The combination of PD-L1 expression and the neutrophil-to-lymphocyte ratio as a prognostic factor of postoperative recurrence in non-small-cell lung cancer: a retrospective cohort study.

BACKGROUND: While PD-L1 expression and neutrophil-to-lymphocyte ratio (NLR) are prognostic biomarkers for lung cancer, few studies have considered their interaction. We hypothesized that the product of PD-L1 expression (tumor proportion score) and the NLR (PD-L1 × NLR) might be a postoperative prognostic marker reflecting the immune microenvironment of lung cancer. METHODS: We analyzed the association between PD-L1 × NLR and postoperative recurrence-free survival in 647 patients with NSCLC using multivariable Cox proportional hazards models. RESULTS: In the analysis of PD-L1 × NLR as a categorical variable, the group with PD-L1 × NLR ≥ 25.8 had a significantly higher hazard ratio (HR) than the group with < 25.8 (adjusted HR 1.78, 95% confidence interval [CI] 1.23-2.60). The adjusted HR for PD-L1 × NLR, considered a continuous variable, was 1.004 (95% CI, 1.002-1.006). The risk of postoperative recurrence increased by 1.004-fold for each unit increase in PD-L1 × NLR, and a more than 2-fold increase in risk was observed for values ≥ 170. CONCLUSIONS: PD-L1 × NLR may be used in real-world clinical practice as a novel factor for predicting the risk of postoperative recurrence after lung cancer surgery.

PIK3CA mutations associated with a poor postoperative prognosis in patients with pulmonary pleomorphic carcinoma: a retrospective cohort study.

BACKGROUND: Pulmonary pleomorphic carcinoma (PPC) is a rare type of non-small cell lung cancer characterized by high malignancy and a poor prognosis. PPC is associated with a high frequency of postoperative relapse, and shows resistance to chemotherapy. The high malignancy of cancers is associated with genomic instability, which is related to mutations of tumor suppressor genes, such as tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM). In addition, signaling pathways involving the oncogenes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and epidermal growth factor receptor (EGFR) are associated with resistance to chemotherapy. However, the association of PPC with these gene mutations remains unknown. We investigated the impact of TP53, ATM, PIK3CA, and EGFR mutations on the postoperative prognosis of PPC. METHODS: Fifty-five patients with PPC who underwent complete resection were studied. A gene mutation analysis was performed using next-generation sequencing. Postoperative overall survival of patients with gene mutations was evaluated using a multivariable Cox proportional hazards model in which the explanatory variables were the presence of each gene mutation, and the confounding factors were pathological stage and age. The robustness of the results was evaluated by a sensitivity analysis. RESULTS: The frequencies of pathogenic mutations in TP53, ATM, PIK3CA, and EGFR were 47, 0, 7, and 9%, respectively. A multivariable analysis adjusted for pathological stage and age showed a significant difference for only PIK3CA mutations. The hazard ratio (HR) for overall survival in cases with pathogenic mutations of PIK3CA for wild type or non-pathogenic mutations was 4.5 (95% confidence interval [CI] 1.1-18.8). Likewise, sensitivity analyses adjusted for pathological stage and sex (HR, 7.5; 95% CI 1.7-32.4) and for age and sex (HR, 5.4; 95% CI 1.4-21.7) resulted in similar findings. Although three patients with pathogenic mutations of PIK3CA that recurred postoperatively were treated by chemotherapy or immunotherapy, they survived for less than 2 years. CONCLUSIONS: The postoperative prognosis of PPC with PIK3CA pathogenic mutations is particularly poor. Pathogenic mutations of PIK3CA may be a postoperative prognostic marker. Inhibition of signaling pathways associated with PIK3CA mutations may also be a target for chemotherapy after relapse of PPC.

[A Case of Anal Canal Adenocarcinoma with Perianal Pagetoid Spread without a Macroscopic Finding].

We report a case of anal canal cancer with Pagetoid spread without a macroscopic skin lesion. A 54-year-old man was admitted to a hospital with complaints of bloody stools. Endoscopic examination revealed a polyp in the anal canal, and endoscopic mucosal resection was performed. Pathological examination revealed an adenocarcinoma accompanied by Pagetoid spread and the positive surgical margin. We additionally performed trans-anal resection twice, but the resected horizontal margin was positive. Mapping biopsy of rectal mucosa and perianal skin revealed adenocarcinoma in only rectal mucosa. Abdominoperineal resection was performed. Histopathological examination showed invasive adenocarcinoma with pagetoid spread and that the surgical margin was negative. Pagetoid spread of anal canal adenocarcinoma usually showed macroscopic abnormal findings, but in this case, there was no skin lesion. It suggests that preoperative mapping biopsy is helpful for determining the excision range. It is necessary to keep in mind that anal canal adenocarcinoma with no skin lesion may cause Pagetoid spread.

[A Case of Recurrent Hepatocellular Carcinoma Successfully Treated by Radiation Therapy].

We report a case of recurrent hepatocellular carcinoma(HCC)successfully treated by radiation therapy. A 79-year-old woman was diagnosed with HCC and underwent liver resection. Seven months after resection, CT and MRI detected a new HCC, and she had a surgery again. One year after the surgery, CT and MRI detected local recurrence, and she underwent the third operation. Three months after the operation, the third liver recurrence was treated by transcatheter arterial chemoembolization( TACE). Four months later, a new lesion was detected and treated by stereotactic body radiation therapy(SBRT) twice. She remains alive without recurrence 27 months after the last radiation therapy. Very few evidence is reported of radiation therapy for HCC, but this case suggests that radiation therapy provides a benefit for patients with HCC after other treatments.

[A Case of Advanced Gastric Cancer with Peritoneal Metastasis Achieved Pathological Complete Response by Chemotherapy(SOX Regimen)].

A 68-year-old woman was presented with anorexia. Upper gastrointestinal endoscopy revealed type 4 gastric cancer at corpus of the stomach. Peritoneal metastasis was detected by staging laparoscopy. After a diagnosis of cT4aN1M1, cStage ⅣB advanced gastric cancer, we performed chemotherapy(SOX regimen; S-1 100 mg/body on day 1-14, followed by 7 days of rest, oxaliplatin 130 mg/m2 on day 1). After the 3 courses of chemotherapy, the primary tumor had been reduced. Second staging laparoscopy revealed no peritoneal metastasis. Then, we performed total gastrectomy with D2 lymph node dissection. Histopathological examination revealed no residual cancer cells, indicating a pathological complete response (Grade 3). We report a case of advanced gastric cancer with peritoneal metastasis achieved pathological complete response by chemotherapy.

Prognosis associated with surgery for non-small cell lung cancer and synchronous brain metastasis.

PURPOSE: Several reports have described extended survival after aggressive surgical treatment for non-small cell lung cancer (NSCLC) and synchronous brain metastasis. This retrospective analysis assesses the prognostic factors in this population. METHODS: We reviewed retrospectively the medical records of 29 patients with synchronous brain metastasis from NSCLC, who underwent surgical treatment in our institution between 1980 and 2008. All patients underwent chest surgery to remove the primary lesion. The impact of several variables on survival was assessed. RESULTS: The median follow-up period was 9.6 months and the 5-year survival rate from the time of lung cancer resection was 20.6 %. Univariate analysis demonstrated that the carcinoembryonic antigen (CEA) level, primary tumor size, and the presence of lymph node involvement were predictive of overall survival (p < 0.05). Multivariate analysis also identified those factors to be independent favorable prognostic factors. CONCLUSIONS: Although the survival of patients with brain metastasis from non-small cell lung cancer remains poor, surgical resection may benefit a select group of patients, particularly those with a normal CEA level, small tumor size, and node-negative status.

Nonlinear association between PD-L1 expression levels and the risk of postoperative recurrence in non-small cell lung cancer.

Accurate prediction of postoperative recurrence is important for optimizing the treatment strategies for non-small cell lung cancer (NSCLC). Previous studies identified the PD-L1 expression in NSCLC as a risk factor for postoperative recurrence. This study aimed to examine the contribution of PD-L1 expression to predicting postoperative recurrence using machine learning. The clinical data of 647 patients with NSCLC who underwent surgical resection were collected and stratified into training (80%), validation (10%), and testing (10%) datasets. Machine learning models were trained on the training data using clinical parameters including PD-L1 expression. The top-performing model was assessed on the test data using the SHAP analysis and partial dependence plots to quantify the contribution of the PD-L1 expression. Multivariate Cox proportional hazards model was used to validate the association between PD-L1 expression and postoperative recurrence. The random forest model demonstrated the highest predictive performance with the SHAP analysis, highlighting PD-L1 expression as an important feature, and the multivariate Cox analysis indicated a significant increase in the risk of postoperative recurrence with each increment in PD-L1 expression. These findings suggest that variations in PD-L1 expression may provide valuable information for clinical decision-making regarding lung cancer treatment strategies.

Cytoreductive surgery and post-operative heated pleural chemotherapy for the management of pleural surface malignancy.

PURPOSE: We retrospectively analysed the long-term outcomes of cytoreductive surgery and post-operative heated pleural chemotherapy (HPC) for thoracic malignancies with pleural spread. MATERIALS AND METHODS: Between 1987 and 2010, 160 patients were enrolled. There were 101 patients with non-small cell lung cancer (NSCLC), 25 with malignant pleural mesothelioma (MPM), 12 with thymoma, and 22 with tumours metastatic to the lung and pleura. Immediately after intra-thoracic administration of cisplatin or carboplatin, hyperthermia was performed by using an 8.00 MHz radiofrequency capacitive heating device for 1 to 4 courses in each patient. RESULTS: There was no systemic toxicity or treatment-related mortality. Five-year overall survival rates were 37.4% in NSCLC, 15.9% in MPM, 91.7% in thymoma, and 25.8% in metastatic lung tumour. Five-year local relapse-free survival (RFS) rates were 55.2% in NSCLC, 24.4% in MPM, 64.8% in thymoma, and 27.2% in tumours metastatic to the lung and pleura. When 101 NSCLCs were categorised into pleural lavage cytology positive (grade 1: n = 37), limited extent of carcinomatous pleuritis (grade 2: n = 21), and extensive carcinomatous pleuritis (grade 3: n = 43), 5-year overall survival rates were 62.5%, 49.2%, and 13.6%, respectively. The local RFS was significantly better in group 1/2 than in group 3. CONCLUSIONS: Although our study has some of the usual weaknesses of a single institution retrospective study, cytoreductive surgery and HPC are feasible and safe. It is suggested that HPC may have a potential role for local control as adjuvant treatment for cytoreductive surgery in patients with minor pleural spread.

Surgical resection of pulmonary metastases from meningioma: report of a case.

Meningiomas rarely metastasize, and little information on pulmonary metastasectomy from meningioma has been documented. We herein report a case of a potentially curative resection for meningioma that metastasized to the lung. A 67-year-old woman was admitted to our hospital because of two masses in the right lung. In 1993, when the patient was 52 years old, she underwent a craniotomy for an atypical meningioma. The meningioma recurred once in the local site and was re-excised in 1997. In 2008, a screening chest X-ray detected two lung nodules in the right lung field. A computed tomographic scan demonstrated round masses with sharp borders, in the right S2 (2.2 cm in diameter) and S4 (1.1 cm in diameter) regions. A whole-body [(18)F]2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/CT examination revealed intense focal FDG uptake (maximum standard uptake value [SUV(max)] = 6.9) in the larger mass, and weak FDG uptake (SUV(max) = 2.3) in the smaller mass. A wedge resection of S2 and a middle lobectomy of the right lung were performed, and the final diagnosis was pulmonary metastases from an intracranial meningioma. The patient is presently doing well 20 months after the surgery without any signs of recurrence. Our case demonstrates that surgery should be considered when pulmonary metastases are deemed completely resectable by a preoperative radiological examination, and that a good clinical outcome can be achieved.

A case of unusually persistent traumatic intrapulmonary hematoma.

Intrapulmonary hematomas are collections of blood within alveolar and interstitial spaces. They occur mainly following thoracic trauma. Typically, intrapulmonary hematomas without bleeding or infection spontaneously disappear after several weeks to 6 months. In the current case, the patient presented with an intrapulmonary nodule 17 months after a chest injury. The size of the nodule had not changed at 4 months after the first visit. Consequently, the patient was diagnosed with an intrapulmonary hematoma by surgical resection. To our knowledge, there are no previous studies that described the cause of the persistent intrapulmonary hematoma. This study reports the case of a patient who underwent surgical resection of a persistent traumatic intrapulmonary hematoma.

Biological implications of thymectomy for myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies to the striated muscle tissue. It is often treated by thymectomy. We review recent studies to investigate the biological implications of thymectomy. In anti-acetylcholine receptor antibody (anti-AchR Ab)-positive patients without a thymoma, abnormal germinal center formation in the thymus seems to play an essential role in the pathogenesis of MG. Specific differentiation of B cells producing anti-AchR Ab takes place uniquely in the thymus, and thymectomy is thought to assist in terminating the provision of high-affinity anti-AchR antibody-producing cells to peripheral organs. Thymectomy is not indicated for anti-AchR Ab-negative MG patients who are antimuscle specific kinase antibody (anti-MuSK Ab)-positive, although some anti-MuSK Ab-negative patients may benefit from the procedure. A thymoma can be considered as an acquired thymus with insufficient function of negative selection. The resection of a thymoma is thought to terminate the production of self-reactive T cells. Thus, the biological implications of thymectomy for MG have been partially revealed. Nevertheless, additional studies are needed to elucidate the ontogeny of T cells that recognize AchR and the mechanism of the activation of anti-AchR antibodies producing B cells.

Intraoperative Diagnosis and Surgical Procedure with Imprint Cytology for Small Pulmonary Adenocarcinoma.

Objectives: For patients with multiple small-sized pulmonary cancers, a lobectomy can disrupt future therapeutic options for other lesions. It was recently reported that limited pulmonary resections were not inferior to lobectomy for the management of selected peripheral small-sized pulmonary adenocarcinomas. Patients with adenocarcinoma in situ or minimally invasive adenocarcinoma, as proposed by the International Association for the Study of Cancer classification, have been reported to have 100% survival after 5 years. However, that classification can be applied postoperatively. Since 2005, we have been intentionally performing limited pulmonary resection procedures for small-sized adenocarcinoma cases based on intraoperative imprint cytological diagnosis and our classification (Nakayama-Higashiyama's classification). Materials and Methods: A total of 120 consecutive cases were included in this study. Lung tumors were removed intraoperatively by wedge resection, and stump smear cytology was performed, from which the cases were classified into 5 groups based on our classification. When the tumor was classified as Group I or II, the operation was finished. When diagnosed as a more advanced classification, a lobectomy and lymph node dissection were additionally performed. Results: The 5-year survival rate for Group I and II was 100%, while those for Group III and IV-V were 95.8% and 94.4%, respectively. The 5-year disease-free survival rates for Group I and Group II were 100% and 97.1%, respectively, and for Group III and IV-V they were 100% and 94.1%, respectively. Conclusion: Use of cytological findings along with Nakayama-Higashiyama's classification for determining operation procedure is effective for treatment of patients with small-sized pulmonary adenocarcinoma.

Novel Imprint Cytological Classification for Small Pulmonary Adenocarcinoma Using Surgical Specimens: Comparison with the 8th Lung Cancer Staging System and Histopathological Classification.

Objectives: Small-size lung lesions suspected of being cancer are now often being identified on computed tomography. Correspondingly, a new lung cancer staging system has been proposed by the International Association for the Study of Lung Cancer (IASLC), in which the T1 factor and adenocarcinoma are re-subclassified. Previously, we proposed an intraoperative cytological diagnosis and its classification of small-size lung adenocarcinoma, which correlated significantly with clinical malignancy, to be used for selecting the surgical strategy. In the current study, the correlation of our intraoperative cytological classification with the new 8th IASLC classification was investigated. Materials and Methods: A total of 139 consecutive small-size lung adenocarcinoma cases were surgically resected from 2000 to 2006 and included in this study. Intraoperative stump imprint cytology using these specimens was performed, and the cases were classified into 5 groups based on our classification. The cytological classification was compared with the IASLC classification and the WHO histopathological grading. Results: According to our classification, 32 patients were in Group I, 38 in Group II, 24 in Group III, 27 in Group IV, and 18 in Group V. Compared with the IASLC classification, most of Group I was pTis or pT1mi, and most of Group II was pT1mi or pT1a (p<0.001). There was also a significant relationship between lymph node metastasis and our cytological classification (p<0.001). The histological patterns according to the WHO classification also had a significant relationship with our classification (p<0.001). Conclusion: Our cytological classification correlated not only with the T classification, but also with the adenocarcinoma subclassification of the 8th IASLC classification.

[Diagnosis and staging of pleural mesothelioma].

Accurate diagnosis and staging are very important for the treatment of pleural mesothelioma. In particular, surgical indications based on diagnosis and staging must be determined carefully, since extrapleural pneumectomy (EPP) is a highly invasive surgical mode. Sufficient biopsy specimens to make a differential diagnosis of this disease should be obtained during video-assisted thoracoscopic surgery (VATS). Currently, the final diagnosis of mesothelioma is based not only on the results of hematoxylin and eosin staining but also of immunostaining using several differential markers. The International Mesothelioma Interest Group (IMIG) classification is widely used for the TNM staging of pleural mesothelioma. The IMIG classification is now applied to clinical staging with the aid of computed tomography and positron-emission tomography images, but the accuracy and usefulness of this classification for surgical indications and outcomes must be improved in future. Extended preoperative staging, for example, mediastinoscopy, contralateral VATS, and laparoscopy, are now selectively performed for the precise diagnosis of potentially resectable mesothelioma.

Diagnostic effectiveness of preoperative water-soluble contrast enema in colorectal perforation.

OBJECTIVE: To evaluate the diagnostic usefulness of performing a preoperative water-soluble contrast enema (WSCE) before emergency surgery for colorectal perforation. METHODS: We retrospectively reviewed 68 consecutive patients who underwent a preoperative WSCE before emergency surgery for colorectal perforation during the period from January 2011 to December 2017. Clinical characteristics and inflammatory biomarkers were compared between patients with Hinchey I-II versus those with Hinchey III-IV. RESULTS: WSCE leakage occurred in 27 of 68 patients (39.7%). Univariate analysis showed that the two groups (Hinchey I-II and Hinchey III-IV) significantly differed regarding age, perforation site, cause of perforation, American Society of Anesthesiologists grade, presence or absence of WSCE leakage, and white blood cell count. Multivariable analysis revealed that WSCE leakage was a predictor of Hinchey III-IV, with an odds ratio of greater than 24 (P = 0.002). The sensitivity and specificity of WSCE leakage for differentiating those with Hinchey III-IV from those with Hinchey I-II were 76.5% and 97.1%, respectively. CONCLUSIONS: This retrospective study indicates that preoperative WSCE before emergency surgery is a useful tool for predicting the presence of Hinchey III-IV in patients with colorectal perforation.

Surgical Treatment following Chemo-Targeted Therapy with Bevacizumab for Lung Metastasis from Colorectal Carcinoma: Analysis of Safety and Histological Therapeutic Effects in Patients Treated at a Single Institution.

BACKGROUND: Recently, therapeutic strategies for a metastasectomy from colorectal carcinoma after chemo-targeted therapy with bevacizumab have been presented, with which some uncommon but serious adverse events have been reported. However, only few reports have investigated the safety of lung resection after such therapy or the histological effects. We retrospectively analyzed the both of them at our institute. METHODS: Of 69 colorectal carcinoma patients who underwent pulmonary metastasectomy procedures from 2009 to 2014, we investigated 11 who also received chemo-targeted therapy prior to surgery. RESULTS: In addition to bevacizumab, 5 fluorouracil (FU)/leucovorin + oxaliplatin or capecitabine was given in 6 cases and 5 FU/leucovorin + irinotecan in 5 cases. The mean period from the end of chemo-targeted therapy to surgery was 2.7 ± 0.9 months. The response to therapy shown in imaging findings was progressive disease in 6, stable disease in 3, and partial response in 2 (response rate, 18.2%). The operation modes were wedge resection (n = 8, 72.3%), segmentectomy (n = 2, 1 in bilateral lobes, 1 in the right lobe, 18.2%), and lobectomy (n = 1, left lower lobectomy, 9.1%). All patients safely underwent a complete resection. As for postsurgical complications, chylothorax occurred in 1 case and prolonged pulmonary air leakage in 1 case. The histological effects of chemo-targeted therapy were slight. There was no relationship between histological findings with imaging findings obtained prior to the operation (p = 0.63). The 5-year disease-free survival rate after metastasectomy was 10.9%. CONCLUSIONS: Pulmonary metastasectomy after chemo-targeted therapy for colorectal carcinoma patients obtained acceptable results. In addition, there was no correlation between imaging and histopathologic results following chemo-targeted therapy.

HER3 expression is enhanced during progression of lung adenocarcinoma without EGFR mutation from stage 0 to IA1.

BACKGROUND: Activating EGFR mutations, HER2, and HER3 are implicated in lung cancer; however, with the exception of EGFR gene amplification in lung adenocarcinoma harboring EGFR mutations, their involvement in disease progression during the early stages is poorly understood. In this paper, we focused on which receptor is correlated with lung adenocarcinoma progression in the presence or absence of EGFR mutation from stage 0 to IA1. METHODS: HER2 and HER3 expression and activating EGFR mutations in surgically resected lung adenocarcinoma exhibiting ground glass nodules on chest computed tomography and re-classified to stage 0 and IA1 were examined by immunohistochemistry and peptide nucleic acid-locked nucleic acid PCR clamp method, respectively. RESULTS: HER2 and HER3 expression was detected in 22.2% and 86.1% of samples, respectively. The frequency of EGFR mutation was 45.7% and was not significantly different between stage 0 and IA1 (40.0% and 48.0%, respectively), suggesting that EGFR mutation does not correlate with cancer progression from stage 0 to IA1. HER2 expression also did not correlate to progression. However, not only the frequency, but also the intensity of HER3 expression was increased in stage IA1 lung adenocarcinoma, particularly in lung adenocarcinoma without EGFR mutation. CONCLUSION: HER3 tends to be intensively expressed during the progression of lung adenocarcinoma without EGFR mutation from carcinoma in situ to invasive carcinoma.

Post-operative AICS status in completely resected lung cancer patients with pre-operative AICS abnormalities: predictive significance of disease recurrence.

The AminoIndexTM Cancer Screening (AICS) system, a plasma-free amino acid (PFAA)-based multivariate discrimination index, is a blood screening test for lung cancer based on the comparison of PFAA concentrations between patients with lung cancer and healthy controls. Pre- and post-operative AICS values were compared among 72 patients who underwent curative resection for lung cancer. Post-operative changes in PFAA concentrations were also evaluated. AICS values were classified as rank A (0.0-4.9), B (5.0-7.9), or C (8.0-10.0). Rank B-C patients were evaluated for outcomes and post-operative changes in their AICS values. Twenty-three of the 44 pre-operative rank B-C patients experienced post-operative reductions in AICS rank. Only one patient experienced cancer recurrence. Post-operative changes in PFAA concentrations were associated with the risk of post-operative cancer recurrence (p = 0.001). Multivariate analysis revealed that the absence of a post-operative reduction in AICS rank independently predicted cancer recurrence (hazard ratio: 14.28; p = 0.012). The majority of patients had high pre-operative AICS values and exhibited a reduction in AICS rank after curative resection. However, the absence of a post-operative reduction in AICS rank was associated with cancer recurrence, suggesting that AICS rank may be a sensitive marker of post-operative recurrence.

Mediastinal lymphangiomatosis coexisting with occult thymic carcinoma.

Mediastinal lymphangiomatosis in a 70-year-old woman was diagnosed on a medical checkup. The tumor was resistant to sclerotherapy with OK432 or bleomycin. The patient continued on a downhill course and died approximately 3 years after the initial diagnosis. Autopsy revealed a large tumor mass occupying the anterior mediastinum and firmly adhered to the pericardium and the pleura. The tumor consisted of two intermingled lesions: dilated vessels lined with D2-40-positive lymphatic endothelium and CD5-positive atypical cell nests with focal keratinization. The former was diagnosed as lymphangiomatosis and the latter as thymic squamous cell carcinoma. Vascular endothelial growth factor (VEGF)-C, a growth factor for lymphatic endothelial cells, was expressed by the carcinoma, and VEGF-C receptor was expressed by the endothelium of lymphangiomatosis. These findings suggested that VEGF-C derived from the thymic carcinoma induced the lymphangiomatosis lesion in a paracrine manner.