall. Histologically, the findings of the tumor were consistent with squamous cell carcinoma (SCC), and immunohistochemistry (IHC) showed positive PD-L1 expression. The renal tumor was excised by robotic-assisted partial nephrectomy (RAPN). Histologically, the renal tumor showed the features of clear cell carcinoma (CCC). Four months after the RAPN, CT revealed left hydronephrosis caused by an enhancing ureteral tumor. Then, multiple right lung metastases appeared, and the left lung tumor increased. Following treatment including atezolizumab, the primary lung SCC and the multiple LNMs almost disappeared completely, while the ureteral and right lung metastases showed progression. The ureteral metastasis was resected by left open nephroureterectomy. Histology of the ureteral tumor revealed features consistent with CCC. Histological examination of the multiple right lung metastases that were resected by partial lobectomy via a small thoracic incision also revealed features consistent with CCC. Two months after nephroureterectomy, a solitary left lung metastasis was treated by nivolumab and ipilimumab. Six months after nephroureterectomy, the patient died of RCC. Further studies of specimens revealed that the tumor cells in the primary RCC and the ureteral and lung metastases showed negative results of IHC for PD-L1. CONCLUSIONS: The responses to ICI therapy of concomitant RCC and NSCLC were quite different. The PD-L1 expression status in individual tumors in cases of multiple primary malignancies (MPMs) may directly predict the response of each malignancy to ICI therapy, because the host immune system, which may affect the response to ICI therapy, could be the same in MPMs.

Development of an artificial portal vein using bioabsorbable polymers.

PURPOSE: During surgical resection of malignant tumors in the hepatobiliary pancreatic region, portal vein resection and reconstruction may be needed. However, there is no alternative to the portal vein. We therefore developed an artificial portal vein that could be used in the abdominal cavity. METHODS: In the experiments, hybrid pigs (n = 8) were included. An artificial portal vein was created using a bioabsorbable polymer sheet (BAPS). Subsequently, the portal vein's anterior wall was excised into an elliptical shape. A BAPS in the form of a patch was implanted at the same site. At 2 weeks (n = 3) and 3 months (n = 5) after the implantation, the BAPS implantation site was resected and evaluated macroscopically and histopathologically. RESULTS: Immediately after the implantation, blood leakage was not detected. Two weeks after implantation, the BAPS remained, and endothelial cells were observed. Thrombus formation was not observed. Three months after implantation, the BAPS had been completely absorbed and was indistinguishable from the surrounding portal vein. Stenosis and aneurysms were not observed. CONCLUSIONS: BAPS can replace a defective portal vein from the early stage of implantation to BAPS absorption. These results suggest that it can be an alternative material to the portal vein in surgical reconstruction.

[A Case of pagetoid Carcinoma of the Breast with Pathological Complete Response by Neoadjuvant Chemotherapy].

We herein report a 63-year-old woman who presented with about 20 mm-sized mass in the right breast and the right nipple with erosion. Preoperative examinations revealed a diagnosis of HER2-type pagetoid carcinoma with axillary lymph node metastasis. After neoadjuvant chemotherapy(pertuzumab, trastuzumab, and docetaxel, followed by adriamycin and cyclophosphamide), a pathological complete response was achieved. The patient was treated with anti-HER2 therapy without recurrence.

[A Case of Robotic Abdominoperineal Resection for Rectal Cancer with Leriche Syndrome].

We report a case of robotic abdominoperineal resection for rectal cancer with Leriche syndrome. Case: A 75-year-old male. Colonoscopy, which was performed due to persistent diarrhea, revealed type 2 lower rectal circumferential tumor. Pathological examination revealed adenocarcinoma. Computed tomography revealed no distant metastasis, and incidentally complete occlusion from the abdominal aorta to both common iliac arteries. He was diagnosed to rectal cancer(RbRaP, cT3N0M0, cStage Ⅱa)with Leriche syndrome. Therefore, robotic abdominoperineal resection(D3 dissection)was performed. There was no complication, and he was discharged 15 days after surgery. Postoperative pathological examination revealed pT3N1asM0, pStage Ⅲb.

[A Case of Perforated Rectal Cancer with Laparoscopic Low Anterior Resection].

We report a case of perforated rectal cancer with laparoscopic low anterior resection. Case: A 60-year-old man was transported to the hospital with a chief complaint of sudden lower abdominal pain. Computed tomography revealed wall thickening of the upper rectum and free air localized around the rectum and fecal mass in the mesorectum. He was diagnosed with perforated rectal cancer. Because of the early onset, young age, and ascites confined to the pelvic floor, we decided to perform laparoscopic low anterior resection(D3 dissection). Intraabdominal observation revealed tumor in the upper rectum with a large rectal perforation 3 cm proximal to the tumor. By using gauze and suction, we were able to complete the surgery with ingenuity laparoscopically. The postoperative course was good, and he was discharged 9 days after surgery. Postoperative pathological examination revealed pT4apN0sM0, pStage Ⅱb. Adjuvant chemotherapy of 8 courses of capecitabine was performed. There has been no recurrence 3 years after surgery.

[A Case of Long-Term Survival Achieved by Multimodal Treatments for Postoperative Lung Metastasis and Mediastinal Lymph Node Metastasis after Surgery for Ascending Colon Cancer].

A 52-year-old male patient with Stage Ⅲc ascending colon cancer underwent laparoscopic right hemicolectomy with D3 lymph node dissection. Adjuvant chemotherapy was administered for 6 months, and no recurrence was observed during the follow-up period. Left lung metastasis was detected and surgically removed 7 years after the initial surgery. He underwent open partial small bowel resection with lymph node dissection when mesenteric lymph node metastasis was identified 2 years later. Although chemotherapy was conducted on the identification of mediastinal lymph node metastasis 2 years later, the mediastinal lymph nodes increased. Although attempted, lymph node dissection was impossible because of the strong adhesion to the trachea. Subsequently, chemotherapy and radiation therapy were administered. However, an infiltration of the mediastinal lymph nodes into the trachea was observed. The patient underwent bronchoscopic laser tumor ablation. The patient died 4 months after the resumption of chemotherapy(18 years after the initial surgery). Mediastinal lymph node recurrence after curative resection for colon cancer is a rare clinical condition. Nevertheless, long-term survival could be achieved by multimodal treatments in such patients.

Plasma exosomal DOK3 reflects immunological states in lung tumor and predicts prognosis of gefitinib treatment.

To identify liquid biomarkers that predict clinical outcomes of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), we enrolled patients with EGFR gene mutation-positive non-small-cell lung cancer who were intended to receive gefitinib treatment. Using plasma samples obtained prior to gefitinib treatment from 12 enrolled patients, we performed comprehensive proteomic analysis of plasma exosomes to explore proteins correlating with tumor reduction rate (TRR), progression-free survival (PFS), or overall survival (OS). Of the detected 1769 proteins, 119, 130, or 119 proteins demonstrated a strong correlation (|r| > 0.5) with TRR, PFS, or OS, respectively. Interestingly, 34 (29%), 41 (32%), or 27 (23%) of them, respectively, were functionally involved in the regulation of the immune response. CD8α chain was consistently listed as a molecule positively correlated with PFS and OS, suggesting that the long-lasting effects of gefitinib may be due to the antitumor effects of CD8+ T cells, as well as the induction of immunogenic apoptosis of tumor cells by blocking the EGFR signaling pathway. Notably, Doking Protein 3 (DOK3), a molecule involved in B-cell receptor signaling, and some immunoglobulin and complement molecules exhibited a clear correlation with PFS longevity of gefitinib treatment. Indeed, the strong expression of DOK3 in B cells was confirmed within tertiary lymphoid structures of lung cancer tissues derived from patients with long PFS. These findings suggest that the patients with active B-cell and T-cell immunity as a host immunological feature are more likely to benefit from gefitinib therapy. Circulating exosomal DOK3 has the potential as a predictive marker of response to gefitinib indicating this immunological feature.

[A Case of Successful Collective Treatment of Rectal Cancer Diagnosed by Liver Abscess].

A 67-year-old woman was found to have multiple liver abscess and pneumonia. Liver abscess was improved after percutaneous transhepatic abscess drainage(PTAD). A diagnosis of rectal cancer was made by colonoscopy and the patient underwent colostomy for rectal cancer on February 2018. Laparoscopic low anterior resection was performed on July 2019 after mFOLFOX plus bevacizumab(BEV)14 courses. Lower leaf partial lung resection was performed on September 2019 and upper leaf partial resection was performed on September 2020 for lung metastasis. The patient is currently alive without relapse after 21 months. Liver abscess was caused by portal vein infection of rectal cancer. Effective chemotherapy with surgery was successful.

[A Case in Which a Laparotomy Transition, in a Patient with Sigmoid Colon Cancer, Prevented Peritoneal Metastasis from Being Missed].

We report a case of laparoscopic sigmoidectomy for sigmoid colon cancer where a laparotomy transition prevented peritoneal metastasis from being missed. Case: A 64-year-old woman was diagnosed with sigmoid colon cancer. Computed tomography revealed a large bowel obstruction and a 12 mm wide basal bulge in the gallbladder. A laparoscopic sigmoidectomy( D3 dissection)was first performed, and intra-abdominal observation revealed no disseminated nodules. A laparoscopic cholecystectomy was performed continuously but, due to strong adhesions, a laparotomy was administered. Three disseminated nodules were observed in the omentum during the laparotomy and a postoperative pathological examination revealed pT4aN1b(2/23)M1c1(P2), pStage Ⅳc. Adjuvant chemotherapy of 8 courses of CAPOX was performed and there has been no recurrence 20 months after surgery.

[A Case of Locally Advanced Rectal Cancer Treated Successfully with TNT].

Local control is important in the treatment of locally advanced rectal cancer(LARC). In Western countries, the standard therapy for LARC is preoperative chemoradiotherapy(CRT)followed by total mesorectal excision. Recently, addition of intensive chemotherapy to CRT known as total neoadjuvant therapy(TNT)is increasing. We herein report a 69-year-old woman who developed LARC(cT3N3M0, cStage Ⅲc). She was diagnosed as clinical complete response after TNT, and she chose"watch and wait". She did not have a recurrence for 16 months.

[A Case of Rectal Cancer with Bladder Invasion Performed with Robot-Assisted Low Anterior Resection after TNT].

A 73-year-old woman was admitted with a chief complaint of weight loss. Colonoscopy revealed rectal cancer. After the placement of a colonic stent, the patient was referred to our department. Computed tomography, magnetic resonance imaging, and cystoscopy indicated extensive invasion of the bladder. Since total pelvic exenteration was necessary at the first diagnosis, total neoadjuvant therapy(TNT)was conducted. The diagnosis after TNT was ycT4bycN0ycM0. Low anterior resection with partial resection of the bladder and a diverting ileostomy were performed. The patient was discharged on the 16th day post-surgery with a good postoperative course. The pathological examination revealed a complete response, ypT0ypN0.

[A Case of Esophagogastric Junction Cancer Treated Successfully with Conversion Surgery after Complete Response to Nivolumab Treatment].

As shown in the ATTRACTION-2 trial, nivolumab is effective as third-line chemotherapy for advanced or recurrent gastric cancer and esophagogastric junction cancer. We report a patient with esophagogastric junction cancer who underwent conversion surgery after third-line chemotherapy with nivolumab. The patient was a 72-year-old woman. Upper gastrointestinal endoscopy revealed advanced esophagogastric junction cancer of Siewert type Ⅱ, and computed tomography revealed multiple hepatic and pulmonary metastases. The esophagogastric junction cancer was diagnosed as cT3N1M1, cStage Ⅳb, and she was administered SP as first-line and nab-PTX/RAM as second-line treatment, but progressive disease remained. Nivolumab as a third-line treatment remarkably reduced the hepatic and pulmonary metastases after its administration was initiated, and conversion surgery was performed after 28 courses. The pathological diagnosis was ypT1b2(SM2), ypN0. After discharge from the hospital, postoperative chemotherapy with nivolumab was continued in the outpatient clinic, and there has been no evidence of disease progression.

[A Case of Advanced Rectal Cancer with Left Hydronephrosis Treated with Left Ureter-Sparing Laparoscopic High Anterior Resection after Chemotherapy].

A 47-year-old woman with a complaint of weight loss for the past 5 months was referred to our hospital. Colonoscopy revealed advanced rectal cancer 20 cm from the anal verge. The patient had left hydronephrosis caused by ureteral invasion. Firstly, we performed transverse colostomy and left nephrostomy. After 8 courses of capecitabine, oxaliplatin plus bevacizumab( CAPOX plus Bmab)therapy, colonoscopy and computed tomography revealed shrinkage of both the primary and metastatic lesions. Laparoscopic high anterior resection was performed, and the left ureter was successfully preserved. The patient received chemotherapy after surgery. Neither local recurrence nor enlargement of metastases has been observed 8 months after surgery.

[A Case of SM Carcinoma of the Sigmoid Colon with Distant Metastasis in the Early Stage after Endoscopic MucosalResection].

INTRODUCTION: We report a case of submucosal(SM)adenocarcinoma of the sigmoid colon which developed distant metastasis 3 months after endoscopic mucosal resection(EMR). CASE: 54-year-old, male. Colonoscopy, which was performed due to positive fecal occult blood test, revealed 18 mm Isp sigmoid polyp. EMR was performed with en bloc resection. Pathological examination revealed adenocarcinoma(tub>por>sig), pT1b, Ly1c, V1a, pHM0, and pVM1. Therefore, laparoscopic sigmoidectomy(D2 dissection)was performed. Postoperative pathological examination revealed pT1b, pN2b(10/11), PN1b, pPM0, pDM0, pStage Ⅲb. Distant nodal involvement were found on computed tomography 3 months after EMR, although systemic chemotherapy(mFOLFOX6 plus panitumumab 18 courses and FOLFIRI plus bevacizumab 4 courses)was performed, the patient died of liver failure caused by liver metastasis 21 months after EMR. CONCLUSION: We present a case of T1 sigmoid adenocarcinoma which developed distant metastasis 3 months after EMR with literature review.

Frequent appearance of club cell (Clara cell)-like cells as a histological marker for ALK-positive lung adenocarcinoma.

Anaplastic lymphoma kinase-rearranged (ALK+ ) lung cancers show characteristic histological features, such as solid signet ring cell patterns and mucinous cribriform patterns; however, these features are not always observed in ALK+ lung cancers. We noticed that club cell (Clara cell)-like cells (CLCs) were frequently present in the papillary portion of ALK+ lung adenocarcinomas. In this study, we investigated the importance of CLCs in papillary patterns of ALK+ lung cancers. We compared the histological features of 18 ALK+ cases with 62 control cases (22 epidermal growth factor receptor-positive (EGFR+ ) and 40 ALK- and EGFR-negative (ALK- /EGFR- ) cases). The present study analyzed presence of papillary pattern, proportion of papillary pattern area, presence of micropapillary pattern, frequency of CLCs and lengths of snout. The frequency of CLCs in ALK+ cases was significantly higher than that in EGFR+ cases and ALK- /EGFR- cases. Micropapillary pattern was more frequently observed in ALK+ cases than that in ALK- /EGFR- cases (P < 0.001). The present study indicated that the high frequency of CLCs in papillary patterns was significantly associated with ALK+ cases. When solid signet ring cell patterns and mucinous cribriform patterns are absent, the high frequency of CLCs in papillary adenocarcinoma could be a useful histological marker for ALK+ lung cancers.

Usefulness of Plasma Exosomal MicroRNA-451a as a Noninvasive Biomarker for Early Prediction of Recurrence and Prognosis of Non-Small Cell Lung Cancer.

OBJECTIVES: The aim of this study was to clarify the usefulness of plasma exosomal microRNA-451a (miR-451a) as a novel biomarker for the early prediction of recurrence and prognosis in non-small cell lung cancer (NSCLC) patients after curative resection. METHODS: Before surgery, plasma samples were collected and exosomal microRNA (miRNA) levels were evaluated. We first profiled specific exosomal miRNAs related to recurrence in 6 NSCLC patients with stage IA cancer by miRNA microarray. We then validated the usefulness of selected miRNAs as biomarkers using the other 285 NSCLC patients. RESULTS: Plasma exosomal miR-451a showed the highest upregulation in the NSCLC patients with recurrence in the miRNA microarray analysis. A significant positive correlation was demonstrated between exosomal miR-451a levels and NSCLC tissue miR-451a levels. Exosomal miR-451a showed a significant association with lymph node metastasis, vascular invasion, and stage. In stage I, II, or III patients, the overall survival (OS) and disease-free survival (DFS) rates among the high-exosomal-miR-451a patients were significantly worse than those among the low-exosomal-miR-451a patients. In Cox multivariate analysis, exosomal miR-451a showed significance for OS and DFS. CONCLUSION: Plasma exosomal miR-451a might serve as a reliable biomarker for the prediction of recurrence and prognosis in NSCLC patients with stage I, II, or III cancer.

Validating margin status in lung wedge resection for clinical stage I non-small cell lung cancer.

Stage I non-small cell lung cancer (NSCLC) is a localized disease without metastasis; therefore, it can be treated effectively with local therapies. Pulmonary resection is the most frequent treatment, performed as pulmonary wedge resection, segmentectomy, lobectomy, or pneumonectomy. Some retrospective clinical studies of pulmonary wedge resection suggest that its outcome may be inferior to that of anatomical pulmonary resection, whereas other recent studies, which assess surgical margin status, leveled acceptable outcomes. Since the outcome of pulmonary wedge resection for lung cancer may depend on tumor size, distance from the surgical margin to the tumor, tumor size/margin distance ratio, and margin cytology results, a prospective study assessing these parameters is ongoing. This will allow us to identify the clinical implications of these factors and predict which patients are likely to have a good outcome.

Nuclear factor-kappa B influences early phase of compensatory lung growth after pneumonectomy in mice.

BACKGROUND: Compensatory lung growth (CLG) is a well-established lung regeneration model. However, the sequential mechanisms, including unknown molecular triggers or regulators, remain unclear. Nuclear factor- kappa B (NF-κB) is known to be essential for inflammation and tissue regeneration; therefore, we investigated the role of NF-κB in CLG. METHODS: C57BL/6 J mice underwent either a left pneumonectomy or a thoracotomy (n = 77). Gene microarray analysis was performed to detect genes that were upregulated at 12 h after pneumonectomy. NF-κB protein expression was examined by immunohistochemistry and Western blot. To investigate the influence of NF-κB on CLG, either an NF-κB inhibitor SN50 or saline was administered following pneumonectomy and the degree of CLG was evaluated in each group by measuring the lung dry weight index (LDWI) and the mean linear intercept. RESULTS: Gene microarray analysis identified 11 genes that were significantly but transiently increased at 12 h after pneumonectomy. Among the 11 genes, NF-κB was selected based on its reported functions. Western blot analysis showed that NF-κB protein expression after pneumonectomy was significantly higher at 12 h compared to 48 h. Additionally, NF-κB protein expression at 12 h after pneumonectomy was significantly higher than at both 12 and 48 h after thoracotomy (p < 0.029 for all). NF-κB protein expression, evaluated through immunohistochemistry, was expressed mainly in type 2 alveolar epithelial cells and was significant increased 12 h after pneumonectomy compared to 48 h after pneumonectomy and both 12 and 48 h after thoracotomy (p < 0.001 for all). SN50 administration following pneumonectomy induced a significant decrease in NF-κB expression (p = 0.004) and LDWI compared to the vehicle administration (p = 0.009). CONCLUSIONS: This is the first report demonstrating that NF-κB signaling may play a key role in CLG. Given its pathway is crucial in tissue regeneration of various organs, NF-κB may shed light on identification of molecular triggers or clinically usable key regulators of CLG.

Histology is a Prognostic Indicator After Pulmonary Metastasectomy from Renal Cell Carcinoma.

OBJECTIVES: There are only a few detailed reports concerning the prognosticators following surgical resection of pulmonary metastases (PMs) from renal cell carcinoma (RCC). We investigated the prognosis of patients with RCC PMs undergoing pulmonary metastasectomy and identified prognostic factors in a multi-institutional retrospective study. METHODS: We retrospectively evaluated 84 patients who underwent resection of PMs from RCC between 1993 and 2014. We assessed the clinicopathological characteristics, focusing on the histological findings of PMs. We classified the histology into three types: pure clear cell carcinoma (N = 68), clear cell carcinoma combined with other histology type (N = 8), and non-clear cell carcinoma (N = 8). We examined the relationship between these histological types and the prognosis of patients with PMs from RCC. RESULTS: Complete resection was achieved in 78 patients (93%). The 5-year overall survival rate after metastasectomy was 59.7%. In multivariate analysis, three factors were found to be independent favorable prognostic factors of overall survival after lung metastasectomy [tumor size <2 cm, hazard ratio (HR) = 0.31, 95% confidence interval (CI) 0.13-0.78, P = 0.012; clear cell type, HR = 0.37, 95% CI 0.16-0.83, P = 0.025; and complete resection, HR = 0.27, 95% CI 0.10-0.78, P = 0.015]. CONCLUSIONS: This study indicates that a histological finding of the clear cell type is a significant favorable prognostic factor in addition to complete resection and a tumor size <2 cm. Histological evaluation of PM lesions is important for predicting survival after metastasectomy.

Predictors of long-term compensatory response of pulmonary function following major lung resection for non-small cell lung cancer.

BACKGROUND AND OBJECTIVE: Long-term pulmonary function which might include compensatory response (CR) significantly influences quality of life of long-term survivor after major lung resection. We investigated long-term pulmonary function after major lung resection. METHODS: A total of 137 patients who had undergone lobar resection for non-small cell lung cancer (NSCLC) from May 2013 to June 2014 had spirometry at 10-14 months after surgery. Actual post-operative forced expiratory volume in 1 s (FEV1 ) (FEV1apo )/predicted post-operative FEV1 (FEV1ppo ), actual post-operative forced vital capacity (FVC) (FVCapo )/predicted post-operative FVC (FVCppo ), its relationship with clinicopathological factors and immunohistochemistry for pro-surfactant protein C (pro-SPC), thyroid transcription factor-1 (TTF-1) and vascular endothelial growth factor receptor 2 (VEGFR2) were investigated. RESULTS: FEV1apo /FEV1ppo showed strong correlation with FVCapo /FVCppo (r = 0.628; P < 0.001). We defined greater CR as both FEV1apo /FEV1ppo and FVCapo /FVCppo were >120%. Greater CR was significantly associated with decreased smoking index (P < 0.001) and greater resected subsegments (P = 0.037). The never-smoker group revealed significantly greater CR compared with the smoker group in both FEV1apo /FEV1ppo (119.9 ± 12.5% vs 107.5 ± 14.2%; P = 0.030) and FVCapo /FVCppo (117.9 ± 9.98% vs 107.2 ± 13.1%; P = 0.046) in case-matched comparison. The expression of pro-SPC, TTF-1 and VEGFR2 in the normal lung parenchyma of greater CR group was significantly higher than those of lesser CR group (P < 0.001 for each). In addition, pro-SPC, TTF-1 and VEGFR2 expressions showed a significant correlation to the degree of CR especially in the smoker group (r = 0.631, 0.705 and 0.732, respectively; P < 0.001 for each). CONCLUSION: Our data suggest that smokers may develop lesser long-term CR after major lung resection. Decreased expression of pro-SPC, TTF-1 and VEGFR2 may indicate decreased capacity of CR, especially in patients who smoke.