Psychiatric manifestations, personality traits and health-related quality of life in cancer of unknown primary site.

OBJECTIVE: Psychiatric manifestations and personality traits are known to influence cancer patients. We aimed to assess psychological distress symptoms, psychosocial factors and health-related quality of life (HRQoL) in cancer of unknown primary site (CUP) and to test whether these parameters differ between CUP and Metastatic (MKPC) or Non-Metastatic Known Primary Cancers (N-MKPC) after controlling for demographics and clinical variables. METHODS: In this cross-sectional study, we recruited 50 CUP, 264 N-MKPC and 52 MKPC participants. We assessed depressive symptoms (Center for Epidemiologic Studies-Depression [CES-D]), psychological distress symptoms (Symptom Distress Checklist-90 Revised), sense of coherence (SOC), ego defense mechanisms (Life Style Index) and HRQoL (World Health Organization Quality of Life Instrument, Short Form). RESULTS: The prevalence of clinically significant depressive symptoms (CES-D ≥ 23) was 40.0% in CUP, 28.8% in MKPC and 23.5% N-MKPC (p=0.037). Multivariate logistic regression analysis showed that N-MKPC patients were 5 times less likely (p=0.028) and MKPC patients 3.3 times less likely (p=0.05) to be assessed with probable depression compared with CUP patients after controlling for the major demographic and clinical variables studied. CUP patients presented also higher levels of somatization, anxiety and depressive symptoms; they also had more impaired Physical (p=0.005), Mental (p=0.041) and Social Relations (p=0.044) HRQoL, along with lower scores on SOC and intellectualization defense and higher scores on repression defense, compared with MKPC and N-MKPC patients. CONCLUSIONS: These findings suggest that psychiatric manifestations are frequent in CUP, and the patients' resources to cope with the burden of their illness are limited. Attention to CUP patients' psychological distress and coping resources and capacities may enable oncologists to identify and manage modifiable aspects of HRQoL.

Self-Reported Real-World Safety and Reactogenicity of COVID-19 Vaccines: A Vaccine Recipient Survey.

An online survey was conducted to compare the safety, tolerability and reactogenicity of available COVID-19 vaccines in different recipient groups. This survey was launched in February 2021 and ran for 11 days. Recipients of a first COVID-19 vaccine dose ≥7 days prior to survey completion were eligible. The incidence and severity of vaccination side effects were assessed. The survey was completed by 2002 respondents of whom 26.6% had a prior COVID-19 infection. A prior COVID-19 infection was associated with an increased risk of any side effect (risk ratio 1.08, 95% confidence intervals (1.05-1.11)), fever (2.24 (1.86-2.70)), breathlessness (2.05 (1.28-3.29)), flu-like illness (1.78 (1.51-2.10)), fatigue (1.34 (1.20-1.49)) and local reactions (1.10 (1.06-1.15)). It was also associated with an increased risk of severe side effects leading to hospital care (1.56 (1.14-2.12)). While mRNA vaccines were associated with a higher incidence of any side effect (1.06 (1.01-1.11)) compared with viral vector-based vaccines, these were generally milder (p < 0.001), mostly local reactions. Importantly, mRNA vaccine recipients reported a considerably lower incidence of systemic reactions (RR < 0.6) including anaphylaxis, swelling, flu-like illness, breathlessness and fatigue and of side effects requiring hospital care (0.42 (0.31-0.58)). Our study confirms the findings of recent randomised controlled trials (RCTs) demonstrating that COVID-19 vaccines are generally safe with limited severe side effects. For the first time, our study links prior COVID-19 illness with an increased incidence of vaccination side effects and demonstrates that mRNA vaccines cause milder, less frequent systemic side effects but more local reactions.

Backward Running: Acute Effects on Sprint Performance in Preadolescent Boys.

The aim of this study was to examine the acute effect of backward running (BwR) during warm-up on a 20-m sprint of boys' performance, compared to forward running (FwR). Fourteen recreationally active preadolescent boys (aged 12.5 ± 0.5 years) were examined in 3 protocols: warm-up (control condition), warm-up with 3 × 10 m additional BwR sprints and warm-up with 3 × 10 m additional FwR sprints. Participants were evaluated 4 minutes after each protocol on a 20-m sprint and intermediate distances, as well as the rate of perceived exertion (RPE). Sprint speed across 10-20 m was significantly higher for the BwR warm-up compared to the regular warm-up (p < 0.05) and a significantly higher RPE after the BwR and FwR protocols compared to the control condition was recorded (p < 0.05). No significant difference was detected across the distances 0-5, 5-10, 0-10 and 0-20 m. Although adding 3 × 10-m sprints of BwR or FwR after the warm-up did not enhance performance in a 20 m sprint of preadolescent boys, the positive effect of BwR across 10-20 m distance suggests that BwR could be an alternative means for enhancing performance for certain phases of a sprint for this age. However, preadolescent boys' response to different sprint conditioning exercise stimuli and the optimization of rest time to maximize performance remain to be determined.

Comprehensive analysis of drugs to treat SARS­CoV­2 infection: Mechanistic insights into current COVID­19 therapies (Review).

The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID­19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID­19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.

COVID­19 in Northern Italy: An integrative overview of factors possibly influencing the sharp increase of the outbreak (Review).

Italy is currently one of the countries seriously affected by the COVID­19 pandemic. As per 10 April 2020, 147,577 people were found positive in a total of 906,864 tests performed and 18,849 people lost their lives. Among all cases, 70.2% of positive, and 79.4% of deaths occurred in the provinces of Northern Italy (Lombardi, Emilia Romagna, Veneto and Piemonte), where the outbreak first started. Originally, it was considered that the high number of positive cases and deaths in Italy resulted from COVID­19 initially coming to Italy from China, its presumed country of origin. However, an analysis of the factors that played a role in the extent of this outbreak is needed. Evaluating which factors could be specific for a country and which might contribute the most is nevertheless complex, with accompanying high uncertainty. The purpose of this work is to discuss some of the possible contributing factors and their possible role in the relatively high infection and death rates in Northern Italy compared to other areas and countries.

SARS-CoV-2 pathophysiology and its clinical implications: An integrative overview of the pharmacotherapeutic management of COVID-19.

Common manifestations of COVID-19 are respiratory and can extend from mild symptoms to severe acute respiratory distress. The severity of the illness can also extend from mild disease to life-threatening acute respiratory distress syndrome (ARDS). SARS-CoV-2 infection can also affect the gastrointestinal tract, liver and pancreatic functions, leading to gastrointestinal symptoms. Moreover, SARS-CoV-2 can cause central and peripheral neurological manifestations, affect the cardiovascular system and promote renal dysfunction. Epidemiological data have indicated that cancer patients are at a higher risk of contracting the SARS-CoV-2 virus. Considering the multitude of clinical symptoms of COVID-19, the objective of the present review was to summarize their pathophysiology in previously healthy patients, as well as in those with comorbidities. The present review summarizes the current, though admittedly fluid knowledge on the pathophysiology and symptoms of COVID-19 infection. Although unclear issues still remain, the present study contributes to a more complete understanding of the disease, and may drive the direction of new research. The recognition of the severity of the clinical symptoms of COVID-19 is crucial for the specific therapeutic management of affected patients.

Economic evaluation of trifluridine and tipiracil hydrochloride in the treatment of metastatic colorectal cancer in Greece.

AIM: To evaluate the cost-effectiveness of trifluridine and tipiracil hydrochloride (FTD/TPI) compared with best supportive care (BSC) or regorafenib for the treatment of patients with metastatic colorectal cancer who have been previously treated with or are not considered candidates for available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents and anti-EGFR agents in Greece. METHODS: A partitioned survival model was locally adapted from a third-party payer perspective over a 10 year time horizon. Efficacy data and utility values were extracted from published studies. Resource consumption data were obtained from local experts using a questionnaire developed for the purpose of the study and was combined with unit costs obtained from official sources. All costs reflect the year 2017 in euros. Primary outcomes were patients' life years (LYs), quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs) per QALY and LYs gained. RESULTS: Total life time cost per patient for FTD/TPI, BSC and regorafenib was estimated to be €10,087, €1,879 and €10,850, respectively. In terms of health outcomes, FTD/TPI was associated with 0.25 and 0.11 increment in LYs compared with BSC and regorafenib, respectively. Furthermore, FTD/TPI was associated with 0.17, and 0.07 increment in QALYs compared with BSC and regorafenib, resulting in ICERs of €32,759 per LY gained and €49,326 per QALY gained versus BSC. Moreover, FTD/TPI was a dominant alternative over regorafenib. CONCLUSION: The results indicate that FTD/TPI may represent a cost-effective treatment option compared with other alternative therapies as a third-line treatment of metastatic colorectal cancer in Greece.

Clinical feasibility of NGS liquid biopsy analysis in NSCLC patients.

BACKGROUND: Analysis of circulating tumor nucleic acids in plasma of Non-Small Cell Lung Cancer (NSCLC) patients is the most widespread and documented form of "liquid biopsy" and provides real-time information on the molecular profile of the tumor without an invasive tissue biopsy. METHODS: Liquid biopsy analysis was requested by the referral physician in 121 NSCLC patients at diagnosis and was performed using a sensitive Next Generation Sequencing assay. Additionally, a comparative analysis of NSCLC patients at relapse following EGFR Tyrosine Kinase Inhibitor (TKIs) treatment was performed in 50 patients by both the cobas and NGS platforms. RESULTS: At least one mutation was identified in almost 49% of the cases by the NGS approach in NSCLC patients analyzed at diagnosis. In 36 cases with paired tissue available a high concordance of 86.11% was observed for clinically relevant mutations, with a Positive Predictive Value (PPV) of 88.89%. Furthermore, a concordance rate of 82% between cobas and the NGS approach for the EGFR sensitizing mutations (in exons 18, 19, 21) was observed in patients with acquired resistance to EGFR TKIs, while this concordance was 94% for the p.T790M mutation, with NGS being able to detect this mutation in three 3 additional patients. CONCLUSIONS: This study indicates the feasibility of circulating tumor nucleic acids (ctNA) analysis as a tumor biopsy surrogate in clinical practice for NSCLC personalized treatment decision making. The use of new sensitive NGS techniques can reliably detect tumor-derived mutations in liquid biopsy and provide clinically relevant information both before and after targeted treatment in patients with NSCLC. Thus, it could aid physicians in treatment decision making in clinical practice.

Iron-substituted cubic silsesquioxane pillared clays: Synthesis, characterization and acid catalytic activity.

Novel pillared structures were developed from the intercalation of iron-substituted cubic silsesquioxanes in a sodium and an acid-activated montmorillonite nanoclay and evaluated as acid catalysts. Octameric cubic oligosiloxanes were formed upon controlled hydrolytic polycondensation of the corresponding monomer (a diamino-alkoxysilane) and reacted with iron cations to form complexes that were intercalated within the layered nanoclay matrices. Upon calcination iron oxide nanoparticles are formed which are located on the silica cubes (pillars) and on the surfaces of the clay platelets. Acid activation of the nanoclay was performed in order to increase the number of acid active sites in the pristine clay and thus increase its catalytic activity. A plethora of analytical techniques including X-ray diffraction, thermal analyses, Fourier transform infrared, electron paramagnetic resonance, Raman, Mössbauer and X-ray photoelectron spectroscopies and porosimetry measurements were used in order to follow the synthesis steps and to fully characterize the final catalysts. The resulting pillared clays exhibit a high specific area and show significant acid catalytic activity that was verified using the catalytic dehydration of isopropanol asa probe reaction.

Comprehensive molecular screening by next generation sequencing reveals a distinctive mutational profile of KIT/PDGFRA genes and novel genomic alterations: results from a 20-year cohort of patients with GIST from north-western Greece.

INTRODUCTION: Gastrointestinal stromal tumours (GIST) are mesenchymal neoplasms that usually carry an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes with predictive and prognostic significance. We investigated the extended mutational status of GIST in a patient population of north-western Greece in order to look at geopraphic/genotypic distinctive traits. PATIENT AND METHODS: Clinicopathological and molecular data of 38 patients diagnosed from 1996 to 2016 with GIST in the region of Epirus in Greece were retrospectively assessed. Formalin-fixed paraffin-embedded tumours were successfully analysed for mutations in 54 genes with oncogenic potential. Next generation sequencing was conducted by using the Ion AmpliSeqCancer Hotspot Panel V.2 for DNA analysis (Thermofisher Scientific). RESULTS: Among 38 tumours, 24 (63.16%) and seven (18.42%) of the tumours harboured mutations in the KIT and PDGFRA genes, respectively, while seven (18.42%) tumours were negative for either KIT or PDGFRA mutation. No mutations were detected in five (13.16%) cases. Concomitant mutations of BRAF and fibroblast growth factor receptor 3 (FGFR3) genes were observed in two patients with KIT gene mutation. Two patients with KIT/PDGFRA wild-type GIST had mutations in either KRAS or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) genes. There was no significant survival difference regarding the exonic site of mutation in either KIT or PDGFRA gene. The presence of a mutation in pathway effectors downstream of KIT or PDGFRA, such as BRAF, KRAS or PIK3CA, was associated with poor prognosis. Adverse prognosticators were also high mitotic index and the advanced disease status at diagnosis. CONCLUSIONS: We report comparable incidence of KIT and PDGFRA mutation in patients with GIST from north-western Greece as compared with cohorts from other regions. Interestingly, we identified rare mutations on RAS, BRAF and PIK3CA genes in patients with poor prognosis.

Diltiazem-induced eosinophilic pleural effusion.

A 68-year-old woman developed eosinophilic pleural effusion and systemic eosinophilia 2 months after starting antihypertensive therapy with diltiazem. Several drugs are known to cause this disorder; however, the only other drug the patient had been taking was clonidine, which she had taken for the past 3-4 years. She was evaluated for all other possible causes of eosinophilia and eosinophilic pleural effusion, including malignancy, infection, and autoimmune disorders. Her symptoms resolved after diltiazem was discontinued, and no recurrence was noted on follow-up. To our knowledge, this is the first case report of eosinophilic pleural effusion caused by diltiazem. According to the Naranjo adverse drug reaction probability scale, a probable relationship existed between diltiazem and the patient's eosinophilia and pleural effusion. Although numerous drugs have been associated with eosinophilia and eosinophilic pleural effusion, the spectrum may actually be wider than is commonly thought and may include such unrecognized agents as diltiazem.

Nivolumab-induced hypothyroidism and selective pituitary insufficiency in a patient with lung adenocarcinoma: a case report and review of the literature.

Immune checkpoint blockade including programmed cell death 1 pathway inhibition with agents such as nivolumab is gaining ground in a wide array of malignancies, so far demonstrating significantly improved survival rates even in metastatic, often multiply pretreated settings. Although targeted in nature and generally well-tolerated compared with conventional anticancer treatments, these agents are often linked to a newly emerged group of adverse reactions, referred to as immune-related adverse events, which can also affect endocrine organs. This is a case report of a patient who received nivolumab for the treatment of recurrent metastatic non-small cell lung cancer and developed primary hypothyroidism and secondary adrenal insufficiency caused by selective pituitary dysfunction (with preservation of all other endocrine functions). After hormone replacement with daily administration of T4, T3 and hydrocortisone, the patient achieved complete recovery. Adequate characterisation of these rare yet potentially severe entities is essential for prompt diagnostic and therapeutic interventions that will permit us to fully benefit from these new agents' therapeutic potential.

CYP polymorphisms and pathological conditions related to chronic exposure to organochlorine pesticides.

The association between genetic variations in the cytochrome P450 (CYP) family genes and pathological conditions related to long-term exposure to organochlorine compounds (OCs) deserves further elucidation. OCs are persistent organic pollutants with bioaccumulative and lipophilic characteristics. They can act as endocrine disruptors and perturb cellular mechanisms. Prolonged exposure to OCs has been associated with different pathological manifestations. CYP genes are responsible for transcribing enzymes essential in xenobiotic metabolism. Therefore, polymorphisms in these genetic sequences a. alter the metabolic pathways, b. induce false cellular responses, and c. may provoke pathological conditions. The main aim of this review is to define the interaction between parameters a, b and c at a mechanistic/molecular level, with references in clinical cases.

A mini review on pregnant mothers with cancer: A paradoxical coexistence.

The diagnosis of cancer during pregnancy at least in the Western world is a rare phenomenon, but this might be raised into the future due to late pregnancies in the modern societies. The coexistence of pregnancy and cancer implicates numerous medical, ethical, psychological and sometimes religious issues between the mother, the family and the treating physician. Breast, cervical cancer, melanoma and lymphoma are the most common malignancies diagnosed during pregnancy. Diagnostic or therapeutic irradiation requires careful application, whereas systemic chemotherapy is not allowed during the first trimester of pregnancy due to lethal or teratogenic effects as well as to congenital malformations. In some gestational cancers, tumor cells can invade the placenta or the fetus.

Lung cancer during pregnancy: A narrative review.

Lung cancer, the leading cause of cancer deaths in males for decades, has recently become one of commonest causes for women too. As women delay the start of their family, the co-existence of cancer and pregnancy is increasingly observed. Nevertheless, lung cancer during pregnancy remains a rather uncommon condition with less than 70 cases published in recent years. Non-small cell lung carcinoma is the commonest type accounting for about 85% of all cases. Overall survival rates are low. Chemotherapy and/or targeted treatment have been used with poor outcomes. The disease has been also found to affect the products of conception with no short- or long-term consequences for the neonate. This article is referring to a narrative review of lung cancers diagnosed in pregnant women around the world.

Bone and soft tissue sarcomas during pregnancy: A narrative review of the literature.

Bone or soft tissue sarcomas are rarely diagnosed during pregnancy. Until today 137 well documented cases have been reported in the English literature between 1963 and 2014. Thirty-eight pregnant mothers were diagnosed with osteosarcoma, Ewing's sarcoma or chondrosarcoma, whereas 95 other cases of soft tissue sarcomas of various types have been documented. We present the clinical picture and therapeutic management of this coexistence.

Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: Where do we stand? A literature review.

BACKGROUND: Cervical cancer is the fourth most common cancer affecting women worldwide. Despite advances in screening and human papillomavirus (HPV) vaccination, a significant number of women present with or develop advanced disease. Palliative platinum-based chemotherapy (CT) is the standard first-line treatment for metastatic/recurrent cervical cancer. The prognosis remains poor and effective second line options are urgently needed. METHODS: We searched the English-language medical literature as well as relevant guideline databases, published from January 1981 to December 2015 and identified publications related to cervical cancer and its therapies. Our effort was to highlight the available treatment options in the setting of recurrent/metastatic disease. RESULTS: Although there have been important advances in the management of women with cervical cancer, the optimal treatment for patients with locally recurrent and metastatic disease after platinum failure is still problematic. Overall, there is a trend in terms of longer overall survival (OS) and better quality of life for the combination of cisplatin/paclitaxel (PC) as compared to the doublets of cisplatin/topotecan (TC), cisplatin/vinorelbine (VC), and cisplatin/gemcitabine (GC). Currently available single agents beyond first-line platinum-based therapy have limited efficacy in this setting and include topoisomerase inhibitors, vinca alkaloids, taxanes, alkylating agents and antimetabolites. Several targeted therapies have demonstrated activity in advanced cervical cancer. Bevacizumab has been evaluated in a phase III trial using doublets of cisplatin with paclitaxel or topotecan and has been approved in the first-line setting by the U. S. Food and Drug Administration. Selective targeting of angiogenic kinases by tyrosine kinase inhibitors (TKIs) may represent a novel therapeutic tool in this setting, but its use alone or in combination with CT is still investigational. Early reports have implicated PI3KCA somatic mutations suggesting that mTOR-targeted agents should be explored in this disease. Development of the immune checkpoint programmed cell death 1 (PD-1) and T-lymphocyte-associated molecule-4 (CTLA-4) inhibitors have been of considerable interest, leading to ongoing phase II studies in patients with advanced cervical cancer. CONCLUSIONS: Progress in the management of recurrent and advanced cervical cancer patients has been slow and restricted to palliative intent. These patients should be considered for clinical trials of novel targeted agents and/or immunotherapy.

Severe resistant hypoglycemia in a patient with a pancreatic neuroendocrine tumor on sunitinib treatment.

OBJECTIVE: Sunitinib is a tyrosine kinase inhibitor used in the therapy of pancreatic neuroendocrine tumors (PNETs), metastatic renal cancer and gastrointestinal stromal tumors. We describe a patient with PNET who presented with severe hypoglycemia following sunitinib administration. CASE REPORT: A 64-year old man with known metastatic PNET presented with a history of recurring episodes of severe, life-threatening hypoglycemia 3 months after initiation of sunitinib treatment. Investigations during symptomatic hypoglycemia revealed inappropriately increased plasma insulin and C-peptide levels, consistent with endogenous hyperinsulinemia. No immune staining for insulin was observed in tissue samples from peritoneal metastatic tumor lesions, and serum anti-insulin antibodies were negative. Medical management with diazoxide, methylprednisolone and ocreotide was ineffective; continuous intravenous infusion of glucagon was required to maintain euglycemia. Following discontinuation of sunitinib there was gradual improvement in both the severity and frequency of the hypoglycemia. Six months later, the patient remained free of hypoglycemic episodes. CONCLUSIONS: We describe a patient with PNET who experienced severe, life-threatening hypoglycemia following sunitinib use. It is important that glucose levels of patients treated with sunitinib are monitored on a regular basis; those patients with diabetes may need to have their antidiabetic treatment adjusted to prevent hypoglycemia.

An unusual presentation of a patient with advanced prostate cancer, massive ascites and peritoneal metastasis: Case report and literature review.

We describe the case of a patient with prostate cancer, ascites, omental and bone metastases, an extremely rare clinical variant that warrants further investigation, and review the relevant literature.

Prognostication in cancer of unknown primary (CUP): development of a prognostic algorithm in 311 cases and review of the literature.

BACKGROUND: CUP represents a heterogeneous population of patients with systemic malignancy and variable outcomes. Identification of clinical, pathologic and laboratory parameters with prognostic utility could contribute to estimation of death hazard and tailoring of therapy. PATIENTS AND METHODS: Clinical, pathologic and laboratory data from 311 patients with CUP diagnosed in a single university centre from 1988 to 2011 were examined for prognostic significance in univariate, multivariate and Classification and Regression Tree (CART) analyses. We analysed all published CUP prognostic algorithms in PubMed and EmBase from 1985 to date in order to describe defining characteristics. RESULTS: Most patients harboured poorly differentiated adenocarcinoma or carcinoma (85%) in visceral sites (62%) and were managed with combination chemotherapy. Median overall survival for all patients was 8 months (95% CI 6.7-9.1). Multivariate analysis established that only leucocytosis (HR 0.37, p=0.001, cut off <10,000/mm(3) leucocytes), clinicopathologic CUP subgroup (HR 2.44, p=0.001 for the visceral subgroup) and performance status (HR 0.58, p=0.002 for PS 0-1) retained independent prognostic significance. These three parameters were used for developing a prognostic algorithm (Ioannina Score for CUP Outpatient Oncologic Prognostication, I-SCOOP) which produced a dynamic 5-tier point score and classified patients in low, intermediate and high risk groups with median survival times of 36, 11-14 and 5-8 months respectively. We identified 15 published CUP series describing prognostic algorithms with common, as well as distinct, patient characteristics and prognosticators. CONCLUSIONS: We developed a simple and easy to use CUP prognostic algorithm based on readily available clinicopathologic and laboratory variables. However, analysis of all published series revealed lack of prognosticator consensus, highlighting the heterogeneity of the disease.