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Purpose Anti-programmed cell death 1 (PD1) is the first-choice treatment in patients with advanced cutaneous squamous cell carcinoma (cSCC), when curative options are unavailable. However, reliable biomarkers for patient selection are still lacking.Experimental design In this translational study, clinical annotations, tissue and liquid biopsies were acquired to investigate the association between sustained objective responses and transcriptional profiles, immune cell dynamics in tumor tissue and peripheral blood samples, as well as circulating cytokine levels.Results First, we investigated the baseline characteristics of the immune landscape of cSCC biopsies. Gene Set Enrichment Analysis showed upregulation of interleukin (IL)2/STAT5 pathways and downregulation of Interferon signatures in non-responder patients compared with responders. Next, we studied the early changes induced by cemiplimab in tissue biopsies. Notably, after only three weeks, cemiplimab treatment induced an increase in B cells and CD8+ T cells in responders, whereas their abundance decreased in non-responder patients. Moreover, analyzing differentially expressed genes modulated early during treatment, compared with baseline biopsies, we found that IL1β and IL8 exhibited early downregulation in responder patients’ tumor specimens. We assessed whether changes in the local tumor microenvironment were mirrored in peripheral blood. Similar to tissue findings, no changes were observed in the whole T regulatory (Treg) population, although PD1+ Tregs, which were downregulated in responder patients (vs T0), showed a rebound enrichment in non-responders after three cycles of cemiplimab. Finally, IL8 mirrored the tissue results, unlike IL1β, with early (T1) and then sustained (T3) downregulation of its levels in responder patients, while increased in non-responders.Conclusions Taken together, these findings shed light on the significance of early transcriptomic and immune cell modulation in predicting responses to cemiplimab therapy. Additionally, our data suggest that IL8 levels in peripheral blood offer promising avenues for personalized treatment selection and response assessment in patients with cSCC receiving cemiplimab, while PD1+Tregs can be followed longitudinally to monitor response to therapy.

Cemiplimab has demonstrated relevant clinical activity in cutaneous squamous cell carcinoma (cSCC) but mechanisms of primary and acquired resistance to immunotherapy are still unknown. We collected clinical data from locally advanced and/or metastatic cSSC patients treated with cemiplimab in two Italian University centers. In addition, gene expression analysis by using Nanostring Technologies platform to evaluate 770 cancer- and immune-related genes on 20 tumor tissue samples (9 responders and 11 non-responders to cemiplimab) was performed. We enrolled 81 patients with a median age of 82 years. After 16.4 months of median follow-up, 12- and 24-months PFS were 53% and 42%, respectively; while 12- and 24-months OS were 71% and 61%, respectively. Treatment was well tolerated. Overall response rate (ORR) was 58%, with a disease control rate (DCR) of 77.8%. The difference between genes expressed in responder versus non-responder patient samples was substantial, particularly for genes involved in immune system regulation. Cemiplimab-resistant tumors were associated with over-expression of CCL-20 and CXCL-8. Cemiplimab confirmed efficacy and safety data in real-life cSCC patients. Overexpression of CCL-20 and CXCL-8 could represent biomarkers of lack of response to immunotherapy.

IntroductionImmune checkpoint inhibitor (ICI)-based immunotherapy targeting programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) has radically changed the management of many types of solid tumors including non-small cell lung cancer (NSCLC). Many clinical trials have demonstrated that ICIs improve the survival and the quality of life of patients with advanced non oncogene NSCLC as compared to standard therapies. However, not all patients achieve a clinical benefit from this immunotherapeutic approach. As a result, real-word validation of the efficacy and safety of ICIs can be useful for defining potential predictive biomarkers as well as for overcoming limitations linked to clinical trial restrictions.MethodsWe retrospectively retrieved the clinical data of patients with advanced non oncogene NSCLC treated with ICIs (anti-PD-1 or anti-PD-L1) as single agent or in combination with chemotherapy at “San Giovanni di Dio e Ruggi D’Aragona” University Hospital from January 2016 to December 2023. Potential correlations between clinical-pathological characteristics and safety or survival outcomes were investigated employing the Fisher’s exact test, Mann-Whitney U test, the Kruskal-Wallis method and log-rank test, as applicable. Multivariate survival analyses were performed using the Cox proportional hazards model.ResultsClinical data of 129 patients were retrieved. At a median follow-up of 29.70 months, progression-free survival (PFS) and overall survival (OS) were 5.27 months and 8.43 months, respectively. At the multivariate analyses, smoking status, presence of bone metastases and the occurrence of immune-related adverse events (irAEs) were correlated with both PFS and OS. Moreover, patients treated with anti-PD-1-based therapy achieved an increased clinical benefit than those treated with anti-PD-L1.DiscussionIn this study we described our real-world experience of ICIs for the treatment of patients with advanced non oncogene NSCLC. A decreased OS in our study population was reported as compared to that of patients included in the clinical trials. Noteworthy, correlations between clinical-pathological characteristics and survival outcomes emerged. Nevertheless, the potential integration of clinical-pathological characteristics as predictive biomarkers in more accurate therapeutic algorithms as well as the underlying biological mechanisms should be further validated in ad hoc studies.

Abstract Introduction Thymic epithelial tumors (TETs) are rare neoplasms often associated with immune-related disorders. Patients with Good’s syndrome (GS), an adult-acquired TET-related immunodeficiency, are at a high risk of mortality due to infectious diseases. This study aims to examine COVID-19 occurrence and severity in TET patients, with or without GS. Methods Clinical records of TET patients referred to the Regional Coordinating Center for Rare Tumors of Campania Region were retrospectively collected. During the observation period, elapsing from March 2020 to April 2023, the following data were collected: occurrence of SARS-CoV-2 infection; COVID-19 severity, according to the National Institute of Health (NIH) illness categories; COVID-19 treatment. COVID-19 occurrence and severity were assessed in the overall population and correlated with the presence of GS and/or other immune-related dysregulations. Results Overall, 47 TET patients were included in the study; 27 of these (57.4%) had GS. All participants had received a full cycle of mRNA vaccine for SARS-CoV2., Thirty-one patients (66.0%) experienced COVID-19, of whom 18 (58.0%) had previously received a diagnosis of GS. No significant association of GS and/or other immune-related dysregulations with SARS-CoV-2 infection occurrence was detected (Fisher’s exact test p = 1 and p = 0.3587, respectively). Among patients with GS, 8 (45.0%) reported a COVID-19 severity score of ≥ 3; whereas, only 1 of the 13 patients without GS (7.7%) had a severity score of ≥ 3. The correlation between presence of GS and COVID-19 severity (score 1 or 2 vs. ≥ 3) was statistically significant (p = 0.0448). No statistically significant association between COVID-19 severity and other immune-related syndromes were found (p = 1). Of note, all the hospitalized patients for NIH 4 and 5 COVID-19 had GS. Conclusions Our data suggest that TET patients, especially those with GS, require a careful multidisciplinary monitoring for SARS-CoV-2 infection, in order to establish tailored treatments and prophylactic protocols.

BackgroundGranular Cell Tumors (GCTs), also known as Abrikossoff tumors, are rare neoplasms that typically originate from Schwann cells. These tumors most commonly occur in the head and neck region, particularly the tongue. While GCTs are generally benign, less than 2% of cases exhibit aggressive biological features such as rapid growth, high recurrence rates, and metastasis. In this report, we present a rare case of a Malignant Granular Cell Tumor (MGCT) of the chest wall, which posed significant challenges in both characterization and management.Case PresentationA fifty-year-old man underwent an ultrasound examination for a nodular mass on his right chest wall. The ultrasound revealed a firm, hard mass measuring 2 cm x 2 cm with an uncertain diagnosis. A fine-needle aspiration biopsy (FNAB) guided by ultrasound was performed, resulting in a diagnosis of Abrikossoff tumor. The patient subsequently underwent radical excision of the mass, which confirmed the initial diagnosis. Nine months after surgery, a new mass with similar characteristics was detected during a physical examination. The patient underwent a second surgery, but this time the histopathological examination was negative for neoplastic cells. However, another mass appeared at the same site as the previous surgical excision. A CT scan and MRI of the right chest wall confirmed the presence of a 2 cm x 2 cm nodular mass. The patient then underwent a deeper excision. Histomorphological and immunohistochemical assessments confirmed the recurrence of MGCT.ConclusionThis case highlights the malignant potential of GCTs. The numerous local recurrences necessitated three surgeries and additional procedures. The aggressive nature of this pathology underscores the complexity of managing these tumors, which are poorly understood and lack proven post-operative strategies for controlling local and distant disease.

Thymic epithelial tumors are rare malignancies with an incidence of 1.7 cases per million people per year. They pose significant management challenges due to their association with autoimmune disorders. In this case report, we present the 21-year history of a patient diagnosed with advanced B2/B3 thymoma and Good’s syndrome. The patient achieved a complete and durable response after receiving only two cycles of the immune checkpoint inhibitor Nivolumab. However, this positive outcome was accompanied by the development of severe immune-related myocarditis complicated by reactivation of cytomegalovirus. Moreover, the patient developed a highly uncommon subdiaphragmatic pararectal dissemination of the thymic tumor, which is a condition rarely described in the literature. Despite the success in achieving complete and durable response with immune checkpoint inhibitors, the emergence of immune-related adverse events highlights the potential challenges associated with these treatments, emphasizing the need for careful monitoring and a comprehensive understanding of the intricate interplay between cancer, immune system dysregulations and immunotherapy.

Abstract Background Pancreatic cancer (PC) first‐line therapy often consists of polychemotherapy regimens, but choosing a second‐line therapy after disease progression, especially following first‐line FOLFIRINOX, remains a clinical challenge. This study presents results from a large, multicenter, retrospective analysis of Italian patients with metastatic PC (mPC) treated with Nab‐paclitaxel/Gemcitabine (AG) as second or later line of treatment. Main objective of the study is to identify prognostic factors that could inform treatment decisions. Methods The study included 160 mPC patients treated with AG in 17 Italian institutions. AG was administered according to labelling dose, until disease progression, unacceptable toxicity or patient refusal. Variations in schedules, dose modifications, supportive measures, and response evaluation were determined by individual clinicians' practice. Results AG was well‐tolerated and exhibited promising clinical activity. The overall response rate (ORR) and the disease control rate (DCR) were 22.5% and 45.6%, respectively. Median progression‐free survival (PFS) and overall survival (OS) were 3.9 and 6.8 months, respectively. Among the patients who received AG as a second‐line therapy (n = 111, 66.9%), median PFS and OS were 4.2 and 7.4 months, respectively. Notably, in the 76 patients (68%) receiving AG after first‐line FOLFIRINOX, an ORR of 19.7% and a DCR of 46.0% were observed, resulting in a median PFS of 3.5 and median OS of 5.7 months. The study identified specific clinical or laboratory parameters (LDH, NLR, fasting serum glucose, liver metastases, ECOG PS, and first‐line PFS) as independent prognostic factors at multivariate level. These factors were used to create a prognostic nomogram that divided patients into three risk classes, helping to predict second‐line OS and PFS. Conclusions This study represents the largest real‐world population of mPC patients treated with AG as a second or later line of therapy. It supports the feasibility of this regimen following first‐line FOLFIRINOX, particularly in patients with specific clinical and laboratory characteristics who derived prolonged benefit from first‐line therapy.

Abstract Obesity and metabolic disorders have been associated with poor outcomes in non-Mediterranean breast cancer (BC) patients. The purpose of this study was to investigate the prognostic potential of anthropometric variables in patients with early BC living in Southern Mediterranean region of Italy. We enrolled 955 consecutive early BC patients treated in hospitals in Naples between 2009 and 2013 (median follow-up 11.8-year ending 15/09/2022). Body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and metabolic syndrome (MetS) were collected. All-cause and BC-specific mortality were calculated. At the last day of contact 208 (22%) patients had died, 131 (14%) from BC. High WC (≥ 88 cm) or WHR (> 0.85) and the MetS were significantly associated with moderately increased risk of all-cause mortality (HR=1.39, 1.62, 1.61, respectively). A significant increased risk of BC-specific mortality was found in obese patients, in those with high WC, high WHR and those with MetS (HR=1.72, 1.71, 1.80, 1.81, respectively). Central obesity significantly increased total and BC-specific mortality particularly in pre-menopausal women and in luminal subtypes, while in post-menopause MetS was a stronger risk factor. Obesity and MetS may impair the effectiveness of BC therapies hence active lifestyle interventions are encouraged.

Abstract Background In addition to improving survival outcomes, new oncology treatments should lead to amelioration of patients’ quality of life (QoL). Herein, we examined whether QoL results correlated with PFS and OS outcomes in phase III randomized controlled trials (RCTs) investigating new systemic treatments in metastatic non-small cell lung cancer (NSCLC). Methods The systematic search of PubMed was conducted in October 2022. We identified 81 RCTs testing novel drugs in metastatic NSCLC and published in the English language in a PubMed-indexed journal between 2012 and 2021. Only trials reporting QoL results and at least one survival outcome between OS and PFS were selected. For each RCT, we assessed whether global QoL was “superior,” “inferior,” or with “non-statistically significant difference” in the experimental arm compared to the control arm. Results Experimental treatments led to superior QoL in 30 (37.0%) RCTs and inferior QoL in 3 (3.7%) RCTs. In the remaining 48 (59.3%) RCTs, a statistically significant difference between the experimental and control arms was not found. Of note, we found a statistically significant association between QoL and PFS improvements (X 2 = 3.93, p = 0.0473). In more detail, this association was not significant in trials testing immunotherapy or chemotherapy. On the contrary, in RCTs testing target therapies, QoL results positively correlated with PFS outcomes (p = 0.0196). This association was even stronger in the 32 trials testing EGFR or ALK inhibitors (p = 0.0077). On the other hand, QoL results did not positively correlate with OS outcomes (X 2 = 0.81, p = 0.368). Furthermore, we found that experimental treatments led to superior QoL in 27/57 (47.4%) trials with positive results and in 3/24 (12.5%) RCTs with negative results (p = 0.0028). Finally, we analyzed how QoL data were described in publications of RCTs in which QoL outcomes were not improved (n = 51). We found that a favorable description of QoL results was associated with sponsorship by industries (p = 0.0232). Conclusions Our study reveals a positive association of QoL results with PFS outcomes in RCTs testing novel treatments in metastatic NSCLC. This association is particularly evident for target therapies. These findings further emphasize the relevance of an accurate assessment of QoL in RCTs in NSCLC.

Abstract Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have been approved in combination with endocrine therapy (ET) to treat estrogen receptor-positive (ER+) metastatic breast cancer (BC). However, drug resistance represents the leading cause of breast cancer patients mortality. This study aimed to identify novel resistance mechanisms to ER antagonists in combination with CDK4/6 inhibitors. We generated two ER+ BC cell lines, T47D and MCF7, resistant to the combination of the ER antagonist fulvestrant and CDK4/6i abemaciclib, named T47D-FAR and MCF7-FAR. Transcriptomic analysis revealed common up-regulation of genes involved in MAPK and epithelial to mesenchymal transition (EMT) pathways in FAR cells, sustaining their hyper-invasive phenotype and increased anchorage-independent growth, compared to sensitive cells. FAR cells showed higher p21-activated kinase 1 (Pak1) expression and phosphorylation levels than parental cells. PAK1 knockdown by siRNAs hampered cell proliferation, reduced anchorage-independent growth and invasive properties of T47D-FAR and MCF7-FAR, re-sensitizing them to fulvestrant and abemaciclib. Conversely, over-expression of PAK1 in MCF7 and T47D cells increased tumor spheroids’ growth and invasion and reduced sensitivity to fulvestrant and abemaciclib, confirming its role in inducing drug resistance. Finally, treatment with Pak1 inhibitors, PF-3758309 (PF309) and NVS-PAK1-1, restored cell sensitivity to fulvestrant and abemaciclib of MCF7-FAR and T47D-FAR cells, both in vitro and in vivo. In conclusion, our data suggested a pivotal role for Pak1 in resistance to ET and CDK4/6i in ER+ breast cancers. These data might promote the rationale for the development of novel Pak1 inhibitors for treatment of patients with ER+ BC progressing on ET plus CDK4/6i.

Background: Lung cancer is the leading cause of cancer death worldwide. Over the last decade, molecular testing of a growing number of predictive biomarkers has become mandatory in the management of NSCLC patients. However, a major obstacle in routine clinical practice is the scant quantity of available tissue specimens obtainable from advanced stage of NSCLC patients. Thus, liquid biopsy, mostly involving blood sampling, has now been integrated in routine diagnostic practice. However, although liquid biopsies constitute a versatile, compliant, and dynamic source of nucleic acids, many of the current testing approaches pose few technical challenges. Here, to validate the feasibility of implementing NGS-based liquid biopsy approaches in routine diagnostic practice, we overviewed the NGS molecular data generated by our in-house narrow gene panel on plasma samples from real-world NSCLC patients. Methods: Our Institution received testing request on liquid biopsy samples from peripheral institutions not equipped to internally analyze liquid biopsy samples. Molecular data from NSCLC patients following oncological requested for clinically approved plasma-based biomarkers evaluated in a diagnostic routine setting from January 2020 to September 2022 were retrieved from our institutional archive. A customized NGS panel integrated with an optimized bioinformatic pipeline was adopted. Results: Overall, a total of n = 185 cases were retrieved. Of note, 103 (55.7 %) and 82 (44.3 %) patients were analyzed at basal setting and after resistance to first line TKI administration, respectively. Moreover, 31 out of 185 (16.7 %) cases reveled EGFR clinically relevant alterations. In particular, 6 out of 31 (19.3 %) and 25 out 31 (80.7 %) EGFR mutated patients were tested in basal setting and after first or second line TKIs progression. In addition, exon 20 p.T790 M mutation was also detected in 12 out of 25 (48.0 %) EGFR concomitant mutated cases. Moreover, KRAS hot spot mutations were found in 24 out of 185 (13.0 %) cases. Among them, exon 2 p.G12C clinically relevant mutations were observed in 8 out 24 cases (33.3 %). Conclusions: This review highlights the technical suitability of an NGS-based liquid biopsy system for the analysis of clinically relevant mutations in NSCLC patients.

BackgroundHER2 is amplified or overexpressed in around 20% of breast cancers (BC). HER2-targeted therapies have significantly improved the prognosis of patients with HER2+ BC, however, de novo and acquired resistance to anti-HER2 treatment is common. Activating mutations in the PIK3CA gene are reported in ∼30% of HER2+ BC and are associated with resistance to anti-HER2 therapies and a poor prognosis. Here, we investigated the in vitro and in vivo antitumor efficacy of the alpha-specific PI3K inhibitor alpelisib alone or in combination with anti-HER2 therapy using a panel of HER2+ BC cell lines. We also generated models of acquired resistance to alpelisib to investigate the mechanisms underlying resistance to alpha-specific PI3K inhibition.Materials and methodsPIK3CA mutant (HCC1954, KPL4 and JMT1) and wild-type (BT474 and SKBR3) HER2+ BC cell lines were used. The HCC1954 and KPL4 cells were chronically exposed to increasing concentrations of alpelisib or to alpelisib + trastuzumab in order to generate derivatives with acquired resistance to alpelisib (AR) and to alpelisib + trastuzumab (ATR). The transcriptomic profiles of HCC1954, KPL4 and their AR and ATR derivatives were determined by RNA sequencing. Cell growth was assessed by MTT assay. Changes in the protein levels of key PI3K pathway components were assessed by Western blotting. Gene expression, cellular and patients’ data from the Cancer Dependency Map (DepMap) and KMPlot datasets were interrogated.ResultsHER2+ BC cell lines harboring activating mutations in PIK3CA were less sensitive to single or dual anti-HER2 blockade compared to PIK3CA wild-type cells. Alpelisib treatment resulted in dose-dependent inhibition of the growth of cells with or without PIK3CA mutations and enhanced the antitumor efficacy of anti-HER2 therapies in vitro. In addition, alpelisib greatly delayed tumor growth of HCC1954 xenografts in vivo. Functional annotation of the significantly differentially expressed genes suggested the common activation of biological processes associated with oxidation reduction, cell proliferation, immune response and RNA synthesis in alpelisib-resistant models compared with native cells. Eight commonly upregulated genes (log2 fold-change >1, False Discovery Rate [FDR]

Abstract Aims As the world population grows older, the co‐existence of cancer and cardiovascular comorbidities becomes more common, complicating management of these patients. Here, we describe the impact of a large Cardio‐Oncology unit in Southern Italy, characterizing different types of patients and discussing challenges in therapeutic management of cardiovascular complications. Methods and results We enrolled 231 consecutive patients referred to our Cardio‐Oncology unit from January 2015 to February 2020. Three different types were identified, according to their chemotherapeutic statuses at first visit. Type 1 included patients naïve for oncological treatments, Type 2 patients already being treated with oncological treatments, and Type 3 patients who had already completed cancer treatments. Type 2 patients presented the highest incidence of cardiovascular events (46.2% vs. 12.3% in Type 1 and 17.9% in Type 3) and withdrawals from oncological treatments (5.1% vs. none in Type 1) during the observation period. Type 2 patients presented significantly worse 48 month‐survival (32.1% vs. 16.7% in Type 1 and 17.9% in Type 3), and this was more evident when in the three groups we focused on patients with uncontrolled cardiovascular risk factors or overt cardiovascular disease at the first cardiologic assessment. Nevertheless, these patients showed the greatest benefit from our cardiovascular assessments, as witnessed by a small, but significant improvement in ejection fraction during follow‐up (Type 2b: from 50 [20; 67] to 55 [35; 65]; P = 0.04). Conclusions Patients who start oncological protocols without an accurate baseline cardiovascular evaluation are at major risk of developing cardiac complications due to antineoplastic treatments.

Mycobacterium chimaera is a slow-growing non-tuberculous mycobacterium already known for being able to colonize cardio surgery heater–cooler units (HCUs). This study aims to describe the real magnitude of the phenomenon, providing a methodological protocol and the results of a longitudinal survey. In the period 1 January 2017–23 May 2022, over 1191 samples were collected on 35 HCUs of two different manufacturers. Among them, we identified 118 (10.3%) positive results for M. chimaera. We propose our 4-year biosurveillance experience as a practical model to minimize microbiological patients’ risk, suggesting the need for new procedures and interventions for a safer and more ecological cardio surgery.

BackgroundVaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective. Nevertheless, immunocompromised participants were excluded from randomized controlled clinical trials. This study evaluates the efficacy and safety of the Pfizer/BioNTech BNT162b2 (BNT162b2) vaccine in patients with breast and gynecological cancer treated with active anticancer therapy versus a control cohort of healthy participants.MethodsImmune responses to the BNT162b2 vaccine in patients with breast cancer (n = 44) or a gynecological malignancy (n = 6) on active anticancer therapy (28 on chemotherapy, mostly anthracycline- or taxane-based, and 22 on target therapy) and in a control cohort of participants without cancer (n = 67) were investigated by SARS-CoV-2 neutralizing antibody titers measured by S1-binding immunoglobulin G (IgG) concentrations assessed using the LIAISON XL tools (DiaSorin S.p.A.). Response was assessed after a second dose of the BNT162b2 vaccine administered before and at least 3 weeks after the vaccine dose.ResultsOverall, 43/50 (86%) patients of the cancer cohort (74% in the breast cancer group and 100% in the gynecological malignancy group) developed IgG antibodies after the second dose of the BNT162b2 vaccine. There were no statistically significant differences in responder rates between patients treated with chemotherapy and those on target therapy. The majority of patients who received chemotherapy with or without target therapy, 21/28 (75%), developed a reliable antibody titer after a vaccine. All seven non-responder patients were undergoing an anthracycline-based regimen. Based on IgG levels (0–400 AU/ml), patients were classified as negative (‘non-responders’), weakly positive, or strongly positive (‘responders’). No delay in cancer therapy schedule or reported side effects were recorded after BNT162b2 vaccine administration. All healthy participants were strongly positive. Responder rates differed significantly between the two study cohorts (p < 0.001).ConclusionsMost patients develop antibody titers after the second immunization. However, given the persistence of non-responders or weak responders, additional immunization booster seems to be required, along with proactive planning in the vaccination schedule, with vaccine administration spaced out over time with respect to chemotherapy.

Background Immunosuppression induced by anticancer therapy in a COVID-19-positive asymptomatic patient with cancer may have a devastating effect and, eventually, be lethal. To identify asymptomatic cases among patients receiving active cancer treatment, the Federico II University Hospital in Naples performs rapid serological tests in addition to hospital standard clinical triage for COVID-19 infection.Methods From 6 to 17 April 2020, all candidates for chemotherapy, radiotherapy or target/immunotherapy, if negative at the standard clinical triage on the day scheduled for anticancer treatment, received a rapid serological test on peripheral blood for COVID-19 IgM and IgG detection. In case of COVID-19 IgM and/or IgG positivity, patients underwent a real-time PCR (RT-PCR) SARS-CoV-2 test to confirm infection, and active cancer treatment was delayed.Results Overall 466 patients, negative for COVID-19 symptoms, underwent serological testing in addition to standard clinical triage. The average age was 61 years (range 25–88 years). Most patients (190, 40.8%) had breast cancer, and chemotherapy with or without immunotherapy was administered in 323 (69.3%) patients. Overall 433 (92.9%) patients were IgG-negative and IgM-negative, and 33 (7.1%) were IgM-positive and/or IgG-positive. Among the latter patients, 18 (3.9%), 11 (2.4%) and 4 (0.9%) were IgM-negative/IgG-positive, IgM-positive/IgG-negative and IgM-positive/IgG-positive, respectively. All 33 patients with a positive serological test, tested negative for RT-PCR SARS-CoV-2 test. No patient in our cohort developed symptoms suggestive of active COVID-19 infection.Conclusion Rapid serological testing at hospital admission failed to detect active asymptomatic COVID-19 infection. Moreover, it entailed additional economic and human resources, delayed therapy administrationand increased hospital accesses.

Background: Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death. In cases with metastasis, the combination of 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine-based chemotherapy regimens are considered the standard of care. However, the optimal sequence of these regimens is unclear. Methods: This retrospective study initially evaluated 186 patients with locally advanced/metastatic pancreatic cancer at three Italian institutions between February 2013 and October 2019. All patients had progressed after receiving gemcitabine-based first-line chemotherapy and were subsequently offered second-line FOLFIRINOX, FOLFOX-6, or FOLFIRI treatment. This study evaluated progression-free survival (PFS), overall survival from the start of second-line treatment (OS2), overall survival from the start of first-line treatment (OS1), and safety outcomes. Results: A total of 77 patients received ⩾4 cycles of second-line chemotherapy and were considered eligible: 15 patients received FOLFIRINOX, 32 patients received FOLFOX-6, and 30 patients received FOLFIRI. The FOLFIRINOX group had median PFS of 26.29 weeks and median OS2 of 47.86 weeks, while the FOLFIRI group had median PFS of 10.57 weeks and median OS2 of 25.00 weeks ( p = 0.038). No significant differences were observed between the FOLFIRINOX and FOLFOX-6 groups in terms of PFS (26.29 weeks versus 23.07 weeks) or OS2 (47.86 weeks versus 42.00 weeks). The most common grade 3–4 toxicities were anemia, neutropenia, and thrombocytopenia, which occurred more frequently in the FOLFIRINOX and FOLFOX-6 groups. Conclusion: Relative to the FOLFIRI regimen, the FOLFIRINOX regimen had a favorable toxicity profile and better survival outcomes. No significant differences were observed relative to the FOLFOX-6 regimen.

Abstract Background Intrahepatic cholangiocarcinoma is an aggressive tumor originating in the epithelium of the bile duct, often associated with distant dissemination. The prognosis is poor and treatment is challenging due to low response rate to standard chemotherapy and lack of targeted therapies. Case presentation Here we report the case of a 74-year-old white woman affected by intrahepatic cholangiocarcinoma with metastatic involvement of spleen, lung, peritoneum, and intra-abdominal lymph nodes. As first-line chemotherapy, she was given cisplatin-gemcitabine chemotherapy. The treatment was well tolerated with the exception of grade 1 constipation and a single episode of grade 4 thrombocytopenia occurring after the fourth course. After the first three courses of chemotherapy a computed tomography scan evaluation demonstrated no change; her CA19-9 levels were slightly decreased. However, after the sixth course of chemotherapy a computed tomography scan revealed a dimensional enlargement of the lung metastases; her CA19-9 levels increased. She was then treated with gemcitabine alone. After 2 months of gemcitabine monotherapy a significant regression of lung and spleen metastases, as well a CA19-9 level reduction, occurred. Eight months after the start of gemcitabine monotherapy no signs of progression were reported. Conclusions Treatment of metastatic intrahepatic cholangiocarcinoma with gemcitabine as maintenance therapy after first-line chemotherapy could be continued until clear evidence of disease progression since delayed responses are possible.

O objetivo da presente revisão é verificar na literatura científica características para prescrição do Treinamento de Força (TF) para a população acometida pela Osteoartrite (OA) de joelho. Foram pesquisados artigos nas bases de dados Scielo, PubMed e biblioteca da Bireme, utilizando para busca os seguintes descritores: Osteoartrite; Treinamento de Força; Envelhecimento. A OA é uma doença crônico-degenerativa caracterizada por degeneração da cartilagem articular, tendo prevalência maior nos idosos, o que comumente mostra-se acompanhado de considerável decréscimo de força muscular. Isso afeta a qualidade de vida e a funcionalidade dessa população, por vezes alterando a capacidade de realizar tarefas simples como marcha. Assim, o TF tem sido uma estratégia utilizada como tratamento não farmacológico da OA, melhorando indicadores relacionados principalmente à mobilidade física e percepção de dor. Sugere-se a implementação do TF no tratamento da doença em portadores de OA de joelho, com o intuito de minimizar os efeitos deletérios da OA e aumentar a funcionalidade desses indivíduos. O TF de alta intensidade se mostra uma alternativa relevante para o aumento da força e área de secção transversa. O principal aspecto a ser considerado na prescrição do TF para pacientes com OA, sobretudo o de alta intensidade, deve ser a ausência de dor durante o treinamento, a qual pode não só comprometer a plena realização dos movimentos, como também afetar o nível de independência física, além de sinalizar um possível agravamento da doença. Por fim, devem ser evidenciados cuidados essenciais no controle da sobrecarga para aplicação do treinamento com essa população. ABSTRACT Characteristics of strength training prescription for individuals with knee osteoarthritis: a brief review The purpose of this review is to verify the scientific literature for Strength Training (ST) prescription for population affected by knee Osteoarthritis (OA). Articles were searched in Scielo, PubMed and Bireme database. The search was conducted using the following keywords: Osteoarthritis; Strength Training; Aging. The OA is a chronic degenerative disease characterized by degeneration of articular cartilage, with higher prevalence in the elderly, which often proves to be accompanied by considerable decrease in muscular strength. This affects the quality of life and functionality of this population, sometimes altering the ability to perform simple tasks as walking. Thus, the ST has been a strategy used as a non-pharmacological treatment of OA, improving indicators mainly related to physical mobility and pain perception. It is suggested implementation of ST as treatment for patients with knee OA in order to minimize the deleterious effects of OA and increase the functionality of these individuals. The high intensity of ST has shown an important alternative for increasing the strength and muscle cross section area. The main aspect to be considered in the prescription of high intensity ST for patients with OA, is avoiding pain sensation during training, because it compromise the full amplitude of motion, it could affect the level of physical independence and may result in a possible worsening of the disease. Finally, essential care should be considered in the control of mechanical loads applied during training with this population.

The purpose of this study was to analyze the kinetic responses of running shoes submitted to prolonged use. Four shoes (R1, R2, T1 and T2) were used for 500 km except for T1 which was used for 1000 km. At every 100 km, Ground Reaction Force (GRF) and plantar pressure measurements were collected. In T2, there was a slight trend of increase in Loading Rate of the first peak of GRF with increasing distance. R1, R2 and T1 showed no trend of increase in Loading Rate values. Shoe T1 showed a slight tendency of increase in Loading Rate values when the distance was considered up to 1000 km. All running shoes showed a high variability in peak pressure values, but no trend of increase was observed. On the contrary, T1, T2 and R2 showed a trend of decrease in peak pressure values with increasing use. Therefore, there is no consistent evidence or trend of increase in Loading Rate and Peak Pressure values that would suggest worsening in external load attenuation.

A corrida e o ciclismo realizados com uma mesma duração e intensidade podem apresentar diferentes respostas biomecânicas e metabólicas durante um protocolo de fadiga devido à sobrecarga mecânica e à especificidade técnica de cada modalidade. O objetivo do presente estudo foi avaliar os efeitos da fadiga proveniente de uma corrida de 10 km, precedida por ciclismo ou corrida, no padrão de passada e no sinal eletromiográfico (EMG). Nove triatletas do sexo masculino com tempo de prática superior a dois anos participaram do estudo. Os testes foram realizados em duas etapas: corrida do "triathlon" (40 km de ciclismo seguidos de 10 km de corrida) e corrida prolongada (corrida com duração igual ao tempo que o atleta levou para percorrer os 40 km de ciclismo, seguidos de mais 10 km de corrida). Uma análise cinemática (frequência e amplitude de passada) e eletromiográfica correspondentes às 10 passadas registradas no 5º km de cada corrida foi realizada. As curvas de EMG foram retificadas e filtradas para cálculo das curvas de RMS. A partir da média das curvas de EMG foram obtidos os valores de pico de RMS para os músculos reto femoral, vasto lateral e bíceps femoral. Maiores valores de frequência de passada e do sinal EMG do músculo bíceps femoral foram obtidos na corrida prolongada quando comparada com a corrida do "triathlon". Esses resultados parecem estar relacionados a maior fadiga proveniente da corrida prolongada devido às maiores exigências mecânicas.

O objetivo do presente estudo foi investigar a influencia da fadiga no equilíbrio do pé de apoio no momento do chute em jogadores de futebol. Participaram desta pesquisa 19 atletas de futebol divididos em dois grupos: grupo exaustão (GEX) que realizou um esforço com carga incremental até a exaustão em esteira rolante, e o grupo controle (GCE) realizou um esforço leve-constante de forma continua em esteira rolante. Antes e após os protocolos foram avaliados parâmetros de equilíbrio estático em apoio unipodal, utilizando uma plataforma de força. O GEX apresentou aumento da área de deslocamento do centro de pressão (COP) (p < 0,05) após exaustão, tanto para o pé direito como para o esquerdo. A velocidade máxima de deslocamento do centro de pressão ântero-posterior da perna direita do GEX aumentou significantemente (p < 0,05) após a exaustão em relação aos valores de repouso. A fadiga pode diminuir a capacidade de equilíbrio do pé de apoio em jogadores de futebol. Principalmente no apoio com o pé que não é o usual de apoio para o chute.The aim of this study was to investigate the influence of fatigue on the balance of the support leg kick in soccer players. 19 soccer players were divided randomly into two groups: group exhauston (GEX), underwent an effort with incremental load at exhaustion on a treadmill, and the control group (GCE) underwent effort with constant lower load. Parameters of static balance in single support (one foot) were evaluated before and after the protocols, using a force platform (AMTI OR6-5). The GEX showed enlargement of the displacement of center of pressure (COP) (p < 0.05) after exhaustion, for the right foot. The maximum displacement of the antero posterior center of pressure of the right leg of the GEX incresead significantly (p < 0.05) after exhaustion in relation to resting values. In conclusion, fatigue can impair the ability to keep balance for the support leg in soccer players. Mainly on support to the foot that is not the usual support for the kick.

O objetivo do presente estudo foi comparar o sinal eletromiográfi co, a frequência e a amplitude de passada entre diferentes intensidades de corrida: 60%, 80% e 100% da velocidade máxima em dois protocolos incrementais. Participaram deste estudo 11 corredores do sexo masculino. Os protocolos de corrida foram realizados com velocidades iniciais de 10 km.hr-1, com incrementos de 1 km.hr-1 a cada três minutos até a exaustão, que diferiram em relação ao intervalo entre cada estágio incremental: 30 e 120 segundos. Foram analisados valores RMS dos músculos iliocostal lombar, reto femoral, vasto lateral, vasto medial, bíceps femoral, tibial anterior, e gastrocnêmio, e a amplitude e frequência de passada. Os valores RMS mostraram aumento entre as intensidades para quase todos os músculos, e não foram influenciados pelo tipo de protocolo utilizado para maioria dos músculos. A frequência e amplitude de passada apresentaram contribuições percentuais diferenciadas para o aumento da velocidade de corrida.El objetivo de este estudio es comparar la actividad electromiográfica, la amplitud y la frecuencia del pasado entre las diferentes intensidades de carrera: 60%, 80% y 100% de la velocidad máxima en dos protocolos adicionales. En el estudio participaron 11 corredores. Los protocolos se realizaron con velocidades de carrera iniciales de 10 km.hr-1, con incrementos de 1 km.hr-1 cada tres minutos hasta que se agoten, que diferían en el intervalo entre cada etapa incremental: 30 a 120 segundos. Se analizaron los valores RMS de las iliocostalis lumbar, rectus femoris, vastus lateralis, vastus medialis, biceps femoris, tibialis anterior, gastrocnemius, la amplitud y la frecuencia del pasado. Los valores de RMS mostró un aumento entre las intensidades para casi todos los músculos, y no fueron influenciadas por el tipo de protocolo utilizado. Las contribuciones de frecuencia y amplitud de pasado presentaran porcentaje diferenciado para aumentar la velocidad de funcionamiento.The aim of this study was to compare the electromyographic signal and the stride frequency and length among different intensities of running: 60%, 80% and 100% of maximum speed in two incremental protocols. The study included 11 male runners. The protocols were performed with initial running speed of 10 km.hr-1, with increments of 1 km.hr-1 at every three minutes until exhaustion. The two protocols differed in the interval between each incremental stage: 30 to 120 seconds. We analyzed RMS values of the iliocostalis lumbar, rectus femoris, vastus lateralis, vastus medialis, biceps femoris, tibialis anterior, gastrocnemius lateralis, and the stride length and frequency. The RMS values showed an increase among intensities for almost all muscles, and were not influenced by the type of protocol used for most muscles. The contribution of stride length and frequency were percentile different as the running speed increased.

Acredita-se que a eficiência do calçado seja afetada pelo uso prolongado, mas as alterações biomecânicas ainda não estão bem compreendidas. O objetivo deste estudo é analisar a influência do uso de calçados de corrida na força de reação do solo e os parâmetros de pressão plantar. Três corredores do sexo masculino receberam quatro calçados de corrida para usarem em suas sessões de treinamento. O Sistema Gaitway e o Sistema de F-scan foram usados para registrar a força de reação do solo e parâmetros pressão plantar em diferentes regiões do pé. As coletas ocorreram em quatro momentos: novo e 100, 200 e 300 km de uso. O primeiro pico diminuiu da condição novo para os 300 km de uso (p < 0,01). A taxa de crescimento 1 diminuiu aos 200 km em relação às condições novas (p < 0,01). A área total aumentou aos 100 km (p < 0,01) de uso e manteve valores semelhantes e mais altos até 300km. No pico de pressão antepé, houve uma diminuição progressiva (p < 0,01) como o aumento quilometragem e os valores de pico de pressão do hálux foram significativamente menores (p < 0,01) aos 300 km do que na condição novo. Como o primeiro pico, a taxa de crecimento 1 e os picos de pressão plantar não aumentaram e a área de contato plantar total aumentou. Conclui-se que o calçado de corrida não sofreu alterações consistentes na força de reação do solo e na pressão plantar após 300 km de uso.The prolonged use of a running shoe is thought to affect the efficiency of its impact attenuation properties. However, its effect over biomechanical variables has yet not been well understood. The aim of this study was to examine the influence of running shoe usage on ground reaction force and plantar pressure parameters. Three male runners received four running shoes each to use at their training sessions. The Gaitway System was used to register the vertical component of the ground reaction force, whereas the contact area and peak plantar pressure at different regions of the foot were assessed via the the F-scan System. Data collection occurred at baseline (when the shoes were new - New) and after 100, 200 and 300km of use. The first peak decreased significantly from New to 300km (p < 0.01) and the loading rate showed a significant decrease at 200km in relation to the New condition (p < 0.01). Total area increased significantly from New to 100km (p < 0.01) of use and maintained a similar value when compared with the other conditions. There was a continuous and significant decrease (p < 0.01) on forefoot peak pressure as the mileage increased from New to 300km. The hallux peak pressure values were significantly smaller (p < 0.01) at 300km when compared with the New condition. Considering that the first peak, loading rate and plantar peak pressure values did not increase and that the plantar total contact area increased, it can be concluded that the running shoe did not suffer consistent alterations in ground reaction force and in plantar pressure after 300km of use.

The discovery of the anti-proliferative activity of nelfinavir in HIV-free models has encouraged its investigation as anticancer drug. Although the molecular mechanism by which nelfinavir exerts antitumor activity is still unknown, its effects have been related to Akt inhibition. Here we tested the effects of nelfinavir on cell proliferation, viability and death in two human breast cancer cell lines and in human normal primary breast cells. To identify the mechanism of action of nelfinavir in breast cancer, we evaluated the involvement of the Akt pathway as well as the effects of nelfinavir on reactive oxygen species (ROS) production and ROS-related enzymes activities. Nelfinavir reduced breast cancer cell viability by inducing apoptosis and necrosis, without affecting primary normal breast cells. The antitumor activity of nelfinavir was related to alterations of the cell redox state, coupled with an increase of intracellular ROS production limited to cancer cells. Nelfinavir treated tumor cells also displayed a downregulation of the Akt pathway due to disruption of the Akt-HSP90 complex, and subsequent degradation of Akt. These effects resulted to be ROS dependent, suggesting that ROS production is the primary step of nelfinavir anticancer activity. The analysis of ROS-producers and ROS-detoxifying enzymes revealed that nelfinavir-mediated ROS production was strictly linked to flavoenzymes activation. We demonstrated that ROS enhancement represents the main molecular mechanism required to induce cell death by nelfinavir in breast cancer cells, thus supporting the development of new and more potent oxidizing molecules for breast cancer therapy.

O câncer de ovário é a terceira causa de morte entre as neoplasias malignas em mulheres e o cistoadenocarcinoma mucinoso é uma neoplasia maligna originária do epitélio ovariano e que pode adquirir grandes dimensões. Alguns estudos sugerem um aumento do risco de neoplasia em pacientes com esclerose sistêmica (ES), mas a associação com neoplasia de ovário, principalmente do subtipo mucinoso, não é comum. Os autores descrevem um caso de cistoadenocarcinoma mucinoso de ovário em uma mulher branca de 52 anos com diagnóstico de ES difusa há seis anos, tratada previamente com D-penicilamina e ciclofosfamida, que procurou o serviço médico com queixa de dor e aumento do volume abdominal há três meses. Ao exame físico apresentava facies esclerodérmica, membros superiores com diminuição da elasticidade e enxerto bitibial em membros inferiores; no abdome havia a presença de uma massa endurecida estendendo-se da região suprapúbica até o epigástrio. Foi realizada laparotomia exploradora onde se encontrou uma massa cística no ovário direito, com peso de 3.300 gramas. Em seguida procedeu-se exérese do tumor com histerectomia total e ooforectomia bilateral. O exame histológico confirmou tratar-se de um cistoadenocarcinoma mucinoso sem invasão de cápsula.Ovarian cancer is the third cause of death among malignant neoplasia in women, and the mucinous cystadenocarcinoma is a malignant neoplasia of the ovarian epithelium, which may achieve great dimensions. Some studies suggest an increased risk of neoplasia in patients with systemic sclerosis (SSc), but the association with ovarian neoplasia, specially the mucinous subtype, is rare. The authors describe a case of ovarian mucinous cystoadenocarcinoma in a 52 year-old Caucasian woman who had the diagnosis of SSc 6 years ago, previously treated with cyclophosphamide and D-penicillamine, who sought for a medical service complaining of pain and increase of abdominal volume during the last three months. At the physical examination, she presented sclerodermic facies, upper limbs with decreased elasticity and bitibial graft in the lower limbs; in the abdomen, a hardened mass extending to the suprapubic region up to the epigastric was observed. Exploratory laparotomy was performed and a cystic mass was found in the right ovary, weighing 3,300 grams. A surgical removal of the tumor with total hysterectomy and bilateral oophorectomy was then performed. Histological examination confirmed the diagnosis of mucinous cystadenocarcinoma without capsule invasion.

Spontaneous esophageal perforation (Boerhaave syndrome) is a very uncommon, life-threatening surgical emergency that should be suspected in all patients presenting with lower thoracic-epigastric pain and a combination of gastrointestinal and respiratory symptoms. Variable clinical manifestations and subtle or unspecific radiographic findings often result in critical diagnostic delays. Multidetector computed tomography complemented with CT-esophagography represents the ideal "one-stop shop" investigation technique to allow a rapid, comprehensive diagnosis of BS, including identification of suggestive periesophageal abnormalities, direct visualization of esophageal perforation and quantification of mediastinitis.

In patients without history of vascular surgery, infectious aortitis is a very uncommon, life-threatening condition with nonspecific clinical manifestations, which exposes the patient to uncontrolled sepsis and to the risk of retroperitoneal rupture. State-of-the-art cross-sectional imaging with contrast-enhanced multidetector computed tomography and magnetic resonance imaging allows confident diagnosis and characterization of unsuspected aortitis in septic patients at an early stage before the development of aneurysmal dilatation. The asymmetric distribution of periaortic inflammatory tissue is helpful for the differentiation of this exceptional disorder from other periaortic abnormalities such as retroperitoneal fibrosis or lymphoma.

Splenic rupture with hemoperitoneum represents a life-threatening surgical emergency. Malaria should be highly suspected as the probable underlying disease in returning travellers, expatriates, or recent immigrants from endemic countries. Malarial complications involving the spleen occur even with appropriate prophylaxis or during antimalarial therapy. Among them, splenic infarction has a favourable course and is treated conservatively, whereas life-threatening rupture requires immediate or delayed splenectomy. Computed tomography (CT) allows confident differentiation between these two complications by identifying ruptured spleen with clotted hematoma and associated high-density peritoneal effusion; furthermore, CT allows differential diagnosis from other causes of spontaneous hemoperitoneum.

One of the rarest complications of endocarditis, infected (mycotic) aneurysms result from haematogenous dissemination of septic emboli and occur more frequently in patients with cardiac valvular abnormalities or prosthetic valves, intravenous drug abuse, diabetes and immunosuppression conditions such as HIV infection. Although often clinically unsuspected, mycotic aneurysms are potentially life-threatening because of disseminated sepsis and propensity to rupture. Contrast-enhanced multidetector CT provides prompt detection, characterization and vascular mapping of these lesions, allowing correct planning of surgical or interventional therapies and reproducible follow-up. Because of their characteristically unpredictable behaviour, mycotic aneurysms may undergo spontaneous thrombosis, size reduction, rapid enlargement or rupture, therefore strict imaging surveillance with CT and/or color Doppler ultrasound is necessary.

Tissue-engineered heart valves are proposed as novel viable replacements granting longer durability and growth potential. However, they require extensive in vitro cell-conditioning in bioreactor before implantation. Here, the propensity of non-preconditioned decellularized heart valves to spontaneous in body self-regeneration was investigated in a large animal model. Decellularized porcine aortic valves were evaluated for right ventricular outflow tract (RVOT) reconstruction in Vietnamese Pigs (n = 11) with 6 (n = 5) and 15 (n = 6) follow-up months. Repositioned native valves (n = 2 for each time) were considered as control. Tissue and cell components from explanted valves were investigated by histology, immunohistochemistry, electron microscopy, and gene expression. Most substitutes constantly demonstrated in vivo adequate hemodynamic performances and ex vivo progressive repopulation during the 15 implantation months without signs of calcifications, fibrosis and/or thrombosis, as revealed by histological, immunohistochemical, ultrastructural, metabolic and transcriptomic profiles. Colonizing cells displayed native-like phenotypes and actively synthesized novel extracellular matrix elements, as collagen and elastin fibers. New mature blood vessels, i.e. capillaries and vasa vasorum, were identified in repopulated valves especially in the medial and adventitial tunicae of regenerated arterial walls. Such findings correlated to the up-regulated vascular gene transcription. Neoinnervation hallmarks were appreciated at histological and ultrastructural levels. Macrophage populations with reparative M2 phenotype were highly represented in repopulated valves. Indeed, no aspects of adverse/immune reaction were revealed in immunohistochemical and transcriptomic patterns. Among differentiated elements, several cells were identified expressing typical stem cell markers of embryonic, hematopoietic, neural and mesenchymal lineages in significantly higher number and specific topographic distribution in respect to control valves. Following the longest follow-up ever realized in preclinical models, non-preconditioned decellularized allogeneic valves offer suitable microenvironment for in vivo cell homing and tissue remodeling. Manufactured with simple, timesaving and cost-effective procedures, these promising valve replacements hold promise to become an effective alternative, especially for pediatric patients.

Septic thrombophlebitis of the pelvic veins may occur secondary to non-sterile intravenous drug injection and represents an uncommon yet life-threatening condition, most usually manifesting with persistent spiking fever and limb edema. Risk is further increased in HIV-infected people. High clinical suspicion and prompt imaging assessment with contrast-enhanced multidetector CT are necessary for correct diagnosis and staging, since early treatment prevents further complications such as systemic embolization.

Pulmonary arterial embolization of polymethylmethacrylate cement, most usually occurring after vertebroplasty or kyphoplasty, is very uncommon following vertebral stabilization procedures. Unenhanced CT scans viewed at lung window settings allow confident identification of cement emboli in the pulmonary circulation along with possible associate parenchymal changes, whereas hyperdense emboli may be less conspicuous on CT-angiographic studies with high-flow contrast medium injection. Although clinical manifestations are largely variable from asymptomatic cases to severe respiratory distress, most cases are treated with anticoagulation.

The acid dissociation of a nitric acid HNO3molecule located at various depths in a water slab is investigated via Car−Parrinello molecular dynamics simulations. HNO3is found to remain molecular when it is adsorbed on top of the surface with two hydrogen-bonds, and to dissociatealthough not alwaysby transferring a proton to a water molecule within a few picoseconds when embedded at various depths within the aqueous layer. The acid dissociation events are analyzed and discussed in terms of the proton donor−acceptor O−O hydrogen bonding distance and the configurations of the nearest-neighbor solvent waters of an HNO3·H2O pair. Four key structural features for the HNO3acid dissociation are identified and employed to analyze the trajectory results. Key solvent motions for the dissociation include the decrease of the proton donor−acceptor O−O hydrogen bonding distance and a 4 to 3 coordination number change for the proton-accepting water. The Eigen cation (H3O+), rather than the Zundel cation (H5O2+), is found to be predominant next to the NO3−ion in contact ion pairs in all cases. [ABSTRACT FROM AUTHOR]

The infrared signatures of nitric acid HNO 3and its conjugate anion NO 3−at the surface of an aqueous layer are derived from electronic structure calculations at the HF/SBK+∗ level of theory on the HNO 3·(H 2O) 3→ NO 3−·H 3O +·(H 2O) 2model reaction system embedded in clusters comprising 33, 40, 45, and 50 classical, polarizable waters, mimicking various degrees of solvation [Bianco, R.; Wang, S.; Hynes, J. T. J. Phys. Chem. A2007, 111, 11033]. The molecular level character of the various bands is discussed, and the solvation patterns are described in terms of hydrogen bonding and resulting polarization of the species’ intramolecular bonds. Connection is made with assorted experimental results, including surface-sensitive Sum Frequency Generation spectroscopy of aqueous nitric acid solutions, infrared spectroscopy of amorphous thin films of nitric acid monohydrate (NAM) and dihydrate (NAD), and infrared and Raman spectroscopic results for bulk aqueous solutions of nitric acid and nitrate salts. [ABSTRACT FROM AUTHOR]

The issue of acid dissociation of nitric acid at an aqueous surface is relevant in various portions of the atmosphere in connection with ozone depletion. This proton-transfer reaction is studied here via electronic structure calculations at the HF/SBK(d) level of theory on the HNO3·(H2O)3model reaction system embedded in clusters comprising 33, 40, 45, and 50 classical, polarizable waters with an increasing degree of solvation of the nitrate group. Free energy estimates for all the cases examined favor undissociated, molecular nitric acid over the 0−300 K temperature range, including that relevant for the upper troposphere, where it is connected to the issue of the mechanism of nitric acid uptake by water ice aerosols. The presence of molecular HNO3at 300 K at the surface is further supported by vibrational band assignments in good agreement with a very recent surface-sensitive vibrational spectroscopy study of diluted HNO3/H2O solutions. [ABSTRACT FROM AUTHOR]

Purpose: The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor A (VEGF‐A) is a key regulator of tumor‐induced endothelial cell proliferation and vascular permeability. ZD6474 is an orally available, small molecule inhibitor of VEGF receptor‐2 (VEGFR‐2), EGFR and RET tyrosine kinase activity. We investigated the activity of ZD6474 in combination with cetuximab, an anti‐EGFR blocking monoclonal antibody, to determine the anti‐tumor activity of EGFR blockade through the combined use of two agents targeting the receptor at different molecular sites in cancer cells and of VEGFR‐2 blockade in endothelial cells. Experimental Design: The anti‐tumor activity in vitro and in vivo of ZD6474 and/or cetuximab was tested in human cancer cell lines with a functional EGFR autocrine pathway. Results: The combination of ZD6474 and cetuximab determined synergistic growth inhibition in all cancer cell lines tested as assessed by the Chou and Talalay method. In nude mice bearing established human colon carcinoma (GEO) or lung adenocarcinoma (A549) xenografts and treated with ZD6474 and/or cetuximab for 4 weeks, a reversible tumor growth inhibition was caused by each drug. In contrast, a more significant tumor growth delay resulted from the combination of the two agents with an approximately 100–110 days increase in mice median overall survival as compared to single agent treatment. Conclusions: This study provides a rationale for evaluating in a clinical setting the double blockade of EGFR in combination with inhibition of VEGFR‐2 signaling as cancer therapy. J. Cell. Physiol. 208: 344–353, 2006. © 2006 Wiley‐Liss, Inc. [ABSTRACT FROM AUTHOR]

Purpose To test the efficacy of adding cisplatin to first-line treatment for elderly patients with advanced non-small-cell lung cancer (NSCLC) within a combined analysis of two parallel phase III trials, MILES-3 and MILES-4. Patients and Methods Patients with advanced NSCLC who were older than age 70 years with Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to gemcitabine or pemetrexed, without or with cisplatin. In each trial, 382 events were required to detect a hazard ratio (HR) of death of 0.75, with 80% power and two-tailed α of .05. Trials were closed prematurely because of slow accrual, but the joint database allowed us to analyze the efficacy of cisplatin on the basis of intention-to-treat and adjusted by trial, histotype, non-platinum companion drug, stage, performance status, sex, age, and size of the study center. Results From March 2011 to August 2016, 531 patients (MILES-3, 299; MILES-4, 232) were assigned to gemcitabine or pemetrexed without (n = 268) or with cisplatin (n = 263). Median age was 75 years, 79% were male, and 70% had nonsquamous histology. At a median 2-year follow-up, 384 deaths and 448 progression-free survival events were recorded. Overall survival was not significantly prolonged with cisplatin (HR, 0.86; 95% CI, 0.70 to 1.05; P = .14) and global health status score of quality of life was not improved, whereas progression-free survival (HR, 0.76; 95% CI, 0.63 to 0.92; P = .005) and objective response rate (15.5% v 8.5%; P = .02) were significantly better. Significantly more severe hematologic toxicity, fatigue, and anorexia were found with cisplatin. Conclusion The addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival, and it does not improve global health status score of quality of life in elderly patients with advanced NSCLC.