Applicability of the PAINESD risk score for 30-day mortality prediction post ventricular tachycardia catheter ablation in Chagas disease.

PURPOSE: The PAINESD risk score was developed in 2015 as a tool to stratify the risk of acute hemodynamic decompensation during ventricular tachycardia (VT) ablation in structural heart disease patients and further then used for post procedure 30-day mortality prediction. The original cohort however did not include Chagas disease (ChD) patients. We aim to evaluate the relevance of the score in a ChD population. METHODS: The PAINESD risk score gives weighted values for specific characteristics (chronic obstructive pulmonary disease, age > 60 years, ischemic cardiomyopathy, New York Heart Association [NYHA] functional class 3 or 4, ejection fraction less than 25%, VT storm, and diabetes). The score was applied in a retrospective cohort of ChD VT ablations in a single tertiary center in Brazil. Data were collected by VT study reports and patient record analysis at baseline and on follow-up. RESULTS: Between January 2013 and December 2018, 157 VT catheter ablation procedures in 121 ChD patients were analyzed. Overall, 30-day mortality was 9.0%. Multivariate analysis correlated NYHA functional class (HR 1.78, 95% CI 1.03-3.08, P 0.038) and the need for urgent surgery (HR 31.5, 95% CI 5.38-184.98, P < 0.001), as well as a tendency for VT storm at presentation (HR 2.72, 95% CI 0.87-8.50, P 0.084) as risk factors for the primary endpoint. The median PAINESD risk score in this population was 3 (3-8). The area under the receiver operating characteristic (ROC) curve was 0.64 (95% CI 0.479-0.814). CONCLUSIONS: The PAINESD risk score did not perform well in predicting 30-day mortality in ChD patients. Pre-procedure NYHA functional class and the need for urgent surgery due to refractory pericardial bleeding were independently associated with increased 30-day mortality. Prospective studies are needed to take final conclusions in Chagas disease when using PAINESD score.

Correlation of [18F] FDG-PET/CT with dosimetry data: recurrence pattern after radiotherapy for head and neck carcinoma.

OBJECTIVE: To analyze the pattern of failure in relation to pre-treatment [18F] FDG-PET/CT uptake in head and neck squamous cell carcinoma (HNSCC) patients treated with definitive radio-chemotherapy (RT-CHT). METHODS AND MATERIALS: From 2012 to 2016, 87 HNSCC patients treated with definitive RT-CHT, with intensity modulated radiation therapy with simultaneous integrated boost, underwent pre-treatment [18F] FDG-PET/CT (PETpre), and MRI/CT for radiotherapy (RT) planning purposes. Patients with local recurrence, received [18F] FDG-PET/CT, (PETrec) at the time of the discovery of recurrence. In these patients, the metabolic target volume (MTV), MTVpre and MTVrec were segmented on PET images by means of an adaptive thresholding algorithm. The overlapping volume between MTVpre and MTVrec (MTVpre&rec) was generated and the dose coverage of MTVrec and MTVpre&rec was checked on the planning CT using the D99 and D95 dose metrics. The recurrent volume was defined as: ''In-Field (IF)'', "Marginal recurrence" or ''Out-of-Field (OF)'' if D95 was respectively equal or higher than 95%, D95 was between 95 and 20% or the D95 was less than 20% of prescribed dose. RESULTS: We found 10/87 patients (11.5%) who had recurrence at primary site. Mean MTVpre was 12.2 cc (4.6-28.9 cc), while the mean MTVrec was 4.3 cc (1.1-12.7 cc). Two recurrences resulted 100% inside MTVpre, 4 recurrences were mostly inside (61-91%) and 4 recurrences were marginal to MTVpre (1-33%). At dosimetric analysis, five recurrences (50%) were IF, 4 (40%) marginal and one (10%) OF. The mean D99 of the overlapping volumes MTVpre&rec was 68.1 Gy (66.5-69.2 Gy), considering a prescription dose of 70 Gy to the planning target volume (PTV). CONCLUSION: Our study shows that the recurrence may originate from the volume with the highest FDG-signal. Tumor relapse in the high-dose volume support the hypothesis that an intensification of the dose on these volumes could be further assessed to prevent local relapse.

Common European Mitochondrial Haplogroups in the Risk for Radiation-induced Subcutaneous Fibrosis in Breast Cancer Patients.

AIMS: The contribution of mitochondrial DNA (mtDNA) variations to clinical radiosensitivity is largely unknown. In the present study, we evaluated the association between mtDNA haplogroups and the risk of radiation-induced subcutaneous fibrosis after postoperative radiotherapy in breast cancer patients. MATERIALS AND METHODS: Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA) scale in 286 Italian breast cancer patients who received radiotherapy after breast-conserving surgery. Eight mtDNA single nucleotide polymorphisms that define the nine major haplogroups in the European population were determined by polymerase chain reaction restriction fragment length polymorphism analysis on genomic DNA extracted from peripheral blood. RESULTS: In a Kaplan-Meier analysis evaluated by the Log-rank test, carriers of haplogroup H were found to be at lower risk of grade ≥2 subcutaneous fibrosis (P = 0.018) compared with all other haplotypes combined. In the multivariate Cox regression analysis adjusted for clinical factors (body mass index, breast diameter, adjuvant treatment, dose per fraction, radiation type and acute skin toxicity), haplogroup H emerged as a protective factor for moderate to severe radiation-induced fibrosis at a nominal significance level (hazard ratio: 0.50, 95% confidence interval 0.27-0.92, P = 0.027), which did not survive correction for multiple testing. CONCLUSIONS: Our results suggest a protective effect of the mitochondrial haplogroup H in the development of radiation-induced fibrosis in breast cancer patients. However, the loss of statistical significance after correction for multiple comparisons and the lack of an independent validation cohort make our findings preliminary, requiring further confirmation in large-scale prospective studies.

Quality of life in patients treated by adjuvant radiotherapy for endometrial and cervical cancers: correlation with dose-volume parameters.

INTRODUCTION: Modern multidisciplinary cancer treatments aim at obtaining minimal influence on patients' quality of life (QoL). The purpose of this study was to assess QoL and correlate it with dose-volume parameters of organ at risks (OARs) in patients who received adjuvant radiotherapy for endometrial and cervical cancers. MATERIALS AND METHODS: We administered the EORTC QLQ-C30 and EN24 or CX24 questionnaires to 124 patients, 100 with endometrial cancer and 24 with cervical cancer treated with postoperative radiotherapy ± chemotherapy in regular follow-up. Bladder function, fecal incontinence or urgency and sexual functioning were investigated and correlated with dose-volume parameters of OAR by multiple linear regression analysis. This correlation was assessed by R (2) value. RESULTS: QoL was very high in the majority of patients (82.3 % of patients). Few patients referred urinary incontinence (3.2 %) or abdominal discomfort of high grade (4.0 %). We found a significant correlation between bladder V40, i.e., absolute percentage of bladder volume that received a dose of 40 Gy, and global health status (p < 0.05, R (2) = 0.17), urinary urgency (p < 0.05, R (2) = 0.24), urinary incontinence (p < 0.05, R (2) = 0.23) and dyspareunia (p < 0.05, R (2) = 0.04). We found also a correlation between global health status and mean dose to vagina (p < 0.05, R (2) = 0.17) and between maximum dose to lumbo-sacral plexus and abdominal pain (p < 0.05, R (2) = 0.07). CONCLUSIONS: Women treated with surgery and adjuvant radiotherapy for endometrial and cervical cancers have good QoL with minimal limitations of daily activities. QoL was correlated with dose-volume parameters such as bladder V40, mean dose to vagina, maximum dose to trigone and LSP.

Orthognathic surgery with or without autologous fat micrograft injection: preliminary report on aesthetic outcomes and patient satisfaction.

Orthognathic surgery leaves the intrinsic volume of the facial soft tissues untouched, sometimes resulting in unsatisfactory improvements in aesthetics. The aim of this study was to evaluate the aesthetic outcomes and patient satisfaction following bimaxillary orthognathic surgery with or without simultaneous facial lipofilling procedures. The preoperative and postoperative facial appearances of 210 patients were compared through analysis of photographs and postoperative clinical evaluation. A patient questionnaire was used to assess the perceived improvement in aesthetics. One hundred and twenty patients (mean age 20.3 years) underwent bimaxillary orthognathic surgery and simultaneous facial lipofilling procedures (group I). The remaining 90 patients (mean age 19.8 years) underwent skeletal procedures only (group II). The overall aesthetic improvement was similar in the two groups (group I 92.5%, group II 91.1%). Greater higher-level aesthetic improvement scores were recorded for group I (group I 80%, group II 55.6%). The overall patient satisfaction was 98.3% for group I and 97.8% for group II. Greater higher-level satisfaction scores were recorded for group I (group I 14.2%, group II 6.7%). The simultaneous use of the autologous fat micrograft is a promising technique that may improve the aesthetic outcomes of orthognathic surgery, leading to greater patient satisfaction.

Clinical and technical characteristics of intraoperative radiotherapy. Analysis of the ISIORT-Europe database.

BACKGROUND: A joint analysis of clinical data from centres within the European section of the International Society of Intraoperative Radiation Therapy (ISIORT-Europe) was undertaken in order to define the range of intraoperative radiotherapy (IORT) techniques and indications encompassed by its member institutions. MATERIALS AND METHODS: In 2007, the ISIORT-Europe centres were invited to record demographic, clinical and technical data relating to their IORT procedures in a joint online database. Retrospective data entry was possible. RESULTS: The survey encompassed 21 centres and data from 3754 IORT procedures performed between 1992 and 2011. The average annual number of patients treated per institution was 42, with three centres treating more than 100 patients per year. The most frequent tumour was breast cancer with 2395 cases (63.8 %), followed by rectal cancer (598 cases, 15.9 %), sarcoma (221 cases, 5.9 %), prostate cancer (108 cases, 2.9 %) and pancreatic cancer (80 cases, 2.1 %). Clinical details and IORT technical data from these five tumour types are reported. CONCLUSION: This is the first report on a large cohort of patients treated with IORT in Europe. It gives a picture of patient selection methods and treatment modalities, with emphasis on the main tumour types that are typically treated by this technique and may benefit from it.

Basal cell carcinoma of the vulva.

Basal cell carcinoma (BCC), the most common human malignancy, accounting for 75% of all non-melanoma skin cancer, is uncommon on unexposed skin such as the perianal and genital regions. We describe a woman with BCC of the vulva treated with local resection. All margins of excision were free of disease. The patient recovered without complication and there have been no recurrences after 2 years of follow-up. Approximately 200 cases of BCC on perianal and genital skin have been reported in the literature. Although the aetiology of vulvar BCC is not known, early diagnosis is important. Because BCC in these sites sometimes seems innocuous, biopsy of all suspect lesions is advisable.

Malignant hypercalcemia in vulvar cancer.

Humoral hypercalcemia of malignancy (HHM) is a common paraneoplastic syndrome, most often associated with squamous cell carcinoma of the lung, esophagus, kidneys and breast, but rarely with vulval cancer. In most patients, HHM is associated with over-production of a peptide analogue of parathormone (parathyroid hormone-related protein, PTHrP). The case of a 70-year-old patient with massive squamous cell epithelioma of the vulva complicated by HHM is reported. To our knowledge, this is the first documented case with high serum concentrations of PTHrP and immunohistochemical confirmation of PTHrP production by neoplastic cells.

Experimental and theoretical study of a surface stabilized monolayer phase of nickel oxide on Pd(100).

A surface stabilized monolayer phase of nickel oxide, c(4 x 2)-Ni(3)O(4), has been found to grow epitaxially under reactive deposition conditions on Pd(100), in the presence of other adsorbed phases and in competition with them. High-quality scanning tunneling microscopy data are reported and discussed, including a detailed analysis of the defects and of the border morphology of this new phase. The data are discussed in the light of ab initio simulations of the electronic, energetic, and geometric properties of such a phase. A hybrid-exchange density functional theory approach has been used, and a slab model is adopted where palladium is simulated by a thin film covered on both sides by regular epilayers. A growth model has been developed that explains both the unusual stoichiometry of the phase and the observed defects.

Protective effect of n-acetylcysteine in a model of influenza infection in mice.

Reactive oxygen intermediates (ROI) and cytokines, particularly tumor necrosis factor (TNF) have been implicated in the pathogenesis of influenza. Using a murine model of influenza, we have studied the levels of TNF, interleukin 6 (IL-6) and of superoxide-generating xanthine oxidase (XO). Mice infected intranasally with influenza virus APR/8 had high levels of XO, TNF and IL-6 in the broncoalveolar lavage, as early as 3 d after infection. XO was elevated also in serum and lung tissue. Administration of the antioxidant N-acetylcysteine (NAC,1 g/kg per day, orally) significantly decreased the mortality in infected mice, indicating a role for RO1 in the lethality associated with influenza infection.

Phase III randomized double-blind study to evaluate the efficacy of a polycarbophil-based vaginal moisturizer in women with breast cancer.

PURPOSE: Vaginal dryness and dyspareunia are significant estrogen-depletion symptoms that affect many breast cancer survivors. The present trial was developed to evaluate the nonhormonal vaginal lubricating preparation, Replens, for alleviating these symptoms. MATERIALS AND METHODS: A double-blind, crossover, randomized clinical trial was developed. Patients received 4 weeks of Replens (Columbia Research Laboratories, Rockville Centre, NY) followed by a 1-week washout period followed by 4 weeks of a placebo lubricating product, or vice versa. Weekly patient-completed diaries were used for measuring efficacies and toxicities of therapy. RESULTS: The 45 assessable patients provided well-balanced treatment groups. During the first 4 weeks, average vaginal dryness decreased by 62% and 64% in the placebo and Replens groups, respectively (P = .3). Average dyspareunia scores also improved by 41% and 60%, respectively (P = .05). Crossover analysis indicated that the bulk of the beneficial effects appeared within the first 2 weeks of the first treatment and remained constant thereafter. Both treatments were relatively well tolerated. CONCLUSION: Both Replens and the placebo appear to substantially ameliorate vaginal dryness and dyspareunia in breast cancer survivors.

Phase I trial of combined recombinant interleukin-2 with levamisole in patients with advanced malignant disease.

A Phase I study of rIL-2 and levamisole was performed to evaluate the activity, toxicity, and effect on immune parameters of this combination of agents in patients with advanced malignancy. Twelve patients with advanced cancer were included and begun on therapy with rIL-2, 1 x 10(6) U/m2 subcutaneously (SQ) daily for 5 days and levamisole beginning at 25 mg/m2 orally three times daily for 5 days. The dose of levamisole was increased to 50 mg/m2 thrice daily during this study. Immune parameter analysis included the percentages of lymphocyte subsets in peripheral blood, cellular cytotoxicity assays versus K562 and Daudi cells, and lymphocyte blastogenesis to the recall antigens tetanus toxoid and Candida albicans. The dose-limiting toxicities were pruritus, nausea, and facial edema. There were no indications of significant hematologic or hepatorenal toxicities. No patient fulfilled the traditional criteria for an objective response. In 8 of 9 patients with immune parameter data available there was an increase in cellular cytotoxicity and in the percentage of lymphocytes with the natural killer phenotype (CD3-, CD16/56+). This regimen can be given as an outpatient with acceptable toxicity. For Phase II investigations the doses of rIL-2, 1 x 10(6) U/m2 SQ daily x 5 days and levamisole, 50 mg/m2 three times daily x 5 days is recommended.

A phase II study of recombinant human alpha-interferon in advanced hormone-refractory prostate cancer.

To determine the efficacy of recombinant human leukocyte alpha-interferon (IFL-RA) in advanced hormone-refractory prostate cancer, the authors treated 40 patients with IFL-RA administered intramuscularly at a dose of 10 x 10(6) U/m2 three times weekly. Toxicity was substantial and necessitated at least a 50% dose reduction in all but five patients during the first 1-2 months of therapy. No responses were observed in patients with bone metastases, but complete and partial regression of nodal disease were observed in two patients with extraosseous disease (overall response rate, 5%; 95% confidence interval, 0.64-17.75%). The authors conclude that IFL-RA cannot be recommended at this dose and schedule in patients with advanced prostate cancer, but additional study of its use in patients with nodal disease may be warranted.

Does histologic grade in soft tissue sarcoma influence response rate to systemic chemotherapy?

To assess whether chemosensitivity in metastatic soft tissue sarcoma (STS) is influenced by the histologic grade of the tumor, the authors retrospectively analyzed tumor responses to doxorubicin-based chemotherapy in four prospective studies conducted at the Mayo Clinic, Rochester, Minnesota, between 1976 and 1984. A total of 131 patients with metastatic STS were included in these trials. All pathologic material was reviewed by one pathologist (H.M.R.) and graded according to the four-tier grading system of Broders. One hundred and sixteen patients were accepted for analysis. Objective regression rates according to grade were as follows: Grade 4, 55% (22 of 40 patients); Grade 3, 23% (7 of 31 patients); Grade 2, 19% (5 of 27 patients); and Grade 1, 0% (0 of 3 patients). Fifteen nongradable sarcomas were analyzed separately (27% [4 of 15]). In contrast to several reports suggesting that grade does not effect response, the authors found differences in response rates to be statistically significant for Grade 2 versus Grade 4 (P = 0.003) and Grade 3 versus Grade 4 (P = 0.006), but not for Grade 2 versus Grade 3 (P = 0.7). Additional comparisons adjusted for the histologic type of STS, chemotherapeutic regimen, performance status, age, and prior treatment confirmed these results. These results suggested that, in addition to being an important prognostic factor for survival in newly diagnosed STS, histologic grade may correlate with the probability of response and should be considered a stratification factor in future studies.

Administration of interleukin-2 (IL-2) results in increased plasma concentrations of IL-5 and eosinophilia in patients with cancer.

Peripheral eosinophilia is almost invariably observed during the course of interleukin-2 (IL-2) therapy and is frequently accompanied by the development of a capillary leak syndrome characterized by edema, weight gain, and oliguria. We studied five patients with advanced malignancy treated with IL-2. Eosinophilia was not present initially but developed in all patients late in the course of therapy, with counts ranging from 2,328/mm3 to 15,958/mm3. In all patients, there was a temporal relationship between the infusion of IL-2 and the appearance of elevated plasma concentrations of IL-5, a growth factor for eosinophils. Granulocyte-macrophage colony-stimulating factor was not detectable in plasma. IL-4 and gamma-interferon plasma levels were variably elevated. Plasma concentrations of major basic protein, a toxic eosinophil granule protein, began increasing before eosinophil counts increased. By the time of the third IL-2 infusion, high concentrations of major basic protein were present in all five patients (up to 5,600 ng/mL) and skin biopsies showed major basic protein deposition in the dermis. Four patients developed significant capillary leak syndrome and all of these patients showed markedly elevated major basic protein levels. The lowest peak plasma concentration of major basic protein (1,751 ng/mL) was observed in the one patient who did not develop edema and weight gain. These results suggest that IL-2 induces IL-5 leading to marked peripheral eosinophilia and extravascular eosinophil degranulation. The release of toxic eosinophil products at extravascular sites and in the circulation may contribute to the pathogenesis of the capillary leak syndrome complicating IL-2 therapy.

Phase I and clinical pharmacological evaluation of pirozantrone hydrochloride (oxantrazole).

Pirozantrone hydrochloride, an anthrapyrazole analogue, was selected for clinical evaluation based on broad antitumor activity against murine tumor systems and on potentially less cardiotoxicity when compared to anthracyclines. This anthrapyrazole analogue is currently under clinical evaluation, and we now report results on a Phase I clinical trial incorporating a pharmacologically guided dose-escalation scheme. Dose escalation was designed to proceed by factors of 2 until the patient drug exposure (concentration x time) was 40% of the murine exposure at the LD10 dose (90 mg/m2). Thereafter, more moderate dose escalations were employed. The target concentration x time value (59 micrograms-min/ml) derived from preclinical pharmacology data was exceeded in all three patients at a dose of 90 mg/m2. A dose of 160 mg/m2 was found to reproducibly result in appropriate myelosuppression. This dose is recommended for further testing in Phase II studies. Nonhematological toxicities encountered in this trial were mild, the most notable being phlebitis at the infusion site. Objective responses were observed in two patients, one with metastatic breast cancer and another with metastatic melanoma. Following a 60-min infusion, pirozantrone hydrochloride plasma elimination was monoexponential, with a half-life of approximately 30 min, mean total body clearance of 1.29 liters/min/m2, and mean steady state volume of distribution of 29 liters/m2.

Cancer immunotherapy: current status of treatment with interleukin 2 and lymphokine-activated killer cells.

In recent years, the medical community has witnessed a growing interest in the use of adoptive immunotherapy in patients with malignant lesions refractory to standard treatments. Systemic administration of interleukin 2, in combination with the adoptive transfer of a patient's own activated immune cells, has resulted in objective regression of several types of advanced cancers. Pronounced regression of tumor has also been observed with use of systemic interleukin 2 alone. This ability to augment the immune defense system of the host against cancer has stimulated intense clinical and laboratory investigations.