Role of indoleamine 2,3-dioxygenase in acute myeloid leukemia.

Indoleamine 2,3 dioxygenase (IDO), first discovered in the 1960s, is an enzyme that has become a highly investigated metabolic target in cancer research. IDO is the rate-limiting step in tryptophan metabolism catabolism into its byproducts - kynurenines. Both IDO and kynurenines have been implicated in altering the tumor microenvironment, allowing for a tolerogenesis by affecting T-cell maturation and proliferation, and more specifically by inducing differentiation into T regulatory cells. Two mechanisms have been suspected in creating this environment: tryptophan starvation and metabolite toxicity. IDO has been shown to be expressed not only in cancer cells but also in antigen-presenting cells. The exact mechanisms underlying the two different sites of expression have not been fully elucidated. To date, most literature has focused on the role of IDO in solid tumors; we provide a review of IDO and its impact on hematological malignancies - more specifically, acute myeloid leukemia. The pathophysiology of IDO will be discussed, including a summarization of the literature to date on how IDO expression effects prognosis and disease progression in acute myeloid leukemia, along with current IDO-specific therapeutics with future considerations.

Hepatic epithelioid hemangioendothelioma in a patient with hemochromatosis.

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare hepatic vascular tumor that represents a diagnostic challenge. The rarity of this neoplasm precludes establishment of a standard-of-care treatment. Risk factors for HEHE are not well-known. Liver transplant remains the most common therapeutic modality for nonmetastatic disease. This article describes a patient who presented with abdominal pain, fatigue, poor appetite, and weight loss. Genetic testing showed that the patient was homozygous for C282Y consistent with hereditary hemochromatosis, and liver biopsy was consistent with malignant epithelioid hemangioendothelioma. The patient was referred for a liver transplant but was deemed inappropriate for transplant secondary to peritoneal studding, with frozen-section analysis showing metastatic disease at the time of surgery.

Pancreatic ductal adenocarcinoma: exploring clinicopathological trends and racial disparities in a comprehensive U.S. population-based study.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy about 50% of PDAC are metastatic at presentation. In this study, we evaluated PDAC demographics, annual trend analysis, racial disparities, survival rate, and the role of different treatment modalities in localized and metastatic disease. METHODS: A total of 144,824 cases of PDAC were obtained from the SEER database from 2000 to 2018. RESULTS: The median age was 69 years, with a slightly higher incidence in males (52%) and 80% of all cases were white. Among cases with available data, 43% were grade III tumors and 57% were metastatic. The most common site of metastasis was the liver (15.7%). The annual incidence has increased steadily from 2000 to 2018. The overall observed (OS) 5-year survival rate was 4.4% (95% CI 4.3-4.6%), and 5 years cause-specific survival (CSS) was 5% (95% CI 5.1-5.4%). The 5-year survival with multimodal therapy (chemotherapy, surgery, and radiation) was 22% (95% CI 20.5-22.8%). 5-year CSS for the blacks was lower at 4.7% (95% CI 4.2-5.1%) compared to the whites at 5.3% (95% CI 5.1-5.4%). Multivariate analysis found male gender and black race associated with worse prognosis. Kaplan-Meier survival analysis found multimodal therapy to have the best outcomes in all three stages. CONCLUSION: PDAC is an aggressive malignancy with male gender and black race are associated with a poor prognosis. Surgery with chemoradiation was associated with the best overall survival. With steadily increasing rates of PDAC, improved treatment modalities are paramount to improving survival in these patients.

Effect of Exercise Training on Quality of Life, Symptoms, and Functional Status in Advanced-Stage Lung Cancer Patients: A Systematic Review.

Advanced-stage lung cancer (LC) causes significant morbidity and impacts patients' quality of life (QoL). Exercise has been proven to be safe, feasible, and beneficial for symptom reduction and QoL improvement in many types of cancers, but research is limited in advanced-stage LC patients. This systematic review evaluates the effect of exercise interventions on the symptoms and QoL in patients with advanced-stage LC. Twelve prospective studies (744 participants) were included, evaluating different combinations of exercises and training such as aerobics, tai chi, strength, inspiratory muscle training, and relaxation. Studies found outcomes including but not limited to improved QoL, symptom burden, psychosocial health, functional status, and physical function. The results of this review support that exercise is safe and feasible with evidence supporting improved QoL and symptom mitigation. Integration of exercise should be considered in the individualized management of advanced-stage LC patients under the guidance of their healthcare providers.

Do Current Lung Cancer Clinical Trials Represent All Patient Populations Including Minorities?

The under-representation of racial, sexual, and gender minorities in cancer clinical trials has long been a deficit in clinical cancer research. This review aims to survey current literature to determine the participation of minorities in the United States in lung cancer clinical trials and to find educational methods that have been studied and researched in order to improve patient clinical trial enrollment. A literature search of relevant articles published since 2015 was conducted using PubMed and Google Scholar. Clinical trials conducted in the United States from Clinicaltrials.gov were also collected to determine minority patient enrollment in lung cancer clinical trials. The results of the literature search yielded 6 relevant articles about racial minority representation in lung cancer clinical trials and one relevant article about LGBTQ+ minority representation in cancer clinical trials. Collectively, the literature highlighted the under-representation of racial minorities (such as Black, Hispanic, and American Indian) in clinical trials. Many articles showed that disparities in enrollment were less significant for Asian patients with lung cancer. However, many articles did not mention minorities like Middle Eastern/North Africans and failed to mention the lack of distinguishment of South Asian minorities from Pacific Asian minorities. The findings of this literature review support the idea that current lung cancer clinical trials lack representation of minority patient populations in the United States. The inclusion of racial, sexual, and gender diversity in clinical trial patient populations will aid providers in determining appropriate therapeutics and could potentially improve lung cancer outcomes. Future directions for improving diversity in lung cancer clinical trial enrollment include the utilization of various educational tools to increase minority patient participation in trials, the inclusion of detailed demographic data in cancer clinical trial analysis, and the recruitment of providers and research staff from various minorities to conduct cancer clinical trials.

Pulmonary large cell neuroendocrine carcinoma (LCNEC): a population-based study addressing recent molecular-genetic advances and emerging therapeutic approaches.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) of the lung is a rare, aggressive cancer most commonly found in the lungs but not exclusively, with a worse prognosis than non-small cell lung carcinomas. Currently, LCNEC patients are treated using small cell and non-small cell protocols. This study aims to use the SEER database to identify demographic, clinical, pathological, and therapeutic factors affecting the prognosis and survival of patients with LCNEC of the lung. METHODS: Demographic, clinical, and management data of patients with lung LCNEC were extracted from the SEER database for the period 2000-2018. RESULTS: In the USA, LCNEC has a higher incidence in elderly white men: M:F ratio = 1.2:1, Caucasian: 83.3%, mean age: 67 ± 10.2 years. The most common treatment modality was chemotherapy only: 29.2%, followed by surgery: 21.5% (but in this group the statuses of chemotherapy were unknown), and combination surgery/chemotherapy: 8.8%. The overall and cause-specific 5-year survival was 17.5% (95% CI 16.3-18.8) and 21.9% (95% CI 20.5-23.4), respectively. By treatment, the best 5-year survival was for surgery alone (48%), followed by multimodality therapy (chemo + surgery + radiation) at 35% (95% CI 27-43). Age > 60 years, male gender, size > 7 cm, and nodal and liver metastasis were independent risk factors associated with increased mortality. CONCLUSION: Lung LCNEC is an aggressive neoplasm most common in older white males that presents at an advanced stage despite small primary tumors. Most patients die within 2 years. The best predictor of survival is surgery with chemotherapy. Given its dismal prognosis, new treatment guidelines are needed for this aggressive cancer.

Clinicopathological and Treatment Patterns of Combined Small-Cell Lung Carcinoma with Future Insight to Treatment: A Population-Based Study.

BACKGROUND: Primary lung cancer is the most common cause of cancer-related mortality in the United States (US). Approximately 90% of lung cancers are associated with smoking and the use of other tobacco products. Based on histology, lung cancers are divided into small-cell lung carcinomas (SCLCs) and non-small-cell lung carcinomas (NSCLCs). Most SCLCs are of the pure subtype, while the rare combined SCLCs contain elements of both small-cell and non-small-cell morphologies. This study sought to evaluate the demographics, clinical factors, molecular abnormalities, treatment approaches, and survival outcomes with combined SCLC and NSCLCs. MATERIALS AND METHODS: Data on 2126 combined SCLC patients was extracted from the Surveillance Epidemiology and End Result (SEER) database from 2000 to 2018. Data extracted for analyses included age, sex, race, tumor size, tumor location, metastasis status, stage at diagnosis, treatment received, and treatment outcomes. Multivariate analysis was performed using Statistical Product and Service Solutions (SPSS) software. RESULTS: The patients had a median age of 68 years; 43.9% of the patients were female and 56.1% were male; 84.5% were White and 11.7% were African Americans. The majority of patients had a poorly differentiated disease at 29.6%; 17% were undifferentiated, 3.2% were moderately differentiated, and 0.8% were well differentiated. Chemotherapy was the most common treatment modality (45.3%); 17% underwent surgery only, 10.3% underwent surgery followed by adjuvant chemotherapy, and 10% underwent radiation after surgery. Five-year cancer-specific survival was 15.2% with surgery alone, and combined surgery and chemotherapy provided the highest percentages (38.3% and 34.7%, respectively). Females had significantly higher 1- and 5-year cancer-specific survival rates compared to males (59.3% and 29.9% vs. 48.0% and 23.7, respectively; p < 0.001). Well-differentiated tumors had significantly higher survival compared to other gradings (p < 0.001). Survival decreased as tumor staging moved distally from localized to regional to distant (p < 0.001). Metastasis to bone, liver, brain, and lung significantly decreased survival in comparison to patients who did not have any metastasis (p < 0.001). Females had significantly shorter survival compared to their counterparts when metastasis was to the bone, brain, or liver (p < 0.001). Multivariate analysis identified male sex (Hazard Ratio (HR) = 1.2), undifferentiated grade (HR = 1.9), regional extent of disease (HR = 1.7), distant extent of disease (HR = 3.7), and metastasis to liver (HR = 3.5) as variables associated with worse survival. CONCLUSION: Combined SCLC is overall very rare. However, the frequency of presentation with combined SCLC is on the rise, in part due to improvements in diagnostic techniques. Despite advances in therapies, treating combined SCLC is challenging, and novel therapies are not utilized, owing to low rates of targetable mutations. Combined SCLC has higher survival rates if well differentiated.

Demographics and Clinicopathologic Profile of Pulmonary Sarcomatoid Carcinoma with Survival Analysis and Genomic Landscape.

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer (NSCLC) with an aggressive clinical nature and poor prognosis. With novel targeted therapeutics being developed, new ways to effectively treat PSC are emerging. In this study, we analyze demographics, tumor characteristics, treatment modalities, and outcomes of PSC and genetic mutations in PSC. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) database were reviewed to analyze cases of pulmonary sarcomatoid carcinoma from 2000 to 2018. The molecular data with the most common mutations in PSC were extracted from the Catalogue Of Somatic Mutations in Cancer (COSMIC) database. Results: A total of 5259 patients with PSC were identified. Most patients were between 70 and 79 years of age (32.2%), male (59.1%), and Caucasian (83.7%). The male-to-female ratio was 1.45:1. Most tumors were between 1 and 7 cm in size (69.4%) and poorly differentiated (grade III) (72.9%). The overall 5-year survival was 15.6% (95% confidence interval (95% CI) = 14.4-16.9)), and the cause-specific 5-year survival was 19.7% (95% CI = 18.3-21.1). The five-year survival for those treated with each modality were as follows: chemotherapy, 19.9% (95% CI = 17.7-22.2); surgery, 41.7% (95% CI = 38.9-44.6); radiation, 19.1% (95% CI = 15.1-23.5); and multimodality therapy (surgery and chemoradiation), 24.8% (95% CI = 17.6-32.7). On multivariable analysis, age, male gender, distant stage, tumor size, bone metastasis, brain metastasis, and liver metastasis were associated with increased mortality, and chemotherapy and surgery were associated with reduced mortality (p < 0.001). The best survival outcomes were achieved with surgery. The most common mutations identified in COSMIC data were TP53 31%, ARID1A 23%, NF1 17%, SMARCA4 16%, and KMT2D 9%. Conclusions: PSC is a rare and aggressive subtype of NSCLC, usually affecting Caucasian males between 70 and 79. Male gender, older age, and distant spread were associated with poor clinical outcomes. Treatment with surgery was associated with better survival outcomes.

Survival Benefit of Adjuvant Chemotherapy in Pulmonary Carcinoid Tumors.

Pulmonary carcinoid tumors are a rare subtype of neuroendocrine cell tumor found in approximately 1-2% of lung cancers. Management is primarily through surgical resection, with limited benefit of adjuvant therapy in the clinical setting. Genomic profiling is in the nascent stages to molecularly classify these tumors, but there are promising insights for future targeted therapy. A total of 80 abstracts were analyzed for further review with 11 included in our final analysis. Only 4 of the 11 reviewed in depth provided statistical analysis. We evaluated PFS, OS, 1- and 5-year survival as mentioned in the studies. Nodal and KI67 status were also analyzed. Based on the current literature, there is no definitive evidence that adjuvant chemotherapy after resection confers a survival benefit in typical or atypical carcinoids.

Would the Addition of Immunotherapy Impact the Prognosis of Patients With Malignant Pericardial Effusion?

Pericardial effusion is a common finding in advanced-stage lung cancer. The presence of malignant cells or drainage of exudate effusion in the pericardial space may cause symptoms of dyspnea, pleuritic chest pain, and syncope. In addition to the difficulty physicians face in the detection and diagnosis of malignant pericardial effusion, treatment may be challenging considering the cancer prognosis and cardiovascular stability of the patient. Despite the availability of several treatment modalities for malignant pericardial effusion, including chemotherapy and surgery, patients with lung cancer historically present with poor prognoses. In addition to lung adenocarcinoma with malignant pericardial effusion, this case was complicated by COVID-19 and malignancy-associated obstructive pneumonia. We present a case of a 64-year-old woman with advanced non-small cell lung carcinoma (NSCLC) with malignant pericardial effusion who, despite testing positive for COVID-19 and having obstructive pneumonia, had favorable outcomes following systemic therapy with combined chemo-immunotherapy.

The Role of Serial Liquid Biopsy in the Management of Metastatic Non-Small Cell Lung Cancer (NSCLC).

Lung cancer is the leading cause of cancer-related deaths. Surgery remains the best option to treat lung cancer when feasible. However, many cases are diagnosed beyond the initial stages. There has been tremendous progress in the treatment of lung cancer over the last few years. Studies have shown that biomarker-driven targeted therapies lead to better outcomes. Due to the technical difficulties and significant procedural risk associated with repeated tissue biopsies, analysis of tumor constituents circulating in the blood, such as circulating tumor DNA (ctDNA) and various proteins, is becoming more widely recognized as an alternative method of tumor sampling, i.e., liquid biopsy. Liquid biopsy is superior to tissue biopsy, as it is minimally invasive and easily repeatable. Given the recent data on changes in mutations as the disease progresses or responds to treatment, liquid biopsies can help monitor the changes and guide us in giving targeted drugs. Here we present a case of advanced NSCLC who was initially started on Alectinib based on positivity for ALK gene rearrangement found in the FISH study. At the time of progression, molecular profiling liquid biopsy was obtained, which revealed KRAS-p.G12C mutation. Thus, the patient's therapy was later on changed to sotorasib after the FDA approved a KRAS-p.G12C mutation inhibitor.

Endobronchial lipoma.

Endobronchial lipomas are rare benign lung tumors that can cause bronchial obstruction and parenchymal damage. While an uncommon etiology, they are often misdiagnosed due to a clinical presentation similar to obstructive pulmonary pathologies such as COPD and asthma. Upon review of English-language literature, under 50 cases of endobronchial lipomas were documented in the prior 10 years (2011-2021). There are no clear guidelines regarding the management of this particular entity, but typically interventional debulking is the treatment of choice. Here we present another unique case of endobronchial lipoma along with our diagnostic and therapeutic methodology. The patient underwent bronchoscopic debulking via a cryotherapy probe. Based on the histopathologic analysis, a diagnosis of endobronchial lipoma was made. Endobronchial lipomas must remain in any clinician's differential when a patient presents with dyspnea. We report the unique location of this lipoma based on our literature review and the importance of investigating endobronchial lesions due to a possible diagnosis of endobronchial lipoma.

A Phase I Trial to Determine the Safety and Tolerability of Autophagy Inhibition Using Chloroquine or Hydroxychloroquine in Combination With Carboplatin and Gemcitabine in Patients With Advanced Solid Tumors.

Background: Autophagy is a catabolic process that is triggered in cells during periods of metabolic or hypoxic stress, which enables their survival during this challenge. Autophagy may also impart survival advantage to tumors cells undergoing attack from chemotherapy or radiation. Inhibition of early-stage autophagy can rescue cancer cells, while inhibition of late-stage autophagy enhances cell death due to accumulation of damaged organelles. The antiparasitic drugs chloroquine (CQ) and hydroxychloroquine (HCQ) inhibit late-phase autophagy. We assessed the safety, tolerability, and efficacy of combining CQ or HCQ with carboplatin and gemcitabine (CG) in patients with refractory advanced solid tumors. Methods: This single institution phase 1 dose-escalation study was designed to evaluate the maximum tolerated dose (MTD) of CQ/HCQ, in combination with CG, in patients with advanced solid tumors. Secondary objectives were to determine overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). A starting dose of CQ or HCQ 50 mg was used in conjunction with standard starting doses of CG and increased in increments of 50 mg in each patient dose cohort. Grade 3 or greater toxicity that is treatment related, and was not self-limited, or not controlled in <7 days was considered dose-limiting toxicity (DLT). Results: Twenty-two patients were enrolled. All patients had at least one prior treatment, and 11 of them had 3 prior regimens. CQ/HCQ 100 mg daily was found to be the MTD in combination with CG with thrombocytopenia and/or neutropenia dose limiting. The median overall (OS) was 11 months, and the 1- and 3-year OS were 30% and 7%, respectively. Median progression-free survival was 5 months, and the 6-, 12-, and 18-month progression-free survivals were 48%, 21%, and 14%, respectively. Conclusion: The MTD identified for CQ/HCQ was lower than previously reported with concomitant use of chemotherapeutic regimes likely due to the myelosuppressive nature of CG in previously treated patients.

Recurrent Metastatic Chordoma to the Liver: A Case Report and Review of the Literature.

Chordoma is a rare malignant neoplasm derived from notochordal tissue that primarily affects the axial skeleton. Almost 40% of patients have non-cranial chordoma metastases. The most common metastatic sites are the lungs, bones, lymph nodes, and subcutaneous tissue. We present a 52-year female with a history of sacral chordoma presenting with abdominal fullness, early satiety, and a palpable abdominal mass. Abdominal magnetic resonance imaging (MRI) revealed an isolated, highly vascularized, and multilobed liver mass in the left lateral segment. The mass was surgically removed using a clean surgical margin. A histological examination and immunohistochemical staining were consistent with a metastatic chordoma. Two years later, follow-up imaging studies showed a 6.5 × 4.0 × 2.0 cm right liver lesion with multiple lungs, chest wall, pleural, and diaphragmatic lesions. Microscopic- and immunohistochemical staining revealed a recurrent metastatic chordoma. Herein, we present a unique case of metastatic recurrent chordoma in the liver with the involvement of other sites. To the best of our knowledge, no other case of recurrent liver metastasis has been reported.

Does Molecular Profiling of KRAS-Mutant Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Help in Treatment Strategy Planning?

Background: Several studies suggest that patients with KRAS-mutant NSCLC fail to benefit from standard systemic therapies and do not respond to EGFR inhibitors. Most recently, KRAS 12c data suggest specific treatment for improving ORR and OS. There is a clear need for therapies specifically developed for these patients. Moreover, data that might be suggestive of a response to specific therapies, such as BRCA1, are needed, and two mutations that were studied in other malignancies show more response to PARP inhibitors. Molecular profiling has the potential to identify other potential targets that may provide better treatment and novel targeted therapy for KRAS-mutated NSCLC. Methods: We purified RNA from archived tissues of patients with stage I and II NSCLC with wild-type (wt) and mutant (mt) KRAS tumors; paired normal tissue adjacent to the tumor from 20 and 17 patients, respectively, and assessed, using real-time reverse transcriptase−polymerase chain reaction (RT-PCR), the expression of four genes involved in DNA synthesis and repair, including thymidylate synthase (TS), BRCA1, ECCR1, RAP80, and the proto-oncogene SRC. Additionally, we assessed the expression of PD-L1 in mt KRAS tumors with immunohistochemistry using an antibody against PD-L1. Results: Our results show that in mtKRAS tumors, the level of expression of ERCC1, TS, and SRC was significantly increased in comparison to paired normal lung tissue (p ≤ 0.04). The expression of BRCA1 and RAP80 was similar in both mt KRAS tumors and paired normal tissue. Furthermore, the expression of BRCA1, TS, and SRC was significantly increased in wt KRAS tumors relative to their expression in the normal lung tissue (p < 0.044). The expression of ERCC1 and RAP80 was similar in wt KRAS tumors and paired normal tissue. Interestingly, SRC expression in mtKRAS tumors was decreased in comparison to wt KRAS tumors. Notably, there was an expression of PD-L1 in the tumor and stromal cells in a few (5 out of 20) mtKRAS tumors. Our results suggest that a greater ERCC1 expression in mt KRAS tumors might increase platinum resistance in this group of patients, whereas the greater expression of BRCA1 in wt KRAS tumor might be suggestive of the sensitivity of taxanes. Our data also suggest that the combination of an SRC inhibitor with a TS inhibitor, such as pemetrexed, might improve the outcome of patients with NSCLC and in particular, patients with wt KRAS tumors. PD-L1 expression in tumors, and especially stromal cells, suggests a better outcome. Conclusion: mt KRAS NSCLC patients might benefit from a treatment strategy that targets KRAS in combination with therapeutic agents based on pharmacogenomic markers, such as SRC and BRCA1. mtKRAS tumors are likely to be platinum-, taxane-, and pemetrexed-resistant, as well as having a low level of PD-L1 expression; thus, they are less likely to receive single-agent immunotherapy, such as pembrolizumab, as the first-line therapy. wt KRAS tumors with BRCA1 positivity tend to be sensitive to taxane therapy and, potentially, platinum. Our results suggest the need to develop targeted therapies for KRAS-mutant NSCLC or combine the targeting of oncogenic KRAS in addition to other therapeutic agents specific to the molecular profile of the tumor.

Autophagy Agents in Clinical Trials for Cancer Therapy: A Brief Review.

Autophagy has been of novel interest since it was first demonstrated to have effect in Burkitt's lymphoma. Since that time, the autophagy agents chloroquine and hydroxychloroquine have become the only FDA (Food and Drug Administration)-approved autophagy inhibitors. While not approved for cancer therapy, there are ongoing clinical trials to evaluate their safety and efficacy. Pevonedistat has emerged as a novel inhibitor through the neddylation pathway and is an autophagy activator. This paper summarizes and presents current clinical trials for hydroxychloroquine (HCQ), chloroquine (CQ), and Pevonedistat for the clinician.

Assessment of Tissue Adequacy by EBUS in Conjunction with PET Scan and Operator's Experience.

Mediastinal lymph node assessment is a crucial step in non-small cell lung cancer staging. Positron emission tomography (PET) has been the gold standard for the assessment of mediastinal lymphadenopathy, though it has limited specificity. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is quick, accurate, and a less invasive method for obtaining a diagnostic sample in contrast to mediastinoscopy. We performed a retrospective chart analysis of 171 patients to assess the adequacy of tissue obtained by EBUS for diagnosis and molecular profiling as well as the assessment of staging and lymph node (LN) stations diagnostic yield, in correlation to PET scan and the operator's level of experience. A significantly increased tissue adequacy was observed based on the operators' experience, with the highest adequacy noted in trained Interventional Pulmonologist (IP) (100%), followed by >5 years of experience (93.33%), and 88.89% adequacy with <5 years of experience (p = 0.0019). PET-CT scan 18F-fluorodeoxyglucose (FDG) uptake in levels 1, 2, and 3 LN had a tissue adequacy of 76.67%, 54.64%, and 35.56%, respectively (p = 0.0009). EBUS bronchoscopy method could be used to achieve an accurate diagnosis, with IP-trained operators yielding the best results. There is no correlation with PET scan positivity, indicating that both PET and EBUS are complementary methods needed for staging.

A Phase I Study of the Non-Receptor Kinase Inhibitor Bosutinib in Combination with Pemetrexed in Patients with Selected Metastatic Solid Tumors.

Src is overexpressed in various cancers, including 27% of non-small cell lung cancer NSCLC, and is correlated with poor clinical outcomes. We hypothesize that Src kinase inhibitors, including Bosutinib, may exhibit clinical synergy in combination with the antifolate drug pemetrexed. In this Phase I, dose-escalation, safety, and maximum tolerated dose (MTD)-determining study, 14 patients with advanced metastatic solid tumors that had progressed on "standard of care" chemotherapy were enrolled in a 3 + 3 dose escalation study. Oral Bosutinib was administered once daily beginning on day 1, where the first cohort started at an oral dose of 200 mg daily with pemetrexed 500 mg/m2 IV on a three-week schedule. The study's primary objective was to determine the dose-limiting toxicity (DLT), the MTD of Bosutinib in combination with pemetrexed, and the type and frequency of adverse events associated with this treatment. Twelve patients were evaluable for response, including ten patients with adenocarcinoma of the lung, one patient with metastatic adenocarcinoma of the appendix, and one patient with urothelial carcinoma. The median number of Bosutinib and pemetrexed cycles received was 4 (range, 1-4). The MTD of oral Bosutinib in this combination was 300 mg daily. Two patients (17%) had a partial response (PR), and seven patients (58%) showed stable disease (SD) as the best response after the fourth cycle (end of treatment). One patient had disease progression after the second cycle, while three patients had disease progression after the fourth cycle. The two responders and the two patients with the longest stable disease duration or stabilization of disease following progression on multiple systemic therapies demonstrated Src overexpression on immunohistochemical staining of their tumor. The median progression-free survival (PFS) was 6.89 months (95% CI (3.48, 30.85)), and the median overall survival (OS) was 11.7 months (95% CI (3.87, 30.85)). Despite the limitations of this Phase I study, there appears to be potential efficacy of this combination in previously treated patients.

Incidence, Survival Analysis and Future Perspective of Primary Peritoneal Mesothelioma (PPM): A Population-Based Study from SEER Database.

BACKGROUND: Primary peritoneal mesothelioma (PPM) is a rare and aggressive tumor arising from the visceral and parietal peritoneum. The diagnosis and treatment of PPM are often delayed because of non-specific clinical presentation, and the prognosis is worse. The current study investigated the demographic, clinical, and pathological factors affecting patient prognosis and survival in PPM. METHODS: Demographic and clinical data of 1998 patients with PPM were extracted from the Surveillance Epidemiology and End Results (SEER) database (1975-2016). The chi-square test, paired t-test, and multivariate analysis were used to analyze the data. RESULTS: The majority of PPM patients were male (56.2%, p < 0.005) and Caucasian (90.4%, p < 0.005, with a mean age of diagnosis was 69 ± 13 years. The grading, histological, and tumor size information were classified as "Unknown" in most of the cases, but when available, poorly differentiated tumors (8.7%), malignant mesothelioma, not otherwise specified (63.4%) and tumors > 4 cm in size (8%), respectively, were most common, p < 0.005. Chemotherapy was administered to 50.6% of patients, followed by resection (29.2%) and radiation (1.5%), p < 0.001. The cohort of PPM had a five-year overall survival of 20.3% (±1.1), compared to 43.5% (±5.9), 25.9% (± 8.4), and 18.7% (±1.6) for those with surgery, radiation, or chemotherapy alone, respectively. Poor differentiation (OR = 4.2, CI = 3.3-4.9), tumor size > 4 cm (OR = 3.9, CI = 3.2-4.5), Caucasian race (OR = 2.9, CI = 2.6-4.4), and distant SEER stage (OR = 2.5, CI = 1.1-3.2) were all linked with increased mortality (p < 0.001). CONCLUSION: An extremely rare and aggressive peritoneal tumor, PPM may be difficult to identify at the time of diagnosis. Radiation therapy likely to have a limited function in the treatment of this condition, with surgery and chemotherapy being the primary choices. All PPM patients should be enrolled in a nationwide registry to improve our understanding of the pathogenesis and identify factors affecting survival.

Current Understanding of "Mixed Corticomedullary Adrenal Tumor" and an Insight into Genomic Profiling.

BACKGROUND: Malignant mixed corticomedullary adrenal tumors (MCMTs) are extremely rare, with limited cases reported in the literature. The pathophysiology of malignant MCMTs is not well understood; the most prevailing theories are that it is a composite tumor of embryologically derived mesodermal (adrenal cortex) and neural crest (medulla) origin, perpetuating as two distinct cell lines forming a singular mass. Clinical features and laboratory diagnosis are associated with hypersecretions of the adrenal cortex and medulla. Surgical resection is curative in an isolated tumor. We reviewed and compared cases in the literature highlighting the pathogenesis and genetics of benign and malignant MCMT. METHODS: Comprehensive literature analysis was conducted on PubMed and all the cases of mixed corticomedullary adrenal tumor published in English were included. RESULTS: Most patients were female (73.1%) with a median age of 49 in women and 50 in men. Surgery was performed in all patients, and in four patients with malignant disease, chemotherapy was used as well. Clinically, most patients presented with hypertension (69%) followed by Cushing syndrome (42%) and diabetes (19%). Tumors often produced cortisol (74%), catecholamines (50%), and adrenocorticotrophic hormone (ACTH) (38%), with lower incidence of aldosterone- (7%) or dopamine (4%)-producing tumors. Immunohistochemical staining of 96% of cases showed Chromogranin-A (73%) and Synaptophysin (62%), followed by Inhibin-α (50%), Melan-A (31%), and S-100 (23%). Of the reported four cases with malignant disease, three showed a Ki-67 index of 40-50% with one showing less than 5%. CONCLUSION: Mixed corticomedullary adrenal tumors rarely present as a malignant disease requiring chemotherapy. Most MCMTs confer a good prognosis and respond well to surgical resection, though their pathogenesis is largely up to speculation because of limited data. Current theories regarding MCMT pathogenesis should be investigated further with genetic testing. Future research on MCMT may provide ways to guide physician diagnosis and subsequent treatment for refractory cases.