Takotsubo Cardiomyopathy in Cancer Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Summary of Included Cases.

BACKGROUND: There are emerging reports of Takotsubo syndrome (TTS) in cancer patients treated with immune checkpoint inhibitors (ICIs); however, the association of the two remains uncertain. METHODS: A systematic literature review was performed in the PubMed database and web sources (Google Scholar) according to the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines. Case reports/series or studies including cancer patients treated with ICIs and presenting with TTS were considered. RESULTS: Seventeen cases were included in the systematic review. Most patients were males (59%) with median age of 70 years (30-83). Most common tumor types were lung cancer (35%) and melanoma (29%). Most patients were on first-line immunotherapy (35%) and after the first cycle (54%) of treatment. The median time on immunotherapy at the time of TTS presentation was 77 days (1-450). The most used agents were pembrolizumab and the combination of nivolumab-ipilimumab (35%, respectively). Potential stressors were recognized in 12 cases (80%). Six patients (35%) presented with concurrent cardiac complications. Corticosteroids were used in the management of eight patients (50%). Fifteen patients (88%) recovered from TTS, two patients (12%) relapsed, and one patient died. Immunotherapy was reintroduced in five cases (50%). CONCLUSION: TTS may be associated with immunotherapy for cancer. Physicians should be alert for TTS diagnosis in any patient with myocardial infarction-like presentation under treatment with ICIs.

Bcl-2 pathway inhibition in solid tumors: a review of clinical trials.

Due to their key role in the pathogenesis of cancer through the regulation of apoptosis, the B-cell leukemia/lymphoma-2 (BCL-2) family proteins have been an attractive target for cancer therapy for the past decades. Throughout the years, many Bcl-2 family inhibitors have been developed, with Venetoclax being now successfully used in treating hematological malignancies. Although their effectiveness in the treatment of solid tumors is yet to be established, some preclinical evidence indicates their possible clinical application. This review aims to summarize current data from completed clinical trials that used Bcl-2 protein family inhibitors as monotherapy or in combination with other agents for the treatment of solid malignancies. We managed to include clinical trials of various phases which analyze the pharmacokinetics and pharmacodynamics of the drugs, as well as the effectiveness and adverse effects. Active and recruiting clinical trials are also briefly presented and future prospects and challenges are discussed.

Capecitabine-associated enterocolitis: Narrative literature review of a rare adverse event and a case presentation.

Capecitabine is an oral 5-fluorouracil prodrug with antimetabolite activity commonly used in advanced colorectal and breast cancer. It presents with a generally good toxicity profile and most of the adverse events can be managed effectively. Enterocolitis is a rare, under-reported, but potentially fatal adverse event associated with capecitabine use. To the best of our knowledge, there are 21 cases of capecitabine-related enterocolitis reported in the literature. We herein present a narrative literature review of enteritis/colitis cases associated with capecitabine use, with highlight to the most common clinical presentation, common imaging and microscopic findings and management approach. We furthermore present a case of severe capecitabine-related enteritis.

Immune Checkpoint Blockade in Hormone Receptor-Positive Breast Cancer: Resistance Mechanisms and Future Perspectives.

Anti-programmed cell death protein 1 immunotherapy has been incorporated in the treatment algorithm of triple-negative breast cancer (TNBC). However, clinical trial results for patients with hormone receptor (HR)-positive disease appear less compelling. HR-positive tumors exhibit lower levels of programmed death-ligand 1 expression in comparison with their triple-negative counterparts. Moreover, signaling through estrogen receptor alters the immune microenvironment, rendering such tumors immunologically "cold." To explain differential responses to immune checkpoint blockade, this review interrogates differences between HR-positive and TNBC. Starting from distinct genomic features, we further present disparities concerning the tumor microenvironment and finally, we summarize early-phase clinical trial results on promising novel immunotherapy combinations.

Assessment of Seroconversion after SARS-CoV-2 Vaccination in Patients with Lung Cancer.

Background: SARS-CoV-2 mortality rates are significantly higher in patients with lung cancer compared with the general population. However, little is known on their immunization status after vaccination. Methods: To evaluate the humoral response (seroconversion) of patients with lung cancer following vaccination against SARS-COV-2 (Group A), we obtained antibodies against SARS-CoV-2 spike (S) protein both at baseline and at different time points after the first dose of SARS-CoV-2 vaccine (two to three weeks [T1], six weeks ± one week [T2], 12 weeks ± three weeks [T3], and 24 weeks ± three weeks [T4]). Antibodies were also acquired from a control cohort of non-lung cancer patients (Group B) as well as a third cohort containing healthy controls (Group C) at all time points and at T4, respectively, to make comparisons with Group A. Analysis of antibody response at different time points, association with clinicopathologic parameters, and comparisons with control groups were performed. Results: A total of 125 patients with lung cancer were included in the analysis (96 males [74.3%], median age of 68 years [46−91]. All study participants received two vaccine doses (BNT162b2, mRNA-1273, AZD1222). Analysis of anti-SARS-CoV-2 S antibody titers showed minimal response at T1 (0.4 [0.4−48.6] IU/mL). Antibody response peaked at T2 (527.0 [0.4−2500] IU/mL) and declined over T3 (323.0 [0.4−2500] IU/mL) and T4 (141.0 [0.4−2500] IU/mL). Active smokers had lower antibody titers at T2 (p = 0.04), T3 (p = 0.04), and T4 (p < 0.0001) compared with former or never smokers. Peak antibody titers were not associated with any other clinicopathologic characteristic. No significant differences were observed compared with Group B. However, lung cancer patients exhibited significantly decreased antibody titers compared with Group C at T4 (p < 0.0001). Conclusions: Lung cancer patients demonstrate sufficient antibody response six weeks after the first dose of vaccine against SARS-CoV-2 when vaccinated with two-dose regimens. Rapidly declining antibody titers six weeks after the first dose underline the need for a third dose three months later, in patients with lung cancer, and especially active smokers.

Enteric plexus neuropathy associated with PD-L1 blockade in a patient with small-cell lung cancer.

Immune checkpoint inhibitors have revolutionized the management of patients with cancer. The increasing use of these agents has brought up a new set of adverse events which are widely heterogenous and potentially life-threatening. Rare immune-related adverse events associated with nervous system have not been described thoroughly, but their early recognition and management may be crucial. Immune-related autonomic neuropathy may be presented with a constellation of symptoms ranging from gastrointestinal and urinary complaints, to sweating and hypotension. Intestinal pseudo-obstruction as consequence of immune-related myenteric autonomic neuropathy is an under-recognized, not-well described and potentially fatal adverse event. We herein, present a unique case of enteric plexus neuropathy induced by PD-L1 blockade in a patient with small-cell lung cancer.

Lay abstract Immunotherapy with immune checkpoint inhibitors has improved the life expectancy in many cancer patients. However, the stimulation of immune system to fight cancer may also affect healthy tissues, bringing about the risk of adverse events. These adverse events may affect almost every organ system of the body and may vary from mild to life-threatening. Immunotherapy-related damage to nervous plexuses, which supply the guts with nerves, has been reported only in a small number of cases. The symptoms usually mimic those of gut inflammation, including diarrhea, constipation, abdominal distension, and vomiting. Upon these symptoms, enteric nervous system toxicity should be considered. Early recognition and management are crucial to stop further neurological damage. We present a rare case of enteric nerve damage in a patient with small-cell lung cancer treated with immunotherapy.

Tumor Dormancy: Implications for Invasion and Metastasis.

Tumor dormancy refers to a critical stage of cancer development when tumor cells are present, but cancer does not progress. It includes both the concept of cellular dormancy, indicating the reversible switch of a cancer cell to a quiescent state, and that of tumor mass dormancy, indicating the presence of neoplastic masses that have reached cell population equilibrium via balanced growth/apoptosis rates. Tumor dormancy provides the conceptual framework, potentially explaining a major challenge in clinical oncology, tumor recurrence, which may occur years after cancer diagnosis. The mechanisms by which tumors are kept dormant, and what triggers their reawakening, are fundamental questions in cancer biology. It seems that a plethora of intracellular pathways and extracellular factors are involved in this process, rewiring the cells to plastically alter their metabolic and proliferative status. This phenomenon is highly dynamic in space and time. Mechanistic insights into both cellular and tumor dormancy have provided the rationale for targeting this otherwise stable period of cancer development, in order to prevent recurrence and maximize therapeutic benefit.

The changing treatment of metastatic her2-positive breast cancer.

Human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer has been historically associated with an aggressive disease course with common distant metastasis and poor prognosis. HER2-targeting therapies have significantly changed treatment and drastically improved outcomes for this group of patients. However, primary or acquired resistance to anti-HER2 regimens leads almost universally to disease progression, often with difficult to treat central nervous system (CNS) metastases. The current review summarized the existing therapeutic options for HER2-positive metastatic disease in the first, second and further line setting. Furthermore, novel agents currently under development were presented, which have demonstrated encouraging results in heavily pretreated patients or specific subgroups, such as HR-positive/HER2-positive tumors and CNS disease.

PET/CT and brain MRI role in staging NSCLC: prospective assessment of the accuracy, reliability and cost-effectiveness.

AIM: To determine whether PET/CT and brain MRI used in staging NSCLC can be accurate, reliable and cost-effective tools. NSCLC represents 80-85% of lung cancer and adequate information on the initial tumor staging is critical for planning an optimal therapeutic strategy. PATIENTS & METHODS: Data from 30 newly diagnosed NSCLC patients in Greece were collected and prospectively recorded. Patients with potential resectable disease were evaluated to ensure that there are no detectable metastases that would rule out the possibility of a curative surgery. RESULTS: Divergence occurred in 50% of cases of staging with CT or PET/CT alone, while metastases undetectable by the CT were revealed using PET/CT. Unnecessary thoracotomies were avoided by 10% of patients and another 10% was operated on after chemotherapy with a better prognosis. CONCLUSION: PET/CT and brain MRI combined are reliable for correct staging, reducing avoidable thoracotomies, morbidity rates and costs.

Optimizing diet and nutrition for cancer survivors: A review.

The number of cancer survivors is increasing and they are often highly motivated to search for information about nutrition and about physical activity in order to try to improve their treatment outcomes, quality of life and overall survival. In the light of these concerns, the World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) as well as the American Cancer Society recommend a largely plant-based diet with limited consumption of red and processed meat, and limited consumption of alcohol, as well as the maintenance of a healthy weight throughout life and regular engagement in physical activity. There is a need for well-designed large observational and intervention studies to shed more light on the association between diet and cancer survivorship, and to suggest additional means for the secondary prevention of cancer.

The Emerging Role of Tyrosine Kinase Inhibitors in Ovarian Cancer Treatment: A Systematic Review.

The present systematic review summarizes current evidence regarding the mechanisms of action, the efficacy, and the adverse effects of tyrosine kinase inhibitors (TKIs) in ovarian cancer patients. Phase II and III clinical trials were sought in the PubMed database and in the Clinical Trials.gov registry through September 30, 2015. Seventy-five clinical trials regarding TKIs targeting mainly vascular endothelial growth factor receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, and sarcoma tyrosine kinase (Src) were yielded. The most promising results were noted with cediranib, nintedanib, and pazopanib. However, drawing universal conclusions about the potential integration of TKIs in ovarian cancer therapy remains elusive. Furthermore, emerging challenges and directions for the future research are critically discussed.

Management and Outcomes in Metaplastic Breast Cancer.

Metaplastic breast cancer (MBC) constitutes a rare clinical entity with special clinicopathologic, immunohistochemical, and molecular features. Resistance to systemic therapies, whether chemotherapy or hormonal therapy, is among its main characteristics, which in turn explains the poor prognosis and renders its management a challenge. Thus, the scope of the present review is to discuss the current therapeutic strategies for MBC in clinical practice and the corresponding outcomes and to suggest possible directions for future research. Potential novel targeted therapies could provide a hope for better outcomes but limited data are available owing to the rarity of MBC. As knowledge accumulates on the pathogenesis and genetic characteristics of MBC, emphasis should be given to the implementation of more targeted treatments, which will allow more efficient and individualized management of the disease.

Profile of capecitabine/temozolomide combination in the treatment of well-differentiated neuroendocrine tumors.

Neuroendocrine tumors are a rare and heterogeneous group of tumors with a variety of primary origins and variable aggressiveness. Platinum-based chemotherapy has been the cornerstone of treatment for the poorly differentiated tumors. However, well-differentiated neuroendocrine tumors are quite chemoresistant and therapy options are limited. Octreotide analogs and tyrosine kinase inhibitors are widely acceptable treatments due to substantial efficacy and tolerable toxicity. On the contrary, monotherapy or combinations of the only approved cytotoxic agent streptozocin with other drugs have been almost abandoned because of excessive toxic events. In recent years, the combination of capecitabine and temozolomide has emerged as the most promising and efficacious treatment. The oral route of administration and the substantial improvement in the outcomes with manageable toxicity are the major advantages. We reviewed the current literature and presented the profile of the capecitabine/temozolomide combination in the management of well-differentiated neuroendocrine tumors.

The intercellular cell adhesion molecule-1 (icam-1) in lung cancer: implications for disease progression and prognosis.

The intercellular cell-adhesion molecule-1 (ICAM-1) is a transmembrane molecule and a distinguished member of the Immunoglobulin superfamily of proteins that participates in many important processes, including leukocyte endothelial transmigration, cell signaling, cell-cell interaction, cell polarity and tissue stability. ICAM-1and its soluble part are highly expressed in inflammatory conditions, chronic diseases and a number of malignancies. In the present article we present the implications of ICAM-1 in the progression and prognosis of one of the major global killers of our era: lung cancer.

Soluble ICAM-1 levels in small-cell lung cancer: prognostic value for survival and predictive significance for response during chemotherapy.

Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule, member of the immunoglobulin gene superfamily that seems to participate in the evolution of the metastatic process. We investigated the significance of baseline soluble ICAM-1 levels on the outcome of patients with small-cell lung cancer and whether soluble ICAM-1 is a predictive marker for objective response during and after chemotherapy in patients with small-cell lung cancer. Fifty patients with recently diagnosed small-cell lung cancer, as well as 27 healthy smokers, were enrolled. Blood samples were collected at the time of diagnosis, during and at the end of chemotherapy. Data were correlated with the characteristics of the patients and survival as well as with ICAM-1 predictive role for objective response. Statistical significant values of baseline soluble ICAM between patients and controls (p < 0.001) were observed. Multivariate analysis revealed an elevated risk of death of 9 % in the first year after diagnosis for every 10 units of increased soluble ICAM-1 at the baseline (p = 0.046). Performance status and disease stage were also independent prognostic factors. Patients with extensive disease who achieved an objective response during chemotherapy showed a significant decrease (25.8 %) in their soluble ICAM-1 levels compared with baseline levels (p = 0.001). Alongside performance status and disease stage, baseline soluble ICAM-1 could be evaluated as an additional prognostic factor in patients with small-cell lung cancer. Also, a possible role for soluble ICAM-1 may exist as a predictive marker for objective response during chemotherapy for patients with extensive disease (p = 0.001).

Targeted therapy for nonsmall cell lung cancer: focusing on angiogenesis, the epidermal growth factor receptor and multikinase inhibitors.

Chemotherapy used to be the only available option to fight advanced nonsmall cell lung cancer. Platinum-based medication combined with taxanes, vinca alkaloids, and antimetabolites improved patient survival rates. Unfortunately, neoplasmatic diseases remain a global killer because chemotherapy benefits have reached a plateau and most patients are diagnosed at the metastatic stage. The urgent need for therapeutic agents, along with advances in the knowledge of the molecular events of oncogenesis, has resulted in the development of medication that specifically targets processes and pathways critical for tumor growth, such as angiogenesis and the epidermal growth factor receptor. Initially, inhibiting these pathways managed to prolong patient survival, although not to the extent desired. Moreover, targeted therapy combined with conventional cytotoxic agents has shown no superiority to chemotherapy alone in terms of patient survival. Hence, numerous multidynamic agents have appeared in the hope that they might help fight nonsmall cell lung cancer. However, no group of patients who will hopefully gain maximum benefit from such interventions has been clearly identified yet. This paper presents current evidence with regard to such novel agents and angiogenesis and epidermal growth factor inhibitors.