A rare case of Takotsubo cardiomyopathy.

BACKGROUND: The recent advent of the cyclin-dependent kinase (CDK) 4/6 inhibitors has considerably evolved hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer treatment. Palbociclib, an orally administered pyridopyrimidine derivative, was the first CDK4/6 inhibitor to be introduced into daily clinical practice in combination with classic endocrine backbone, based on progression-free survival (PFS) benefit assessed in the pivotal PALOMA series of randomized clinical trials. Regarding its safety profile, neutropenia and leukopenia are the most common and well-defined adverse effects, while cardiac complications are rather scarce. CASE REPORT: We present the rare case of a middle-aged female patient with HR+/HER2- metastatic breast cancer, without prior exposure to cardiotoxic antineoplastic agents, who developed Takotsubo cardiomyopathy (TTC) in the context of systemic therapy with palbociclib plus letrozole combination. CONCLUSIONS: Pharmacovigilance and experimental studies are warranted to confirm any causative relationship and to explore the underlying pathophysiology, respectively.

Differential immunohistochemical expression of hTERT in lung cancer patients with and without idiopathic pulmonary fibrosis.

BACKGROUND: Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase enzyme, which adds nucleotides to telomeres and counteracts their length shortening. The development of a telomere maintenance mechanism represents a hallmark of cancer. On the other hand, idiopathic pulmonary fibrosis (IPF) is associated with mutations in telomerase genes and shorter telomeres. IPF is frequently complicated with lung cancer. AIM: To investigate the expression of hTERT in lung cancer with co-existing IPF and to compare with lung cancer without fibrosis. METHODS: Diagnostic lung cancerous biopsies were retrieved from 18 patients with lung cancer and concomitant IPF, as well as 18 age and gender matched controls with lung cancer without pulmonary fibrosis. The expression of hTERT was studied with immunohistochemistry. ImajeJ software was used to quantitate subcellular stain intensity. Immunohistochemical investigation of two senescence-associated markers, p16 and p21, was also performed in all 36 cases. RESULTS: Both groups highly expressed hTERT, without significant difference (100% vs 95%, p = 0.521). Evaluation of p16 and p21 immunostaining revealed negative to minimal immunoreactivity in both groups. hTERT localization exhibited higher median nuclear intensity in the group of lung cancer with IPF (0.62 vs 0.45, p = 0.016), while cytoplasmic intensity did not differ significantly (0.17 vs 0.15, p = 0.463). Higher median nuclear intensity was also correlated with small cell lung cancer subtype in the whole study sample (0.69 vs 0.45, p = 0.09). CONCLUSION: hTERT is highly expressed in lung cancer with concomitant IPF, but with differential localization compared to lung cancer without IPF, implying differences in pathogenicity and requiring further investigation.

Central-line-associated bloodstream infections, multi-drug-resistant bacteraemias and infection control interventions: a 6-year time-series analysis in a tertiary care hospital in Greece.

BACKGROUND: Central-line-associated bloodstream infections (CLABSIs) are serious healthcare-associated infections with substantial morbidity and hospital costs. AIM: To investigate the association between the incidence of CLABSIs, the implementation of specific infection control measures, and the incidence of multi-drug-resistant (MDR) bacteraemias in a tertiary care hospital in Greece from 2013 to 2018. METHODS: Analysis was applied for the following indices, calculated monthly: CLABSI rate; use of hand hygiene disinfectants; isolation rate of patients with MDR bacteria; and incidence of bacteraemias [total Gram-negative carbapenem-resistant Acinetobacter baumanii, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Klebsiella pneumoniae; and Gram-positive meticillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci]. FINDINGS: The total number of bacteraemias from carbapenem-resistant Gram-negative pathogens was significantly correlated with an increased CLABSI rate for all (total) hospital departments [incidence rate ratio (IRR) 1.17, 95% confidence interval (CI) 1.05-1.31, P=0.006] and the adult intensive care unit (ICU) (IRR 1.37, 95% CI 1.07-1.75, P=0.013). In the adult ICU, every increase in the incidence of each resistant Gram-negative pathogen was significantly correlated with a decreased CLABSI rate (carbapenem-resistant A. baumanii: IRR 0.59, 95% CI 0.39-0.90, P=0.015; carbapenem-resistant K. pneumoniae: IRR 0.48, 95% CI 0.25-0.94, P=0.031; carbapenem-resistant P. aeruginosa: IRR 0.54, 95% CI 0.33-0.89, P=0.015). The use of hand disinfectants was correlated with a decreased CLABSI rate 1-3 months before the application of this intervention for all (total) hospital departments (IRR 0.80, 95% CI 0.69-0.93, P=0.005), and for scrub disinfectants in the current month for the adult ICU (IRR 0.34, 95% CI 0.11-1.03, P=0.057). Isolation of patients with MDR pathogens was not associated with the incidence of CLABSIs. CONCLUSION: Hand hygiene was associated with a significant reduction in the incidence of CLABSIs at the study hospital. Time-series analysis is an important tool to evaluate infection control interventions.

Cyclin-dependent kinase (CDK) inhibitors in solid tumors: a review of clinical trials

Cyclin-dependent kinases (CDKs) play a key regulating role in the cell cycle, which is almost universally altered in cancer, leading to sustained proliferation. Early pan-CDK inhibitors showed poor results in clinical trials for solid malignancies, as the lack of selectivity produced significant toxicity. The production of more selective inhibitors led to significant developments in cancer therapy, as CDK4/6 inhibitors in combination with endocrine therapy changed the landscape of the treatment of hormone-receptor positive (HR +) metastatic breast cancer. Recently, Trilaciclib demonstrated benefits regarding hematological toxicity compared to placebo when administered in combination with chemotherapy in small cell lung cancer. Newer agents, such as SY-5609, a selective CDK7 inhibitor, have also shown promising results in early clinical trials. In this paper, we review the data from clinical trials of CDK inhibitors in solid tumors, either as a monotherapy or in combination with other agents, with an emphasis on novel agents and potential new indications for this drug class.

Cyclin-dependent kinase (CDK) inhibitors in solid tumors: a review of clinical trials.

Cyclin-dependent kinases (CDKs) play a key regulating role in the cell cycle, which is almost universally altered in cancer, leading to sustained proliferation. Early pan-CDK inhibitors showed poor results in clinical trials for solid malignancies, as the lack of selectivity produced significant toxicity. The production of more selective inhibitors led to significant developments in cancer therapy, as CDK4/6 inhibitors in combination with endocrine therapy changed the landscape of the treatment of hormone-receptor positive (HR +) metastatic breast cancer. Recently, Trilaciclib demonstrated benefits regarding hematological toxicity compared to placebo when administered in combination with chemotherapy in small cell lung cancer. Newer agents, such as SY-5609, a selective CDK7 inhibitor, have also shown promising results in early clinical trials. In this paper, we review the data from clinical trials of CDK inhibitors in solid tumors, either as a monotherapy or in combination with other agents, with an emphasis on novel agents and potential new indications for this drug class.

Treating patients with ALK-rearranged non-small-cell lung cancer: mechanisms of resistance and strategies to overcome it.

Anaplastic lymphoma kinase (ALK) rearrangement is detected in 3-7% of patients with non-small-cell lung cancer. Crizotinib is an ALK inhibitor, which was approved in 2011 for the treatment of ALK-positive lung cancer. Despite the initial enthusiasm, most of the patients develop resistance within the first year of treatment. The main mechanisms are secondary mutations and bypass track activation. Moreover, crizotinib has low penetration into the central nervous system. The need to overcome these limitations has led to the development of second-generation inhibitors that have better effectiveness against crizotinib-resistant mutations and brain metastases. Ceritinib and alectinib are the only approved drugs of this group. Many ongoing trials try to define the most appropriate agent for the treatment of ALK-positive lung cancer depending on the responsible mechanism. This review focuses on the current data regarding the potential mechanisms of resistance to ALK inhibitors and the strategies to overcome it.

Neuroendocrine Merkel cell nodal carcinoma of unknown primary site: management and outcomes of a rare entity.

Merkel cell nodal carcinoma of unknown primary (MCCUP) is a rare neuroendocrine tumour with distinct clinical and biological behaviour. We conducted a review of retrospective data extracted from 90 patients focusing on the management and outcome of this disease. We also compared life expectancy of these patients with the outcome of patients with known Merkel primaries and with neuroendocrine cancers of unidentifiable primary. There is a limited body of data for this type of malignancy, however, patients with Merkel cell nodal carcinoma of unknown primary site, seem to have better survival when treated aggressively than patients with cutaneous Merkel tumours of the same stage and equal survival with patients with low-grade neuroendocrine tumour of unknown origin. The lack of prospective trials, and the inadequate data, hamper the management of these tumours. Establishment of treatment guidelines is urgently needed.

Mutational profiling of the RAS, PI3K, MET and b-catenin pathways in cancer of unknown primary: a retrospective study of the Hellenic Cooperative Oncology Group.

Cancer of unknown primary origin (CUP) had a poor prognosis, determined by clinico-histological characteristics, partly due to the lack of insights on its biology. We screened tumour DNA from 87 patients with CUP for CTNNB1 (coding exons 2,3,4,5), MET (coding exon 18), PIK3CA (coding exons 9,20), KRAS (coding exons 1,2), BRAF (coding exon 15) gene mutations by using dd-sequencing and evaluated their impact on prognosis. Mutated gene incidences in the 87 CUP cases were: KRAS 11 (12.6 %), BRAF 5 (5.7 %), PIK3CA 8 (9 %), MET 6 (6.7 %) and CTNNB1 18 (20.7 %). Several mutations in the KRAS gene were not the commonly encountered mutations in other solid tumours. Activating mutations were observed in 10.2 % in KRAS, 4.5 % in BRAF, 6.6 % in PIK3CA, 4.5 % in MET, and 19.5 % in CTNNB1. Activating mutations in PIK3CA coding exon 9 were inversely correlated with MET coding exon 18 activating mutations (p = 0.036). MET activating mutations were prognostic for poor Progression-Free Survival (median PFS 5 vs 9 months, p = 0.009) and Overall Survival (median OS 7 vs 20 months, p = 0.005). The complex profile of either CTNNB1 or MET mutations also had an adverse prognostic significance (median OS 11 vs 21 months, p = 0.015). No other gene mutation exhibited prognostic significance. In multivariate analysis, poor performance status, male gender, visceral disease and adenocarcinoma histology, but not gene mutations, were independently associated with poor patient outcome. CTNNB1 gene mutations are frequent, and along with MET mutations have an adverse prognostic effect in patients with CUP.

Gastrointestinal bleeding as initial presentation of melanoma of unknown primary origin: report of a case and review of the literature.

The case of an 81-year-old patient, initially presenting with gastrointestinal (GI) bleeding, including melena and hematemesis is reported. Endoscopy revealed an ulcerated mass of the stomach corpus with immunohistochemistry stains consistent with metastatic melanoma. The thorough physical and paraclinical examination did not reveal any lesions or nodules as a primary site of the disease. The literature concerning this rare presentation of melanoma is also reviewed.

Targeted therapy for oesophageal cancer: an overview.

Oesophageal cancer (OC), is an aggressive cancer constituting a major cause of cancer-related deaths worldwide. Recent advances in surgical techniques, incorporation of new therapeutic approaches -- adjuvant/neoadjuvant chemoradiotherapy -- and integration of new cytotoxic drugs into the management of oesophageal cancer have increased the response rate percentages to 40-50%, with minor impact on the overall survival. The need for an efficacious therapy with minimal toxicity along with a better understanding of molecular pathways of oesophageal carcinogenesis has led to the development of novel anticancer agents. These agents have targeted mechanisms of action such as: (1) inhibitors of the ErbB receptor family, (2) vascular endothelial growth factor (VEGF) inhibitors, (3) selective inhibitors of cycloxygenase-2, (4) matrix metalloproteinase inhibitors, (5) cell-cycle regulators, and (6) promoters of apoptosis. The incorporation of these agents into combined modality treatment schedules for advanced and early stage tumors together with the identification of patients who will most likely benefit will provide novel opportunities in the treatment of oesophageal cancer.