Dosimetric study to assess the feasibility of intraoperative radiotherapy with electrons (ELIOT) as partial breast irradiation for patients with cardiac implantable electronic device (CIED).

PURPOSE: To report in-vivo dosimetry in the infraclavicular region, a potential site of a cardiac implantable electronic device (CIED) and to evaluate the absorbed dose from intraoperative radiotherapy with electrons (ELIOT). METHODS: 27 non-cardiopathic breast cancer (BC) patients without CIED received quadrantectomy and ELIOT as partial breast irradiation. Before delivering ELIOT, two catheters, each containing eight thermoluminescent dosimeters (TLDs), were positioned in the infraclavicular region. TLDs internal catheter was located deep in the tumor bed while the external catheter was placed on patient's skin. RESULTS: Data were available for 24/27 patients. The absorbed doses were referred to the dose of 21 Gy. Values measured by the external catheter were low, although statistically significant higher doses were found close to the applicator (mean values 0.26-0.49 Gy). External TLD doses in proximity of the applicator were lower than those detected by their internal counterparts. Values measured by the internal catheter TLDs varied according to the distance from the applicator while no correlation with tumor site and beam energy was found. The distance from the applicator to deliver < 2 Gy to a CIED was 2 cm, while from 2.5 cm the dose measured in all the patients became negligible. CONCLUSIONS: This dosimetric study provided data to support the clinical use of ELIOT in BC patients having CIEDs as long as the suggested minimum safe distance of 2.5 cm is taken from the RT field in case of ELIOT single dose of 21 Gy, in the energy range of 6-10 MeV.

Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy.

BACKGROUND: Three types of anthracycline-induced cardiotoxicities are currently recognized: acute, early-onset chronic, and late-onset chronic. However, data supporting this classification are lacking. We prospectively evaluated incidence, time of occurrence, clinical correlates, and response to heart failure therapy of cardiotoxicity. METHODS AND RESULTS: We assessed left ventricular ejection fraction (LVEF), at baseline, every 3 months during chemotherapy and for the following year, every 6 months over the following 4 years, and yearly afterward in a heterogeneous cohort of 2625 patients receiving anthracycline-containing therapy. In case of cardiotoxicity (LVEF decrease >10 absolute points, and <50%), heart failure therapy was initiated. Recovery from cardiotoxicity was defined as partial (LVEF increase >5 absolute points and >50%) or full (LVEF increase to the baseline value). The median follow-up was 5.2 (quartile 1 to quartile 3, 2.6-8.0) years. The overall incidence of cardiotoxicity was 9% (n=226). The median time elapsed between the end of chemotherapy and cardiotoxicity development was 3.5 (quartile 1 to quartile 3, 3-6) months. In 98% of cases (n=221), cardiotoxicity occurred within the first year. Twenty-five (11%) patients had full recovery, and 160 (71%) patients had partial recovery. At multivariable analysis, end-chemotherapy LVEF (hazard ratio, 1.37; 95% confidence interval, 1.33-1.42 for each percent unit decrement) and cumulative doxorubicin dose (hazard ratio, 1.09; 95% confidence interval, 1.04-1.15 for each 50 mg/m(2) increment) were independent correlates of cardiotoxicity. CONCLUSIONS: Most cardiotoxicity after anthracycline-containing therapy occurs within the first year and is associated with anthracycline dose and LVEF at the end of treatment. Early detection and prompt therapy of cardiotoxicity appear crucial for substantial recovery of cardiac function.

Prevention of Atrial Fibrillation in High-risk Patients Undergoing Lung Cancer Surgery: The PRESAGE Trial.

OBJECTIVE: We performed a prospective, randomized clinical study to assess whether prophylactic treatment with metoprolol or losartan, initiated soon after lung cancer surgery in patients with elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, reduces the incidence of postoperative atrial fibrillation. BACKGROUND: Postoperative atrial fibrillation is a well recognized complication after lung cancer surgery, with an incidence as high as 30%. Perioperative increase of NT-proBNP has been demonstrated to be a strong independent predictor of postoperative atrial fibrillation in this setting. METHODS: NT-proBNP concentration was measured 24 hours before surgery and soon after surgery in 1116 patients. Three hundred twenty (29%) patients showed a high NT-proBNP value and were enrolled: 108 were assigned to the metoprolol group, 102 to the losartan group, and 110 to the control group. RESULTS: Overall, the incidence of postoperative atrial fibrillation was 20% (n = 64); it was significantly lower in the metoprolol and losartan groups compared with the control group [6%, 12%, and 40%, respectively; relative risk 0.19, 95% confidence intervals (CIs), 0.09-0.37; P < 0.001 in the metoprolol group; and 0.29, 95% CI, 0.16-0.52; P < 0.001 in the losartan group). No significant difference was found when the metoprolol and losartan groups were directly compared (P = 0.21). CONCLUSIONS: A prophylactic treatment with metoprolol or losartan, initiated soon after lung cancer surgery in patients with high NT-proBNP levels, significantly reduced the occurrence of postoperative atrial fibrillation.

Highly Polymorphic Materials and Dissolution Behaviour: The Peculiar Case of Rifaximin.

Rifaximin is a locally acting antibiotic practically insoluble in water. It presents several crystal phases characterized by different degrees of hydration. The aim of this work is to investigate the dissolution behaviour of rifaximin α, ß, and amorphous forms in relation to their relative thermodynamic stability to contribute to clarifying possible solvent- or humidity-mediated conversion patterns. Kinetic and intrinsic solubility were investigated along with particle size distribution, specific surface area, and external morphology. The solution and moisture mediated conversion from metastable α and amorphous forms to stable ß form were elucidated by coupling intrinsic dissolution test with chemometric analysis as well as by dynamic vapour sorption measurements. The dissolution behaviour of the α form stems mainly from the transition to ß form that occurs upon exposition to relative humidity higher than 40%. The α form converted more rapidly than the amorphous form due to the smaller supersaturation ratio. It can be concluded that, due to its marked tendency to transform into ß form, the dissolution test for the α form, even if conducted according to compendial procedures, needs to be accompanied by a panel of further tests that allow to uniquely identify the solid phase under investigation.

Sentinel lymph node biopsy in pregnant patients with breast cancer.

PURPOSE: Sentinel lymph node biopsy (SLNB) is currently not recommended in pregnant patients with breast cancer due to radiation concerns. METHODS: Twelve pregnant patients with breast cancer received low-dose (10 MBq on average) lymphoscintigraphy using (99m)Tc human serum albumin nanocolloids. RESULTS: The sentinel lymph node (SLN) was identified in all patients. Of the 12 patients, 10 had pathologically negative SLN. One patient had micrometastasis in one of four SLN. One patient had metastasis in the SLN and underwent axillary clearance. From the 12 pregnancies, 11 healthy babies were born with no malformations and normal weight. One baby, whose mother underwent lymphatic mapping during the 26th week of gestation, was operated on at the age of 3 months for a ventricular septal defect and at 43 months was in good health. This malformation was suspected at the morphological US examination during week 21, well before lymphoscintigraphy, and was confirmed a posteriori by a different observer based on videotaped material. No overt axillary recurrence appeared in the patients with negative SLNs after a median follow-up of 32 months. CONCLUSION: Our experience supports the safety of SLNB in pregnant patients with breast cancer, when performed with a low-dose lymphoscintigraphic technique.

Cardioncological Approach for Trastuzumab Therapy in Breast Cancer Patients With Cardiotoxicity: Impact on Adherence and Clinical Outcome.

BACKGROUND: Treatment with Trastuzumab is associated with cardiotoxicity. If Trastuzumab could be administered in a safe manner to patients who develop a reduced left ventricular ejection fraction (EF) of < 50% remains poorly understood. OBJECTIVE: To evaluate the impact of a cardioncological approach in terms of adherence and continuation of oncological therapy with Trastuzumab. METHODS AND RESULTS: Internal databases of candidates for trastuzumab chemotherapy with evidence of cardiotoxicity according to echocardiographic criteria were retrospectively evaluated. Eighty-four female patients (age 51.7 years, 95% CI 49.5-53.8), were finally included. Patients were divided to receive a standard (n 27) or cardioncological (n 57) scheme. Baseline EF values were within normal limits (60.9, 95% CI 60 - 61.9%; p=0.5 between groups). The nadir of EF observed during trastuzumab therapy was more pronounced in the standard care group (40.6, 95% CI 37.3-43.9% vs. 46.3, 95% CI 44.3-48.3%; p=0.002). At re-challenge, after cardiotoxicity detection, all patients in the cardioncological arm resumed and completed trastuzumab therapy (p<0.0001). An overall reduction of EF was observed at the final evaluation (p <0.0001 vs. baseline). Cardioncological approach was the only independent determinant of ΔEF from baseline to final evaluation (R20.12; p=0.004). We observed a total of 13 (15%) HF events, seven (26%) in the standard, and six (10%) in the cardioncological approach group (p =0.1). Patients in the cardioncological approach arm had a better outcome (Log Rank Chi-squared 4.89; p=0.02). CONCLUSIONS: A targeted cardioncological approach, in patients with evidence of cardiotoxicity during HER-2 inhibitor therapy, could favorably influence the oncological management of breast cancer patients, reducing the adverse cardiovascular impact of chemotherapy.

Increased perioperative N-terminal pro-B-type natriuretic peptide levels predict atrial fibrillation after thoracic surgery for lung cancer.

BACKGROUND: Postoperative atrial fibrillation (AF) is a complication of thoracic surgery for lung cancer, with a reported incidence that can run as high as 42%. Recently, it has been observed retrospectively that B-type natriuretic peptide predicts AF after cardiac surgery. We performed a prospective study to evaluate the role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a marker for risk stratification of postoperative AF in patients undergoing thoracic surgery for lung cancer. METHODS AND RESULTS: We measured NT-proBNP levels in 400 patients (mean age, 62+/-10 years; 271 men) 24 hours before and 1 hour after surgery. The primary end point of the study was the incidence of postoperative AF. Overall, postoperative AF occurred in 72 patients (18%). Eighty-eight patients (22%) showed an elevated perioperative NT-proBNP value. When patients with either preoperatively or postoperatively elevated NT-proBNP were pooled, a greater incidence of AF was observed compared with patients with normal values (64% versus 5%; P<0.001). At multivariable analysis, adjusted for age, gender, major comorbidities, echocardiography parameters, pneumonectomy, and medications, both preoperative and postoperative NT-proBNP values were independent predictors of AF (relative risk, 27.9; 95% CI, 13.2 to 58.9; P<0.001 for preoperative NT-proBNP elevation; relative risk, 20.1; 95% CI, 5.8 to 69.4; P<0.001 for postoperative NT-proBNP elevation). CONCLUSIONS: Elevation of perioperative NT-proBNP is a strong independent predictor of postoperative AF in patients undergoing thoracic surgery for lung cancer. This finding should facilitate studies of therapies to reduce AF in selected high-risk patients.

Rainfall as primary driver of discharge and solute export from rock glaciers: The Col d'Olen Rock Glacier in the NW Italian Alps.

Three hypotheses exist to explain how meteorological variables drive the amount and concentration of solute-enriched water from rock glaciers: (1) Warm periods cause increased subsurface ice melt, which releases solutes; (2) rain periods and the melt of long-lasting snow enhance dilution of rock-glacier outflows; and (3) percolation of rain through rock glaciers facilitates the export of solutes, causing an opposite effect as that described in hypothesis (2). This lack of detailed understanding likely exists because suitable studies of meteorological variables, hydrologic processes and chemical characteristics of water bodies downstream from rock glaciers are unavailable. In this study, a rock-glacier pond in the North-Western Italian Alps was studied on a weekly basis for the ice-free seasons 2014 and 2015 by observing the meteorological variables (air temperature, snowmelt, rainfall) assumed to drive the export of solute-enriched waters from the rock glacier and the hydrochemical response of the pond (water temperature as a proxy of rock-glacier discharge, stable water isotopes, major ions and selected trace elements). An intra-seasonal pattern of increasing solute export associated with higher rock-glacier discharge was found. Specifically, rainfall, after the winter snowpack depletion and prolonged periods of atmospheric temperature above 0 °C, was found to be the primary driver of solute export from the rock glacier during the ice-free season. This occurs likely through the flushing of isotopically- and geochemically-enriched icemelt, causing concomitant increases in the rock-glacier discharge and the solute export (SO42-, Mg2+, Ca2+, Ni, Mn, Co). Moreover, flushing of microbially-active sediments can cause increases in NO3- export.

Radiotherapy in patients with cardiac implantable electronic devices: clinical and dosimetric aspects.

As a result of aging, the number of patients with cardiac implantable electronic device (CIED) requiring radiotherapy (RT) continues to rise. The aim of this work was to evaluate RT-related malfunctions of CIED in a cohort of patients who underwent RT in our clinic from June 2010 to December 2016. We retrospectively analyzed 93 RT treatments in 63 patients with CIEDs. Patients were treated with 3D conformal RT, intensity-modulated RT and stereotactic RT. We collected clinical characteristics of cancer, models of CIEDs, total RT dose to tumor and radiation energy. Radiation dose delivered to CIED and its dysfunctions after RT was evaluated. Subgroup analysis of 48 RT treatments (32 patients) on chest and neck plus on 13 RT treatments (12 patients) with 18 MV neutron-producing photon energy considered as high risk was performed. The number of treatments of patients with CIEDs increased from 0.3% in 2011 to 1.2% in 2016. Two patients, treated with 18 MV photon beam, with implantable cardioverter-defibrillators (ICDs) that received a maximum dose of around 2.1 Gy, experienced adverse events: a reprogramming of ICD when the patient reached a delivered dose to the tumor of 32 Gy, and an altered sensing function requiring replacement after 11 months from the end of RT. Nearly 2% of patients with CIEDs from high-risk patients subgroup had experienced a damage of the device. Close cooperation between radiation oncologists, cardiologists, medical physicists and radiation technologists is needed to achieve the best practice management in these patients.

Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition.

BACKGROUND: An increase in troponin I soon after high-dose chemotherapy (HDC) is a strong predictor of poor cardiological outcome in cancer patients. This finding has important clinical implications and provides a rationale for the development of prophylactic strategies for preventing cardiotoxicity. Angiotensin-converting enzyme inhibitors slow the progression of left ventricular dysfunction in different clinical settings, but their role in the prevention of cardiotoxicity has never been investigated. METHODS AND RESULTS: Of the 473 cancer patients evaluated, 114 (72 women; mean age, 45+/-12 years) who showed a troponin I increase soon after HDC were randomized to receive (angiotensin-converting enzyme inhibitor group; 20 mg/d; n=56) or not to receive (control subjects; n=58) enalapril. Treatment was started 1 month after HDC and continued for 1 year. Cardiological evaluation was performed at baseline and at 1, 3, 6, and 12 months after HDC. The primary end point was an absolute decrease >10 percent units in left ventricular ejection fraction, with a decline below the normal limit value. A significant reduction in left ventricular ejection fraction and an increase in end-diastolic and end-systolic volumes were observed only in untreated patients. According to the Kaplan-Meier analysis, the incidence of the primary end point was significantly higher in control subjects than in the angiotensin-converting enzyme inhibitor group (43% versus 0%; P<0.001). CONCLUSIONS: In high-risk, HDC-treated patients, defined by an increased troponin I value, early treatment with enalapril seems to prevent the development of late cardiotoxicity.

Early reduction in left ventricular contractile reserve detected by dobutamine stress echo predicts high-dose chemotherapy-induced cardiac toxicity.

BACKGROUND: High-dose chemotherapy (HDC) is utilized in high-risk cancer patients. This type of treatment may induce cardiac toxicity which becomes clinically evident weeks or months after HDC. Hence, the possibility of early identification of patients who will develop cardiac impairment is strategic for its clinical implications. The aim of this study was to identify possible early changes of left ventricular contractile reserve (LVCR) in cancer patients undergoing HDC, as well as to evaluate the relevance of such changes as predictors of chemotherapy-induced cardiotoxicity. METHODS: In forty-nine female patients scheduled for HDC, due to poor-prognosis breast cancer, dobutamine stress echocardiography (DSE) was performed, before each of the three HDC cycles (C1, C2, C3), and 1, 4, and 7 months after the end of chemotherapy. According to rest left ventricular ejection fraction (LVEF) evaluated within 18 months after HDC (f-LVEF), patients were allocated to Group A (LVEF < 50% and >10 absolute units reduction) and to Group B (LVEF > or = 50%). RESULTS: Rest LVEF didn't show any significant difference between the two groups except at f-LVEF. Peak LVEF and LVCR significantly decreased in Group A only, starting from C3. At C3, a > or = 5 units fall in LVCR was found to be predictive for f-LVEF drop below 50%. CONCLUSIONS: In patients undergoing HDC, low-dose DSE allows the early identification of patients at a high risk of developing cardiac dysfunction.

Acute coronary syndrome induced by oral capecitabine.

A 41-year-old woman who was undergoing oral chemotherapy with capecitabine for metastatic breast cancer presented with recurrent episodes of chest pain associated with electrocardiographic signs of diffuse ST segment elevation. After spontaneous pain relief, the electrocardiogram showed ischemic evolution in the anterior precordial leads. Coronary and ventricular angiography, performed 24 h later, showed normal coronary arteries and normal left ventricular function. After therapy with capecitabine was discontinued, the patient did not experience further episodes of chest pain. After a nine-month follow-up, she remains alive, with a good performance status and without clinical evidence of persistent ischemia.

Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy.

BACKGROUND: In patients with aggressive malignancies who are undergoing high-dose chemotherapy, even minimal elevation of troponin I (TnI) is associated with late left ventricular dysfunction. The time course of the subclinical myocardial damage and its impact on the clinical outcome have never been investigated previously. METHODS AND RESULTS: In 703 cancer patients, we measured TnI soon after chemotherapy (early TnI) and 1 month later (late TnI). Troponin was considered positive for values > or =0.08 ng/mL. Clinical and left ventricular ejection fraction evaluation (echocardiography) were performed before chemotherapy, 1, 3, 6, and 12 months after the end of the treatment, and again every 6 months afterward. Three different TnI patterns were identified, and patients were grouped accordingly. In 495 patients, both early and late TnI values were <0.08 ng/mL (TnI-/- group); in 145, there was only an early increase (TnI+/- group); and in 63 patients, both values increased (TnI+/+ group). In the TnI-/- group, no significant reduction in ejection fraction was observed during the follow-up, and there was a very low incidence of cardiac events (1%). In contrast, a greater incidence of cardiac events occurred in TnI-positive patients, particularly in the TnI(+/+) group (84% versus 37% in the TnI+/- group; P<0.001). CONCLUSIONS: TnI release pattern after high-dose chemotherapy identifies patients at different risks of cardiac events in the 3 years thereafter. This stratification allows us to differentiate the monitoring program and to plan, in selected patients, preventive strategies aimed at improving clinical outcome.

Primary cardiac lymphoma with isolated parenchymal central nervous system relapse: report of two cases and review of the literature.

Primary cardiac lymphoma (PCL) is a rare subset of non-Hodgkin's lymphoma involving the heart and/or pericardium with no or minimal evidence of extracardiac involvement at presentation. Distant relapses have infrequently been observed. We report two cases of this disorder that showed isolated central nervous system (CNS) relapse. Diagnosis by endomyocardial biopsy was consistent with diffuse large B-cell lymphoma. After immunochemotherapy they achieved complete remission (CR). Eight and five weeks after, isolated CNS relapses were observed respectively. The first patient was treated with high-dose methotrexate (HD-MTX) and high-dose cytarabine, resulting in a second CR. She then went onto receive autologous stem-cell transplantation but unfortunately died shortly after because of infection. The second patient received systemic CNS prophylaxis with HD-MTX, and later she was treated with an induction chemotherapy strategy with evidencing of progressive disease after two courses of treatment. She was subsequently initiated on a salvage therapy with cytarabine, followed by whole-brain radiotherapy, and autologous stem-cell transplant (ASCT), finally achieving a complete remission. Isolated CNS relapse is a very uncommon pattern in PCL and a standard approach to treatment is not yet well established. Nevertheless, the importance of CNS evaluation, using magnetic resonance imaging (MRI) and lumbar puncture, in patients with PCL should be considered, and further studies are recommended to determine the appropriate management of this complication.

Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy.

OBJECTIVES: The purpose of this study was to evaluate the clinical relevance of anthracycline-induced cardiomyopathy (AC-CMP) and its response to heart failure (HF) therapy. BACKGROUND: The natural history of AC-CMP, as well as its response to modern HF therapy, remains poorly defined. Hence, evidence-based recommendations for management of this form of cardiomyopathy are still lacking. METHODS: We included in the study 201 consecutive patients with a left ventricular ejection fraction (LVEF)

Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation.

PURPOSE: Treatment of breast cancer with trastuzumab is complicated by cardiotoxicity in up to 34% of the patients. In most patients, trastuzumab-induced cardiotoxicity (TIC) is reversible: left ventricular ejection fraction (LVEF) improves after trastuzumab withdrawal and with, or sometimes without, initiation of heart failure (HF) therapy. The reversibility of TIC, however, is not foreseeable, and identification of patients at risk and of those who will not recover from cardiac dysfunction is crucial. The usefulness of troponin I (TNI) in the identification of patients at risk for TIC and in the prediction of LVEF recovery has never been investigated. PATIENTS AND METHODS: In total, 251 women were enrolled. TNI was measured before and after each trastuzumab cycle. LVEF was evaluated at baseline, every 3 months during trastuzumab therapy, and every 6 months afterward. In case of TIC, trastuzumab was discontinued, and HF treatment with enalapril and carvedilol was initiated. TIC was defined as LVEF decrease of > 10 units and below 50%. Recovery from TIC was defined as LVEF increase above 50%. RESULTS: TIC occurred in 42 patients (17%) and was more frequent in patients with TNI elevation (TNI+; 62% v 5%; P < .001). Twenty-five patients (60%) recovered from TIC. LVEF recovery occurred less frequently in TNI+ patients (35% v 100%; P < .001). At multivariate analysis, TNI+ was the only independent predictor of TIC (hazard ratio [HR], 22.9; 95% CI, 11.6 to 45.5; P < .001) and of lack of LVEF recovery (HR, 2.88; 95% CI,1.78 to 4.65; P < .001). CONCLUSION: TNI+ identifies trastuzumab-treated patients who are at risk for cardiotoxicity and are unlikely to recover from cardiac dysfunction despite HF therapy.