Tumor Budding, p53, and DNA Mismatch Repair Markers in Sinonasal Intestinal-Type Adenocarcinoma: A Retrospective Study Supports the Adverse Prognostic Impact of Tumor Budding.

Sinonasal intestinal-type adenocarcinoma (ITAC) is a very rare, closely occupational-related tumor with strong histological similarities to colorectal cancer (CRC). In the latter, tumor budding (TB) is widely recognized as a negative prognostic parameter. The aim of this study was to evaluate the prognostic role of TB in ITAC and to correlate it with other established or emerging biomarkers of the disease, such as p53 and deficient DNA mismatch repair (MMR) system status/microsatellite instability (MSI). We retrospectively analyzed 32 consecutive specimens of patients with ITAC diagnosis treated in two institutions in Northern Italy. We reviewed surgical specimens for TB evaluation (low-intermediate/high); p53 expression and MMR proteins were evaluated via immunohistochemistry. Results were retrospectively stratified using clinical data and patients' outcomes. According to bud counts, patients were stratified into two groups: intermediate/high budding (>4 TB) and low budding (≤4 TB). Patients with high TB (>4) have an increased risk of recurrence and death compared to those with low TB, with a median survival of 13 and 54 months, respectively. On multivariate analysis, considering TB, therapy, and stage as covariates, TB emerged as an independent prognostic factor net of the stage of disease or type of therapy received. No impact of p53 status as a biomarker of prognosis was observed and no alterations regarding MMR proteins were identified. The results of the present work provide further significant evidence on the prognostic role of TB in ITAC and underline the need for larger multicenter studies to implement the use of TB in clinical practice.

Electrochemotherapy as adjuvant treatment in a sinonasal mucosal melanoma in elderly patient: a case report.

BACKGROUND: Sinonasal Mucosal Melanoma (SNMM) is a rare but aggressive disease. Surgery with free margins, when feasible, is the treatment of choice. In the last three decades, electrochemotherapy (ECT) has emerged as a local ablative procedure, performed with the Cliniporator, for cutaneous and mucosal tumours of different histology. We present a case report of an ECT treatment performed by means of a new endoscopic electrode, on an elderly patient affected by primary SNMM. METHODS: An 88-year-old man with a diagnosis of SNMM (cT4aN0M0)-Stage IV, of the left nasal fossa presented at our institution. Symptoms were epistaxis and complete left nasal obstruction. He refused sinonasal extended surgery and radiotherapy. He underwent a tumor debulking followed by ECT exclusively for symptom control, with palliative intent. RESULTS: The patient underwent SNMM debulking under general anaesthesia, followed by ECT on tumour margins. After the procedure, he had been free from symptoms for 5 months, with a good quality of life. Local recurrence was controlled with a new local debulking and ECT procedure on margins. The patient remained symptom free for the next 4 months. Seventeen months after diagnosis, the patient is mild symptomatic for sinonasal disease. Therefore, he developed a systemic disease progression. CONCLUSIONS: In our experience, ECT can be used as an adjuvant tool for symptom and local control in SNMM when extended surgery is out of curative intent or unfeasible. As expected, ECT does not appear to have any effect on systemic disease progression.

Cardiac wasting in head and neck cancer and in cardiac autopsies from different cancer types: A study in a chemo-naïve setting.

BACKGROUND: Cardiac wasting is a detrimental consequence of cancer that has been traditionally ignored and often misinterpreted as an iatrogenic effect. METHODS: We conducted a retrospective study on 42 chemo-naive patients affected by locally advanced head and neck cancer (HNC). Based on unintentional weight loss, patients were divided into cachectic and non-cachectic. Left ventricular mass (LVM), LV wall thickness (LVWT), interventricular septal (IVS) thickness, left ventricular internal diameter diastolic (LVIDd), left ventricular internal diameter systolic (LVIDs), internal ventricular septum diastolic (IVSd), left ventricular posterior wall thickness diastolic (LVPWd) and LV ejection fraction (LVEF) were analysed by echocardiography. In parallel, we retrospectively analysed 28 cardiac autoptic specimens of patients who either died of cancer before chemotherapy or with a diagnosis of cancer at autopsy. Presence or absence of myocardial fibrosis at microscopic observation was used for sample stratification. Conventional histology was performed. RESULTS: Cachectic and non-cachectic patients had a significantly different value of LVWT and IVS thickness and LVPWd. LVWT was 9.08 ± 1.57 versus 10.35 ± 1.41 mm (P = 0.011) in cachectic and non-cachectic patients, IVS was 10.00 mm (8.50-11.00) versus 11.00 mm (10.00-12.00) (P = 0.035), and LVPWd was 9.0 (8.5-10.0) and 10.00 mm (9.5-11.0) (P = 0.019) in cachectic and non-cachectic patients. LVM adjusted for body surface area or height squared did not differ between the two populations. Similarly, LVEF did not show any significant decline. At multivariate logistic regression analysis for some independent predictors of weight loss, only LVWT maintained significant difference between cachectic and non-cachectic patients (P = 0.035, OR = 0.240; P = 0.019). The secondary analysis on autoptic specimens showed no significant change in heart weight, whereas LVWT declined from 9.50 (7.25-11.00) to 7.50 mm (6.00-9.00) in cardiac specimens with myocardial fibrosis (P = 0.043). These data were confirmed in multivariate logistic regression analysis (P = 0.041, OR = 0.502). Histopathological analysis confirmed severe atrophy of cardiomyocytes, fibrosis and oedema as compared with controls. CONCLUSIONS: Subtle changes in heart structure and function occur early in HNC patients. These can be detected with routine echocardiography and may help to select appropriate cancer treatment regimens for these patients. Histopathological analysis provided conclusive evidence that atrophy of cardiomyocytes, oedema and fibrosis occur during cancer progression and may precede the onset of overt cardiac pathology. To our knowledge, this is the first clinical study that establishes a direct relationship between tumour progression and cardiac remodelling in HNCs and the first pathological study conducted on human cardiac autopsies from selected chemo-naïve cancer patients.

Clinical profile and mortality of Sars-Cov-2 infection in cancer patients across two pandemic time periods (Feb 2020-Sep 2020; Sep 2020-May 2021) in the Veneto Oncology Network: The ROVID study.

INTRODUCTION: We analyzed a cohort of patients with cancer and Sars-Cov-2 infection from the Veneto Oncology Network registry across two pandemic time periods. MATERIALS AND METHODS: 761 patients with cancer and SARS-CoV-2 infection were included. RESULTS: 198 patients were diagnosed during the first pandemic time period (TP1; February 2020 September 2020), 494 during TP2 before the vaccination campaign (TP2/pre-vaccination; September 2020-21 February 2021) and 69 in TP2/post-vaccination (22 February 2021-15 May 2021). TP2 vs TP1 patients were younger (p = 0.004), showed more frequently a good performance status (p < 0.001) and <2 comorbidities (p = 0.002), were more likely to be on active anticancer therapy (p = 0.006). Significantly fewer patients in TP2 (3-4%) vs TP1 (22%) had an in-hospital potential source of infection (p < 0.001). TP2 patients were more frequently asymptomatic (p = 0.003). Significantly fewer patients from TP2 were hospitalized (p < 0.001) or admitted to intensive care unit (p = 0.006). All-cause mortality decreased from 30.3% in TP1, to 8.9% and 8.7% in the two TP2 periods (p < 0.001), reflected by a significant reduction in Sars-Cov-2-related mortality (15.2%, 7.5% and 5.8% in the three consecutive time periods, p = 0.004). CONCLUSIONS: Differences in clinical characteristics and features of Sars-Cov-2 infection between TP1 and TP2 reflect the effects of protective measures and increased testing capacity. The lower mortality in TP2 is in line with a less frail population. However, the vast majority of death events in TP2 were related to COVID-19, reinforcing the priority to protect cancer patients.

Epidemiology and clinical course of severe acute respiratory syndrome coronavirus 2 infection in cancer patients in the Veneto Oncology Network: The Rete Oncologica Veneta covID19 study.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) pandemic started in Italy with clusters identified in Northern Italy. The Veneto Oncology Network (Rete Oncologica Veneta) licenced dedicated guidelines to ensure proper care minimising the risk of infection in patients with cancer. Rete Oncologica Veneta covID19 (ROVID) is a regional registry aimed at describing epidemiology and clinical course of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with cancer. MATERIALS AND METHODS: Patients with cancer diagnosis and documented SARS-CoV-2 infection are eligible. Data on cancer diagnosis, comorbidities, anticancer treatments, as well as details on SARS-CoV-2 infection (hospitalisation, treatments, fate of the infection), have been recorded. Logistic regression analysis was applied to calculate the association between clinical/laboratory variables and death from any cause. RESULTS: One hundred seventy patients have been enrolled. The median age at time of the SARS-CoV infection was 70 years (25-92). The most common cancer type was breast cancer (n = 40). The majority of the patients had stage IV disease. Half of the patients had two or more comorbidities. The majority of the patients (78%) presented with COVID-19 symptoms. More than 77% of the patients were hospitalized and 6% were admitted to intensive care units. Overall, 104 patients have documented resolution of the infection. Fifty-seven patients (33%) have died. In 29 cases (17%), the cause of death was directly correlated to SARS-CoV-2 infection. Factors significantly correlated with the risk of death were the following: Eastern Cooperative Oncology Group performance status (PS), age, presence of two or more comorbidities, presence of dyspnoea, COVID-19 phenotype ≥ 3, hospitalisation, intensive care unit admission, neutrophil/lymphocyte ratio and thrombocytopenia. CONCLUSIONS: The mortality rate reported in this confirms the frailty of this population. These data reinforce the need to protect patients with cancer from SARS-CoV-2 infection.

Breakthrough Cancer Pain Clinical Features and Differential Opioids Response: A Machine Learning Approach in Patients With Cancer From the IOPS-MS Study.

PURPOSE: A large proportion of patients with cancer suffer from breakthrough cancer pain (BTcP). Several unmet clinical needs concerning BTcP treatment, such as optimal opioid dosages, are being investigated. In this analysis the hypothesis, we explore with an unsupervised learning algorithm whether distinct subtypes of BTcP exist and whether they can provide new insights into clinical practice. METHODS: Partitioning around a k-medoids algorithm on a large data set of patients with BTcP, previously collected by the Italian Oncologic Pain Survey group, was used to identify possible subgroups of BTcP. Resulting clusters were analyzed in terms of BTcP therapy satisfaction, clinical features, and use of basal pain and rapid-onset opioids. Opioid dosages were converted to a unique scale and the BTcP opioids-to-basal pain opioids ratio was calculated for each patient. We used polynomial logistic regression to catch nonlinear relationships between therapy satisfaction and opioid use. RESULTS: Our algorithm identified 12 distinct BTcP clusters. Optimal BTcP opioids-to-basal pain opioids ratios differed across the clusters, ranging from 15% to 50%. The majority of clusters were linked to a peculiar association of certain drugs with therapy satisfaction or dissatisfaction. A free online tool was created for new patients' cluster computation to validate these clusters in future studies and provide handy indications for personalized BTcP therapy. CONCLUSION: This work proposes a classification for BTcP and identifies subgroups of patients with unique efficacy of different pain medications. This work supports the theory that the optimal dose of BTcP opioids depends on the dose of basal opioids and identifies novel values that are possibly useful for future trials. These results will allow us to target BTcP therapy on the basis of patient characteristics and to define a precision medicine strategy also for supportive care.

Development of Cancer in Patients With Heart Failure: How Systemic Inflammation Can Lay the Groundwork.

In the last decade, cardiologists and oncologists have provided clinical and experimental evidence that cancer, and not only chemotherapeutic agents, can cause detrimental effects on heart structure and function, a consequence that has serious clinical implications for patient management. In parallel, the intriguing idea that heart failure (HF) may be an oncogenic condition has also received growing attention. A number of epidemiological and clinical studies have reported that patients with HF have a higher risk of developing cancer. Chronic low-grade systemic inflammation has been proposed as a major pathophysiological process linking the failing heart to the multi-step process of carcinogenesis. According to this view, pro-inflammatory mediators secreted by the damaged heart generate a favorable milieu that promotes tumor development and accelerates malignant transformation. HF-associated inflammation synergizes with tumor-associated inflammation, so that over time it is no longer possible to distinguish the effects of one or the other. Experimental studies have just begun to search for the molecular effectors of this process, with the ultimate goal that of identifying mechanisms suitable for anti-cancer target therapy to reduce the risk of incident cancer in patients already affected by HF. In this review we critically discuss strengths and limitations of clinical and experimental studies that support a causal relationship between HF and cancer, and focus on HF-associated inflammation, cardiokines and their endocrine functions linking one and the other disease.

How progressive cancer endangers the heart: an intriguing and underestimated problem.

Since it came into being as a discipline, cardio-oncology has focused on the prevention and treatment of cardiotoxicity induced by antitumor chemotherapy and radiotherapy. Over time, it has been proved that even more detrimental is the direct effect generated by cancer cells that release pro-cachectic factors in the bloodstream. Secreted molecules target different organs at a distance, including the heart. Inflammatory and neuronal modulators released by the tumor bulk, either as free molecules or through exosomes, contribute to the pathogenesis of cardiac disease. Progressive cancer causes cachexia and severe cardiac muscle wasting accompanied by cardiomyocyte atrophy, tissue fibrosis, and several functional impairments up to heart failure. The molecular mechanisms responsible for such a cardiac muscle wasting have been partially elucidated in animal models, but minimally investigated in humans, although severe cardiac dysfunction exacerbates global cachexia and hampers efficient anti-cancer treatments. This review provides an overview of cancer-induced structural cardiac and functional damage, drawing on both clinical and scientific research. We start by looking at the pathophysiological mechanisms and evolving epidemiology and go on to discuss prevention, diagnosis, and a multimodal policy of intervention aimed at providing overall prognosis and global care for patients. Despite much interest in the cardiotoxicity of cancer therapies, the direct tumor effect on the heart remains poorly explored. There is still a lack of diagnostic criteria for the identification of the early stages of cardiac disease in cancer patients, while the possibilities that there are for effective prevention are largely underestimated. Research on innovative therapies has claimed considerable advances in preclinical studies, but none of the molecular targets suitable for clinical application has been approved for therapy. These issues are critically discussed here.

Clinical outcomes and prognostic factors in recurrent and/or metastatic head and neck cancer patients treated with chemotherapy plus cetuximab as first-line therapy in a real-world setting.

AIM: The aims of the study are to evaluate the clinical outcomes of first-line treatment with platinum-based chemotherapy and cetuximab in patients with relapsing/metastatic head and neck cancer (RM HNC) and to identify predictors of treatment response. METHODS: This is a retrospective, observational, longitudinal, real-world study involving 6 oncology centres in Italy. All consecutive patients with RM HNC treated between January 2007 and December 2016 with a first-line therapy consisting of a platinum-based chemotherapy regimen plus cetuximab were included. The primary objective of the study was to assess overall survival (OS) and progression-free survival (PFS). Secondary objectives included the identification of predictors of treatment response. RESULTS: Overall, 297 patients were identified. Median OS was 10.8 months (95% confidence interval [CI] 9.3-12.2), whereas median PFS was 4.8 months (95% CI 4.3-5.5). On multivariable analysis, independent unfavourable prognostic factors for OS were performance status (PS) Eastern Cooperative Oncology Group (ECOG) >0, presence of residual tumour at primary site, platinum resistance and lack of objective response. Unfavourable predictors for PFS included cancer primary site (paranasal sinuses, hypopharynx), PS ECOG >0, presence of residual tumour at primary site, platinum resistance and lack of objective response. Independent unfavourable predictors of objective response were tumour site (oral cavity, larynx-hypopharynx), residual tumour at primary site and prior chemotherapy. CONCLUSIONS: The availability of new treatment modalities and epidemiological changes make the periodic reassessment of prognostic factors of great relevance to guide clinical practice and the design of future randomised clinical trials.

Oral prolonged-release Oxycodone-Naloxone: analgesic response, safety profile, and factors influencing the response in advanced cancer patients.

BACKGROUND: Oxycodone-Naloxone (OXN) aims to reduce opioid-related constipation while being successfully analgesic. METHODS: We evaluated the analgesic response, prevalence, and severity of side effects in 176 cancer patients with moderate to severe pain and treated with OXN. Patients were followed for 28 days and evaluated every seven. Pain intensity, changes of therapy, and adverse drug reactions were recorded at each visit. The primary efficacy endpoint was the proportion of responders (≥30% reduction of pain intensity from baseline to final) and final average pain score ≤4 on a 0-10 scale. RESULTS: Average and worst pain intensity, and breakthrough pain (BTP) prevalence decreased over time and 81.3% of patients were responders. The starting daily dose of OXN was raised from 25.1±13.0 mg to 44.1±29.9 mg, and dose escalation >5%/day was observed in 19.4% of patients; 40.8-46.2% and 11.0-17.0% experienced any and severe grade of constipation during the follow-up visit, respectively. Digestive system tumor, thyroid endocrinopathies, psychological irritability, and BTP increased the risk of analgesic non-response. CONCLUSIONS: OXN had strong analgesic effect in moderate to severe cancer pain patients: the safety profile is in line with the common adverse effects of opioids and severe constipation was uncommon. This article is protected by copyright. All rights reserved.

Factors Influencing the Clinical Presentation of Breakthrough Pain in Cancer Patients.

Background: The aim of this study was to identify potential variables influencing the clinical presentation of breakthrough cancer pain (BTP). Methods: Cancer patients with a diagnosis of BTP were enrolled. Demographic and clinical characteristics, as well as background pain and BTP characteristics were collected. Multivariate analyses were conducted to assess the correlation between BTP characteristics and the variables examined. Results: Data of 4016 patients were analysed. Average daily number of BTP episodes was 2.4, mean intensity was 7.5, and a mean duration was 43.3 min. A short onset BTP was observed in 68.9% of patients. In 30.5% of patients BTP was predictable. There were 86.0% of participants who reported a marked interference of BTP with their daily activities. Furthermore, 86.8% of patients were receiving opioids for the management of BTP. The average time to meaningful pain relief was 16.5 min and 70.9% of patients were satisfied with their BTP medications. Age, head and neck cancer, Karnofsky, background pain intensity, predictable and fast onset BTP were independently associated with the number of BTP episodes. BTP pain intensity was independently associated with background pain intensity, fast onset BTP, and Karnofsky. Neuropathic pain mechanism was independently associated with unpredictable BTP. Variables independently associated with a longer duration of BTP were age, place of visit, cancer diagnosis, disease-oriented therapy, background pain intensity and mechanism, and unpredictable BTP. Age, Karnofsky, background pain intensity, fast onset, and long duration of BTP were independently associated with interference with daily activity. Conclusions: BTP has a variable presentation depending on interdependent relationships among its different characteristics.

Multicenter research into the quality of life of patients with advanced oropharyngeal carcinoma with long-term survival associated with human papilloma virus.

The treatment of advanced-stage oropharyngeal squamous cell carcinoma may utilize various modes, including combining surgery with chemoradiotherapy (CTRT), or primary CTRT followed by rescue surgery. In previous literature it has been revealed how patients treated with combined modes report a low quality of life (QoL) and severe consequences following surgery, radiotherapy and chemotherapy, in the short and in the long-term. The decrease in the QoL of patients treated with high-intensity multi-modal strategies highlights the necessity of modifying treatments, particularly for young HPV-positive patients, where an increased survival rate has already been reported. The modified treatment for HPV-positive tumors in the tonsils and at the base of the tongue is based on the deintensification of therapies aiming to reduce toxicity and thereby improve QoL in the long term, whilst still maintaining therapeutic effectiveness. The aim of the present study was to evaluate the QoL in patients with a long-term survival, who were treated with combined therapy for squamous cell tumors in the tonsils and at the base of the tongue, and to compare the results observed in HPV-positive and HPV-negative patients. According to statistical analysis, differences in the general QoL and in the single scales of the European Organization for the Research and Treatment of Cancer questionnaires were not correlated with the type of therapy selected for the particular patient. QoL considered the presence of HPV, the type of treatment, the subregion of the tonsils vs. the base of the tongue and the disease stage at the time of diagnosis, and was determined to be non-influential with regard to these specific variables.

Follow-up of oral and oropharyngeal cancer using narrow-band imaging and high-definition television with rigid endoscope to obtain an early diagnosis of second primary tumors: a prospective study.

Narrow-band imaging (NBI) is an optical technique enhancing mucosal vasculature. The aim of this study is to assess the effectiveness of rigid NBI endoscopy in the early detection of second primaries or local recurrences after treatment for oral (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC), its advantage over standard white-light (WL) endoscopy, and the influence of previous radiotherapy, the learning curve, and lesion site. Between January 2013 and June 2015, 195 patients treated for OSCC or OPSCC with surgery alone (group A) or radiotherapy with or without surgery and/or chemotherapy (group B) underwent additional follow-up assessments using NBI. Sensitivity, specificity, positive/negative predictive values (PPV and NPV), and accuracy for detecting second primaries or local recurrences were calculated for patients with at least two NBI assessments. The effect of previous radiotherapy was determined by test of proportions and that of the learning curve and lesion site with Fisher's exact test. 138/195 patients were included in the analysis. NBI sensitivity, specificity, PPV, NPV, and accuracy for groups A and B were 89.5 vs 100%, 85.2 vs 81.5%, 65.4 vs 69.7%, 96.3 vs 100%, and 86.3 vs 87%, respectively. The diagnostic gain of NBI was 88.2% in group A and 69.6% in group B. The learning curve was the main source of false positives (p = 0.025), whereas radiotherapy and lesion site were uninfluential (p = NS). NBI appears useful for follow-up after treatment for OSCC or OPSCC, its performance being affected only by the learning curve and not by previous treatment or lesion site.

Breakthrough Cancer Pain: Preliminary Data of The Italian Oncologic Pain Multisetting Multicentric Survey (IOPS-MS).

INTRODUCTION: An ongoing national multicenter survey [Italian Oncologic Pain multiSetting Multicentric Survey (IOPS-MS)] is evaluating the characteristics of breakthrough cancer pain (BTP) in different clinical settings. Preliminary data from the first 1500 cancer patients with BTP enrolled in this study are presented here. METHODS: Thirty-two clinical centers are involved in the survey. A diagnosis of BTP was performed by a standard algorithm. Epidemiological data, Karnofsky index, stage of disease, presence and sites of metastases, ongoing oncologic treatment, and characteristics of background pain and BTP and their treatments were recorded. Background pain and BTP intensity were measured. Patients were also questioned about BTP predictability, BTP onset (≤10 or >10 min), BTP duration, background and BTP medications and their doses, time to meaningful pain relief after BTP medication, and satisfaction with BTP medication. The occurrence of adverse reactions was also assessed, as well as mucosal toxicity. RESULTS: Background pain was well controlled with opioid treatment (numerical rating scale 3.0 ± 1.1). Patients reported 2.5 ± 1.6 BTP episodes/day with a mean intensity of 7.5 ± 1.4 and duration of 43 ± 40 min; 977 patients (65.1%) reported non-predictable BTP, and 1076 patients (71.7%) reported a rapid onset of BTP (≤10 min). Higher patient satisfaction was reported by patients treated with fast onset opioids. CONCLUSIONS: These preliminary data underline that the standard algorithm used is a valid tool for a proper diagnosis of BTP in cancer patients. Moreover, rapid relief of pain is crucial for patients' satisfaction. The final IOPS-MS data are necessary to understand relationships between BTP characteristics and other clinical variables in oncologic patients. FUNDING: Molteni Farmaceutici, Italy.

Targeting cellular and molecular drivers of head and neck squamous cell carcinoma: current options and emerging perspectives.

Despite improvements in functional outcomes attributable to advances in radiotherapy, chemotherapy, surgical techniques, and imaging techniques, survival in head and neck squamous cell carcinoma (HNSCC) patients has improved only marginally during the last couple of decades, and optimal therapy has yet to be devised. Genomic complexity and intratumoral genetic heterogeneity may contribute to treatment resistance and the propensity for locoregional recurrence. Countering this, it demands a significant effort from both basic and clinical scientists in the search for more effective targeted therapies. Recent genomewide studies have provided valuable insights into the genetic basis of HNSCC, uncovering potential new therapeutic opportunities. In addition, several studies have elucidated how inflammatory, immune, and stromal cells contribute to the particular properties of these neoplasms. In the present review, we introduce recent findings on genomic aberrations resulting from whole-genome sequencing of HNSCC, we discuss how the particular microenvironment affects the pathogenesis of this disease, and we describe clinical trials exploring new perspectives on the use of combined genetic and cellular targeted therapies.

Unusual cardiac metastasis of uterine leiomyosarcoma: case report and literature review.

BACKGROUND: Uterine leiomyosarcoma (LMS) is a rare malignancy of mesenchymal tissues and in advanced stages its prognosis is very poor. Surgery followed by radiotherapy and/or chemotherapy is the treatment of choice for advanced disease. Cardiac metastases are very uncommon and only a few cases have been described to date. CASE: A 55-year-old woman was referred to our center for a uterine LMS with lung metastases at diagnosis. After 3 lines of chemotherapy for persistent lung disease, CT scan showed suspected thrombosis in the right pulmonary vein, along with disease progression in the lungs. The patient started treatment with low-molecular-weight heparin and a fourth line of chemotherapy. After 3 months of therapy, a new CT scan showed a larger thrombus and she underwent a cardiology visit that revealed an intracardiac mass. Submitting the patient to palliative surgery or radiation therapy was not possible because of the aggressiveness of the lung metastases, so she continued chemotherapy, resulting in disease stabilization. CONCLUSIONS: Surgery is the best option for intracardiac dissemination of uterine LMS, but when this is not possible based on the performance status of the patient and spread of the disease, the combination of chemotherapy and radiotherapy seems to be the best option according to the literature. In our case we treated the patient only with chemotherapy.

Genotype-driven phase I study of irinotecan administered in combination with fluorouracil/leucovorin in patients with metastatic colorectal cancer.

PURPOSE We aimed to identify the maximum-tolerated dose (MTD) of irinotecan in patients with cancer with UGT1A1*1/*1 and *1/*28 genotypes. We hypothesize that the patients without the *28/*28 genotype tolerate higher doses of irinotecan. PATIENTS AND METHODS Patients undergoing first-line treatment for metastatic colorectal cancer (CRC) eligible for treatment with irinotecan plus infusional fluorouracil/leucovorin (FOLFIRI) were screened for the UGT1A1*28/*28 genotype and excluded from the study. Fifty-nine white patients with either the *1/*1 or the *1/*28 genotype were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 215 mg/m(2) for both genotype groups, whereas the dose of infusional fluorouracil was fixed. Pharmacokinetic data of irinotecan and metabolites were also obtained. Results The dose of irinotecan was escalated to 370 mg/m(2) in patients with the *1/*28 genotype and to 420 mg/m(2) in those with the *1/*1 genotype. Dose-limiting toxicities (DLTs) were observed in two of four of *1/*28 patients at 370 mg/m(2) and in two of three of *1/*1 patients at 420 mg/m(2). No DLTs were observed in 10 *1/*28 patients at 310 mg/m(2) and in 10 *1/*1 patients at 370 mg/m(2); hence these dose levels were the MTD for each genotype group. The most common grade 3 to 4 toxicities were neutropenia and diarrhea. The pharmacokinetics of irinotecan and SN-38 exhibit linear kinetics. CONCLUSION The recommended dose of 180 mg/m(2) for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated when patients with the UGT1A1*28/*28 genotype are excluded. Prospective genotype-driven studies should test the efficacy of higher irinotecan doses in the FOLFIRI schedule.

Effects of exercise training on endothelial progenitor cells in patients with chronic heart failure.

BACKGROUND: The enhancement of circulating endothelial progenitor cells (EPCs) obtained by exercise training can be beneficial to patients with cardiac disease. Changes in the levels and differentiation of CD34(pos)/KDR(pos) EPCs, as well as the plasma concentration of vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1 EPC-mobilizing cytokines, were evaluated in patients with chronic heart failure after 8 weeks of supervised aerobic training (SAT) and 8 weeks of subsequent discontinued SAT (DSAT). METHODS AND RESULTS: The levels of circulating EPC and EPC differentiation potential of 22 patients who underwent SAT were studied by fluorescence-activated cell sorter analysis and colony forming-unit assay, respectively. The plasma levels of VEGF and SDF-1 were measured by enzyme-linked immunosorbent assay. In response to SAT, the levels of both EPC and VEGF/SDF-1 markedly increased (P < .001 vs baseline) but returned to the baseline levels after DSAT. A similar change was observed with the EPC clonogenic potential, but on DSAT the baseline level was incompletely attained. CONCLUSIONS: In response to SAT, patients with chronic heart failure show enhanced EPC levels and clonogenic potential that is mirrored by increased plasma VEGF and SDF-1 levels. DSAT can interfere with the maintenance of training-acquired VEGF/SDF-1-related EPC levels and clonogenic potential.

Amino-bisphosphonates decrease hTERT gene expression in breast cancer in vitro.

BACKGROUND AND AIMS: Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase. hTERT expression and telomerase activity are elevated in most human tumors. Bisphosphonates play an important role in the management of tumors with the secondary involvement of bone. METHODS: We investigated the effect on hTERT gene expression of clodronate, alendronate, and pamidronate (from 10(-6) M to 10(-5) M) on MCF-7 and T47D human breast cancer cells, using real time RTPCR. RESULTS: At 10(-5) M, amino-bisphosphonates (alendronate and pamidronate) inhibited breast cancer cell viability and induced a significant decrease in hTERT gene expression with respect to controls (82% and 71% in MCF-7 cells; 74% and 60% in T47D, p<0.0001). No effect was observed with clodronate. CONCLUSIONS: Amino-bisphosphonates down-regulate hTERT gene expression. The role of hTERT is a new finding, which gives an alternative explanation for the direct effect of bisphosphonates on tumor cells.

The effect of bisphosphonates on gene expression: GAPDH as a housekeeping or a new target gene?

BACKGROUND: RT-PCR has been widely used for the analysis of gene expression in many systems, including tumor samples. GAPDH (Glyceraldehyde-3-phosphate dehydrogenase) has been frequently considered as a constitutive housekeeping gene and used to normalize changes in specific gene expression. However, GAPDH has been shown to be up-regulated in many cancers and down-regulated by chemotherapic drugs. Bisphosphonates, potent inhibitors of bone resorption, have recently shown a direct and indirect antitumor effect in vitro and in animal models. They exert their effects mainly by inhibiting the mevalonate pathway but also by modulating the expression of many genes not only in osteoclasts but also in cancer cells. METHODS: We evaluated GAPDH gene expression by real time RT PCR in breast (MCF-7 and T47D) and prostate (PC3 and DU-145) cancer cell lines treated with amino and non-amino bisphosphonates. RESULTS: Our results showed that amino-bisphosphonates significantly decrease in a dose-dependent manner the expression of GAPDH gene. CONCLUSION: Therefore, GAPDH is inaccurate to normalize mRNA levels in studies investigating the effect of bisphosphonates on gene expression and it should be avoided. On the other hand, this gene could be considered a potential target to observe the effects of bisphosphonates on cancer cells.