Microbiota and lung cancer.

Until recently, bacteria have been studied in terms of their roles in infectious diseases and mainly by using isolation and culture methods. However, in practice, many bacteria existing on the earth are difficult to isolate and culture, and thus only a limited number of them have been studied to date. On the other hand, in 2005, the next-generation sequencing technology became generally available, and since then genomic analysis of bacterial flora has become widespread. As a result, it has been revealed that the lower respiratory tract, which was previously thought to be sterile, in fact has bacterial flora (a microbiome) with a high level of biodiversity. In addition, it has been found that various diseases develop and worsen depending on the balance of the bacterial flora, and in recent years, a relationship has been established between various disorders. Recent research on cancer-associated microbial communities has elucidated the reciprocal interactions among bacteria, tumors and immune cells, the bacterial pathways associated with induction of oncogenesis, and their translational significance. Nevertheless, despite the increasing evidence showing that dysbiosis is associated with lung oncogenesis, the detailed mechanisms remain to be fully elucidated. Microorganisms seem to trigger tumor initiation and progression, presumably through the production of bacterio-toxins and other pro-inflammatory factors. The purpose of this review is to present a context for the basic mechanisms and molecular functions of the airway microbiome in oncogenesis, in an effort to prevent cancer by strategies utilizing the airway microbiota, as well as summarizing the mechanisms wherein the microbiome acts as a modulator of immunotherapies in lung cancer.

Airway Microbiota as a Modulator of Lung Cancer.

Recent research on cancer-associated microbial communities has elucidated the interplay between bacteria, immune cells, and tumor cells; the bacterial pathways involved in the induction of carcinogenesis; and their clinical significance. Although accumulating evidence shows that a dysbiotic condition is associated with lung carcinogenesis, the underlying mechanisms remain unclear. Microorganisms possibly trigger tumor initiation and progression, presumably via the production of bacterial toxins and other pro-inflammatory factors. The purpose of this review is to discuss the basic role of the airway microbiome in carcinogenesis and the underlying molecular mechanisms, with the aim of developing anticancer strategies involving the airway microbiota. In addition, the mechanisms via which the microbiome acts as a modulator of immunotherapies in lung cancer are summarized.

Immunosurveillance and Immunoediting of Lung Cancer: Current Perspectives and Challenges.

The immune system plays a dual role in tumor evolution-it can identify and control nascent tumor cells in a process called immunosurveillance and can promote tumor progression through immunosuppression via various mechanisms. Thus, bilateral host-protective and tumor-promoting actions of immunity are integrated as cancer immunoediting. In this decade, immune checkpoint inhibitors, specifically programmed cell death 1 (PD-1) pathway inhibitors, have changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). These agents are approved for the treatment of patients with NSCLC and demonstrate impressive clinical activity and durable responses in some patients. However, for many NSCLC patients, the efficacy of immune checkpoint inhibitors is limited. To optimize the full utility of the immune system for eradicating cancer, a broader understanding of cancer immunosurveillance and immunoediting is essential. In this review, we discuss the fundamental knowledge of the phenomena and provide an overview of the next-generation immunotherapies in the pipeline.

Molecular Mechanisms: Connections between Nonalcoholic Fatty Liver Disease, Steatohepatitis and Hepatocellular Carcinoma.

Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), causes hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The patatin-like phospholipase-3 (PNPLA3) I148M sequence variant is one of the strongest genetic determinants of NAFLD/NASH. PNPLA3 is an independent risk factor for HCC among patients with NASH. The obesity epidemic is closely associated with the rising prevalence and severity of NAFLD/NASH. Furthermore, metabolic syndrome exacerbates the course of NAFLD/NASH. These factors are able to induce apoptosis and activate immune and inflammatory pathways, resulting in the development of hepatic fibrosis and NASH, leading to progression toward HCC. Small intestinal bacterial overgrowth (SIBO), destruction of the intestinal mucosa barrier function and a high-fat diet all seem to exacerbate the development of hepatic fibrosis and NASH, leading to HCC in patients with NAFLD/NASH. Thus, the intestinal microbiota may play a role in the development of NAFLD/NASH. In this review, we describe recent advances in our knowledge of the molecular mechanisms contributing to the development of hepatic fibrosis and HCC in patients with NAFLD/NASH.

Molecular Mechanisms of Pulmonary Fibrogenesis and Its Progression to Lung Cancer: A Review.

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, and limited to the lungs. Despite the increasing research interest in the pathogenesis of IPF, unfavorable survival rates remain associated with this condition. Recently, novel therapeutic agents have been shown to control the progression of IPF. However, these drugs do not improve lung function and have not been tested prospectively in patients with IPF and coexisting lung cancer, which is a common comorbidity of IPF. Optimal management of patients with IPF and lung cancer requires understanding of pathogenic mechanisms and molecular pathways that are common to both diseases. This review article reflects the current state of knowledge regarding the pathogenesis of pulmonary fibrosis and summarizes the pathways that are common to IPF and lung cancer by focusing on the molecular mechanisms.

Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review.

Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.

Lymph node cancer of the mediastinum with a putative necrotic primary lesion in the lung: a case report.

BACKGROUND: Although mediastinal lymph node cancer is presumed to originate in the lung, the primary site is usually unidentified, so the pathological course remains unclear. We recently encountered a case of mediastinal lymph node cancer having a putative primary lesion remaining in the lung as a necrotic focus. CASE PRESENTATION: The patient was a 56-year-old man who visited our department because computed tomography screening had revealed a nodular shadow in the lingular segment. However, on positron emission tomography, fluorine-18 deoxyglucose accumulation was detected in a subcarinal lymph node and not in the nodule in the lingular segment. Biopsy of the lung tumor and the lymph node was performed via minimal thoracotomy. Intraoperative pathologic examination showed necrosis alone and no malignant findings in the lung tumor. By contrast, carcinoma was detected in the lymph node. Additional subcarinal lymph node dissection was performed. Results of postoperative histopathologic examination indicated poorly differentiated adenocarcinoma of the subcarinal lymph node. Meanwhile, the nodule in the lingular segment was speculated to be a spontaneously resolved primary focus of lung cancer. CONCLUSIONS: In this case, the primary lung cancer focus resolved spontaneously after lymph node metastasis, explaining the pathogenesis underlying mediastinal lymph node cancer of unknown primary site. For similar cases of malignancy, aggressive treatment, including surgery, is effective.

Stepwise addition of genetic changes correlated with histological change from "well-differentiated" to "sarcomatoid" phenotypes: a case report.

BACKGROUND: Sarcomatoid cancer is defined by the World Health Organization as a category of non-small cell lung cancers with sarcoma or sarcoma-like differentiation. They are characterized by poor prognosis and resistance to conventional chemotherapy. However, the mutational profile of sarcomatoid cancer remains yet to be elucidated. Sarcomatoid cancers are usually biphasic tumors composed of carcinomatous and sarcomatous components, but the evolutional development of sarcomatoid cancer is controversial. CASE PRESENTATION: We present an illustrative case of sarcomatoid cancer composed of three different histological areas. Targeted sequencing of 53 lung cancer-related genes was performed in each component and their phenotypic changes were correlated with stepwise addition of genetic changes. CONCLUSION: Sarcomatous change of carcinoma occurs in the case of sarcomatoid cancer, and phenotypic changes to sarcomatoid cancer are associated with the addition of mutation patterns and derived from poorly differentiation tumor.

Debulking surgery for venous hemangioma arising from the epicardium: report of a case.

BACKGROUND: Cardiac hemangiomas are rare benign vascular tumors that can occur in any cardiac layer: endocardium, myocardium, or epicardium. Histologically, cardiac hemangiomas may be classified as capillary, cavernous, or arteriovenous; venous hemangiomas are extremely rare. CASE PRESENTATION: A 46-year-old man reported experiencing precordial discomfort. Computed tomography revealed a massive tumor adjacent to the right ventricle. The right coronary artery was found to be located at the center of the tumor. Cardiovascular angiography showed that the artery was completely encased by the tumor without any obstruction and that the right ventricular lumen was compressed by the tumor. Surgical debulking of the tumor was performed under cardiopulmonary bypass, and the frozen section led to a diagnosis of benign hemangioma. The tumor was debulked as much as possible until the right coronary artery appeared. For decompression of the heart, the pericardium was left open to the thoracic cavity and unsutured. Histopathologic examination revealed a diagnosis of epicardial venous hemangioma. CONCLUSIONS: Cardiac hemangioma should be included in the differential diagnosis of mediastinal tumor in reference to the location and flow of the coronary artery. Surgical resection, or at least tumor debulking, is required to confirm the diagnosis and prevent further complications and has a favorable clinical outcome.

Surgical treatment for mediastinal abscess induced by endobronchial ultrasound-guided transbronchial needle aspiration: a case report and literature review.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a useful and less invasive procedure for the definitive diagnosis of mediastinal and hilar lymph nodes. However, infectious complications can occur after EBUS-TBNA, although they are extremely rare. CASE PRESENTATION: A 66-year-old man with necrotic and swollen lower paratracheal lymph nodes underwent EBUS-TBNA. A mediastinal abscess developed 9 days post-procedure. Surgical drainage and debridement of the abscess were performed along with lymph node biopsy followed by daily washing of the thoracic cavity. Surgical treatment was effective, leading to remission of the abscess. Biopsy revealed that the tumor was squamous cell carcinoma with no radiologically detected cancer elsewhere in the body. Mediastinal lung cancer was thus confirmed. Subsequent chemoradiotherapy led to the remission of the tumor. CONCLUSIONS: Mediastinitis after EBUS-TBNA is rare but should be considered, particularly if the target lymph nodes are necrotic. Mediastinitis can lead to serious and rapid deterioration of the patient's condition, for which surgical intervention is the treatment of choice.

Carbon monoxide-releasing molecule attenuates allograft airway rejection.

Acute rejection after lung transplantation is the main risk factor for the development of bronchiolitis obliterans (BO). Carbon monoxide (CO) can provide anti-inflammatory effects and may serve to limit tissue injury in airway transplant. Here, we tested the ability of carbon monoxide releasing molecule-2 (CORM-2) to prevent airway rejection. Tracheal grafts from BALB/c or C57BL/6 were transplanted to C57BL/6 recipients. Experimental groups were treated with multiple doses of CORM-2. Histopathological evaluation of luminal obliteration was blindly reviewed. Immunohistochemistry and real-time RT-PCR analyses were performed. Allografts treated with CORM-2 revealed a striking reduction of thickening in epithelial and subepithelial airway layers (P < 0.01) at day 7 in orthotopic trachea transplantation model compared with allografts treated with vehicle. In heterotopic trachea transplantation model, CORM-2 treated allografts showed a reduction of luminal obliteration (P < 0.01) at days 14 and 21. There was also a concordant decrease in CD3(+) lymphocytes and macrophages in CORM-2 treated allografts. IFN-γ, IL-2 and IL17A mRNA expressions were reduced dramatically by systemic administration of CORM-2. These data implicate CORM-2-derived CO has an important protective function in experimental BO, and may represent a target for the therapeutic intervention of chronic lung allograft rejection.

Idiopathic pulmonary fibrosis as a prognostic factor in non-small cell lung cancer.

BACKGROUND: We investigated the postoperative mortality and long-term survival of lung cancer patients with underlying idiopathic pulmonary fibrosis (IPF). METHODS: The data of 387 primary lung cancer patients treated by surgical resection at our hospital between 1995 and 2008 were retrospectively reviewed. Clinicopathological characteristics such as age, gender, survival, presence/absence of underlying IPF, atypical adenomatous hyperplasia (AAH), and the associations among these factors were examined. RESULTS: Among the 387 patients, 65 (16.8 %) had underlying IPF as detected by histopathology of the resected specimen (IPF group). The percentages of men and squamous cell carcinomas were significantly higher in the IPF group. None of our patients showed concomitant presence of AAH and IPF. Four of the 65 patients showed acute exacerbation of the IPF postoperatively, and all 4 of these patients died in hospital. In patients with non-small cell lung carcinoma, the postoperative survival tended to be lower in the IPF group than in the non-IPF group. Analysis using a Cox proportional hazards model by disease stage revealed that presence of underlying IPF was a risk factor for postoperative mortality in patients with pathological stage I/II but not for stage III/IV. Respiratory failure was the second main cause of death in the stage I/II lung cancer patients of the IPF group. CONCLUSION: Histopathological evidence of IPF was a risk factor for postoperative mortality and poor long-term survival, especially in patients with stage I/II non-small cell lung cancer, with postoperative respiratory failure representing the major cause of death.

Rapidly growing glandular papilloma associated with mucus production: a case report.

BACKGROUND: Pulmonary glandular papillomas are rare neoplasms, and their very slow or absent growth over time generally facilitates establishing the diagnosis. CASE PRESENTATION: In an 84-year-old woman who underwent surgery for sigmoid colon cancer, a growing solitary pulmonary nodule was identified on postoperative follow-up computed tomography. A computer tomography-guided needle biopsy was performed under suspicion that the nodule was malignant. The histopathological findings suggested a glandular papilloma. Right basilar segmentectomy was carried out, and the lesion was completely resected. Postoperative histopathological examination revealed a benign glandular papilloma accompanied by mucus retention in the surrounding alveolar region. CONCLUSIONS: A malignant neoplasm is usually suspected when a pulmonary tumor shows rapid growth. However, glandular papillomas associated with mucus retention also tend to grow in some cases, and should be included in the differential diagnosis.

Surgical treatment of a solitary pulmonary metastasis from eyelid sebaceous carcinoma: report of a case.

BACKGROUND: Ocular sebaceous carcinoma is an uncommon, aggressive ocular neoplasm with potential for regional and distant metastasis. CASE PRESENTATION: A 77-year-old woman was found to have a solitary pulmonary lesion 6 years after the initial treatment of sebaceous carcinoma of the eyelid. Video-assisted lung wedge resection of an undetermined pulmonary nodule was carried out successfully. Microscopically, the tumor showed foamy cytoplasm and atypical nuclei, consistent with metastasis of eyelid sebaceous carcinoma. CONCLUSION: This is the first case report of resected solitary pulmonary metastasis of eyelid sebaceous carcinoma. Pulmonary resection is a good option for the treatment and diagnosis of metastatic eyelid sebaceous carcinoma.

[Resection and reconstruction of sternum].

We have experienced 6 cases with resection and reconstruction of sternum. They were 1 with osteosarcoma, 1 with synovial sarcoma, 1 with sternal metastasis of fallopian tube cancer, 1 with sternal metastasis of thyroid cancer, 1 with desmoid tumor, and 1 with dermatofibrosarcoma protuberance. Resection of both manubrium and sternum was performed in 3 cases and sternum resection in 3. There was no total resection. We used a titanium reconstruction plate and titanium mesh in 3 cases, a titanium reconstruction plate and polypropylene mesh in 2, titanium mesh in 1 for reconstruction of bony defect, and rectus abdominis myocutaneous flap in 3, pectralis major muscle flap in 2, latissimus doris myocutaneous flap in 1 for reconstruction of soft tissue defect. Postoperative courses were uneventful, and flail chest was not observed. Reconstruction of the bony defect of the anterior chest wall with the titanium reconstruction plate and titanium mesh or polypropylene mesh was effective by providing sufficient rigidity as well as protection of the thoracic organs.

Simulation analysis of EGFR mutation detection: Oncomine Dx target test and AmoyDx panel impact on lung cancer treatment decisions.

Lung cancer is a leading cause of cancer-related deaths worldwide. Epidermal growth factor receptor (EGFR) driver mutations are crucial for treatment decisions for patients with non-small cell lung cancer (NSCLC). This study aimed to assess the differences in EGFR mutation detection between two companion diagnostic (CDx) tests-the Oncomine Dx Target Test (ODxTT) and the AmoyDx Pan Lung Cancer PCR Panel-and their impact on treatment applicability. To this end, we used an in-house targeted sequencing dataset of 282 samples from 127 EGFR-mutated NSCLC patients to simulate the concordance between the EGFR variants targeted by the ODxTT and AmoyDx panel, the oncogenicity of the variants, and their therapeutic potential. Of the 216 EGFR mutations identified by the in-house panel, 51% were detectable by both CDx tests, 3% were specific to ODxTT, and 46% were not targeted by either test. Most non-targeted mutations did not have oncogenicity and were located outside exons 18-21. Notably, 95% of the mutations detectable by both tests had potential oncogenicity. Furthermore, among the 96 patients harboring actionable EGFR mutations, 97% had mutations detectable by both CDx tests and 1% by ODxTT, while 2% had mutations not covered by either test. These findings suggest that while both CDx tests are effective in detecting almost all actionable EGFR mutations, ODxTT provides slightly broader coverage. These results emphasize the importance of selecting appropriate CDx tests to inform treatment decisions for EGFR-positive NSCLC patients.

Comparison of diagnostic performance between Oncomine Dx target test and AmoyDx panel for detecting actionable mutations in lung cancer.

Companion diagnostic (CDx) tests play important roles in identifying oncogenic driver genes and tailoring effective molecularly targeted therapies for lung cancer patients. In Japan, the Oncomine Dx target test (ODxTT) and the AmoyDx pan lung cancer PCR panel (AmoyDx) are prominent CDx tests and only one of these tests is covered by the domestic insurance system. However, these CDx tests cover different target regions and apply different technologies (ODxTT is amplicon-based next-generation sequencing and AmoyDx is multiplex PCR-based assay), which may lead to missing of actionable mutations affecting patient prognosis. Here, we performed a direct comparison analysis of 1059 genetic alterations of eight driver genes from 131 samples and evaluated the concordance between two CDx tests for detecting actionable variants and fusions. When excluding the eight uncovered variants (ODxTT: two variants, AmoyDx: six variants), the overall percent agreement was 97.6% (1026/1051) with 89.0% of overall positive percent agreement (89/100) and 98.5% of overall negative percent agreement (937/951). Of the 25 discordant genetic alterations, two were undetected despite being covered in the AmoyDx (one EGFR variant and one ROS1 fusion). Furthermore, there were potential false positives in the ODxTT (nine MET exon 14 skippings) and in the AmoyDx (five variants, six ROS1 and three RET fusions). These potential false positives in the AmoyDx likely due to non-specific amplification, which was validated by the unique molecular barcoding sequencing. The ODxTT missed two uncovered EGFR rare variants, which was visually confirmed in the raw sequencing data. Our study provides insights into real-world performance of CDx tests for lung cancer and ensures reliability to advance precision medicine.