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The adsorption of the anionic dyes orange IV, orange G and xylenol orange on chitin was studied, employing the Langmuir isotherm. The adsorption parameters were determined utilizing various linear regressions of the isotherm. The results showed that the adsorption capacity is dependent on pH. In acid pH, the polymer amino groups are protonated and the polymer chain is positively charged, with a predominance of adsorption through ion exchange. Van der Waals adsorption, as well as adsorption through hydrogen bonding, is also likely to occur to some extent. For xylenol orange, a linear regression was found, with an angular coefficient of 0.726 L mg-1. The temperature increase reduces adsorption capacity by chitin, due to the enhancement of the desorption step in the mechanism. deltaH values of -10.9 kJ mol-1 for orange G and -28.9 kJ mol-1 for orange IV prove the physical nature of the adsorption by these dyes on the chitin surface.

Background: Whether, and to what extent, frailty and other geriatric domains are linked to health status in patients with transthyretin cardiac amyloidosis (ATTR-CA) is unknown., Aims: To determine the association of frailty with health status [defined by the Kansas City Cardiomyopathy Questionnaire (KCCQ)] in patients with ATTR-CA., Methods: Consecutive ATTR-CA patients undergoing cardiovascular assessment at a tertiary care clinic from September 2021 to September 2023 were invited to participate. KCCQ, frailty and social environment were recorded. Frailty was assessed using the modified Frailty Index (mFI), mapping 11 variables from the Canadian Study of Health and Aging (frailty ≥0.36)., Results: Of 168 screened ATTR-CA patients, 138 [83% men, median age of 79 (75-84) years] were enrolled in the study. Median KCCQ was 66 (50-75). wtATTR-CA was the most prevalent form (N = 113, 81.9%). The most frequent cardiac variant was Ile68Leu (17/25 individuals with vATTR-CA). Twenty (14.5%) patients were considered frail, and prevalence of overt disability was 6.5%. At multivariable linear regression analysis, factors associated with worsening KCCQ were age at evaluation, the mFI, NYHA Class, and NAC Score. Gender, ATTR-CA type, phenotype, and LVEF were not associated with health status., Discussion: In older patients diagnosed with ATTR-CA, frailty, symptoms, and disease severity were associated with KCCQ., Conclusions: Functional status is a determinant of quality of life and health status in older individuals with a main diagnosis of ATTR-CA. Future research may provide more in-depth knowledge on the association of frailty in patients with ATTR-CA with respect to quality of life and prognosis., (© 2024. The Author(s).)

N6-methyladenosine (m6A) is the most abundant internal eukaryotic mRNA modification, and is involved in the regulation of various biological processes. Direct Nanopore sequencing of native RNA (dRNA-seq) emerged as a leading approach for its identification. Several software were published for m6A detection and there is a strong need for independent studies benchmarking their performance on data from different species, and against various reference datasets. Moreover, a computational workflow is needed to streamline the execution of tools whose installation and execution remains complicated. We developed NanOlympicsMod, a Nextflow pipeline exploiting containerized technology for comparing 14 tools for m6A detection on dRNA-seq data. NanOlympicsMod was tested on dRNA-seq data generated from in vitro (un)modified synthetic oligos. The m6A hits returned by each tool were compared to the m6A position known by design of the oligos. In addition, NanOlympicsMod was used on dRNA-seq datasets from wild-type and m6A-depleted yeast, mouse and human, and each tool's hits were compared to reference m6A sets generated by leading orthogonal methods. The performance of the tools markedly differed across datasets, and methods adopting different approaches showed different preferences in terms of precision and recall. Changing the stringency cut-offs allowed for tuning the precision-recall trade-off towards user preferences. Finally, we determined that precision and recall of tools are markedly influenced by sequencing depth, and that additional sequencing would likely reveal additional m6A sites. Thanks to the possibility of including novel tools, NanOlympicsMod will streamline the benchmarking of m6A detection tools on dRNA-seq data, improving future RNA modification characterization., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Women with a cancer history report high distress during pregnancy and infant feeding. Despite the clear advantages of breastfeeding, little is known about factors influencing infant feeding behavior in women with cancer history., Research Aim: This three-time point longitudinal study aimed to explore the centrality of pregnancy and infant feeding experiences in 17 pregnant women with a cancer history (cases) compared to 17 pregnant women without cancer history (controls)., Methods: During pregnancy, participants filled out the Centrality of Events Scale and an ad hoc questionnaire about specific emotions, concerns, and expectations about infant feeding (T1), and their childbirth and infant feeding experiences during hospitalization (T2), and at 3-months postpartum (T3)., Results: Results at T1 demonstrated that participants with a history of cancer reported a higher perception of negative judgment and moral choice about breastfeeding than participants without a history of cancer. At T2 they reported a more positive childbirth experience than controls. From T2 to T3 participants with a history of cancer breastfed at a higher percentage than controls, and at T3 they reported higher levels of emotional and physical pleasure about the infant feeding experiences., Conclusions: Women with cancer history may experience a higher emotional and physical pleasure with infant feeding. Despite initial difficulties, a greater prevalence of breastfeeding was present for women with a history of cancer. Although this is a small sample, this research suggests that support and promotion of breastfeeding might be very effective after a serious medical diagnosis.

In medical statistics, when the effect of a binary risk factor on a binary response is of interest, relative risk is often the preferred measure due to its direct interpretation. However, statistical inference on this quantity is not as straightforward as for other measures of association, especially when further explanatory variables have to be taken into account. Starting from a review of available methods for inference on relative risk, this paper deals with small and moderate sample size settings for which we show that classical approaches can be problematic. For this reason, we propose the use of improved estimation procedures, aiming at mean or median bias reduction of the maximum likelihood estimator. In particular, these methods are developed for a new alternative specification of a model recently proposed by Richardson et al, where higher computational stability of the estimation methods is achieved. A real-data example and extensive simulation studies show that the proposed methods perform remarkably better than the standard ones.

Aim of the study was to explore frailty and quality of the relationship with the caregiver in a cohort of older patients with transthyretin cardiac amyloidosis (ATTR-CA). Sixty-eight consecutive ATTR-CA patients were recruited and assessed for frailty, depressive symptoms, quality of the relationship in terms of social support, or conflict toward caregivers, New York Heart Association Class (NYHA), and National Amyloid Center score (NAC Score) for grading disease severity. Results showed that 10% of patients were frail. Depressive symptoms were present in 46% of patients. Regression analyses showed that both mFI and depression were associated with worse perception of social support, and that mFI and NAC score were associated with higher levels of conflict perceived in the caregivers' relationship. Overall, the mFI score was associated with worse perceived social support and caregiver relationship quality. Tertiary care heart failure clinics should actively support the patient-caregiver relationship to improve quality of life., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The subjective perception of cardiac symptom severity is considered a main treatment target in the management of transthyretin-related cardiac amyloidosis (CA), as opposed to objective prognostic markers such as N-terminal pro b-type natriuretic peptide (NT-proBNP), which objectively reflects the severity of heart disease. Nevertheless, anxious and depressive symptoms in patients with CA might affect subjects perceptions of disease, creating a potential gap between objective and subjective parameters. We assess the impact of such bias in consecutive patients with CA. A total of 60 patients aged 62 to 88 years with CA were recruited. The level of anxiety and depression was measured by the Hospital Anxiety and Depression Scale and the subjective perception of symptoms severity by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Finally, NT-proBNP plasma levels at rest and glomerular filtration rate were measured. Nearly 1/2 of the patients (48%) reported clinically relevant levels of psychologic symptoms. Higher levels of anxious and depressive symptoms were significantly linked to lower KCCQ scores. Furthermore, the relation between NT-proBNP and KCCQ was significant only when anxious and depressive symptoms were low (β = -0.86, p = 0.002; β = -0.86, p = 0.002, respectively) and medium (β = -0.49, p = 0.004; β = -0.45, p = 0.004, respectively) but was otherwise lost. Depression and anxiety in patients with transthyretin-related CA required assessment and management. In conclusion, patients with depression/anxiety have a clear disconnect between their personal assessment and objective measures of cardiac symptoms, with a major influence on the patients' wellbeing and on their subjective response to treatments in clinical trials., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Dry granulation through roll compaction followed by milling is a widely used pharmaceutical process. The material properties of powders and the roll compaction process conditions affect the strength of ribbons, and subsequently the granule size distribution (GSD). Accurate prediction of the granule size distribution from milling of ribbons with different properties is essential for ensuring tablet quality in the final compaction stage. In this study, MCC, PH-102 ribbons with precisely controlled porosities were produced and milled in a cutting mill and granule size distribution was analysed using QicPic. A population balance model with a new breakage function based on the Weibull function was developed to model the ribbon milling process. Eight model parameters were initially obtained for each ribbon porosity and very good agreement between the model and experimental results was obtained. Sensitivity analysis was then performed and thus reduced the number of model parameters that changed with ribbon porosity to two in the breakage function. The refined model was able to predict the granule size distribution both within and outside the experimental boundaries. It was shown that the model developed in this study has a great potential for predicting granule properties and therefore the optimisation of the dry granulation process., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Since 2010 Veneto region (North-Eastern Italy) planned a special integrated surveillance of summer fevers to promptly identify cases of West Nile Fever (WNF), dengue (DENV) and chikungunya (CHIKV). The objectives of this study were (i) To increase the detection rate of imported CHIKV and DENV cases in travellers from endemic areas and promptly identify potential autochthonous cases.(ii) To detect autochthonous cases of WNF, besides those of West Nile Neuroinvasive Disease (WNND) that were already included in a national surveillance., Methods: Human surveillance: a traveler who had returned within the previous 15 days from endemic countries, with fever >38°C, absence of leucocytosis (leukocyte count <10,000 μL), and absence of other obvious causes of fever, after ruling out malaria, was considered a possible case of CHIKV or DENV. A possible autochthonous case of WNF was defined as a patient with fever >38°C for <7 days, no recent travel history and absence of other obvious causes of fever. Entomologic surveillance: for West Nile (WNV) it was carried out from May through November placing CDC-CO2 traps in five provinces of Veneto Region, while for DENV and CHIKV it was also performed around residences of viremic cases., Results: Human surveillance: between 2010 and 2012, 234 patients with fever after travelling were screened, of which 27 (11,5%) were found infected (24 with DENV and 3 with CHIKV). No autochthonous case of DENV or CHIKV was detected. Autochthonous patients screened for WNF were 408, and 24 (5,9%) were confirmed cases. Entomologic surveillance: the WNV was found in 10, 2 and 11 pools of Culex pipiens from 2010 to 2012 respectively, in sites of Rovigo, Verona, Venezia and Treviso provinces). No infected Aedes albopictus with DENV or CHIKV was found., Conclusions: Veneto is the only Italian region reporting WNV human cases every year since 2008. WNV is likely to cause sporadic cases and unforeseeable outbreaks for decades. Including WNF in surveillance provides additional information and possibly an early alert system. Timely detection of DENV and CHIKV should prompt vector control measures to prevent local outbreaks.

The goal of this study was to describe and comment the experience of the Veneto Region in the bacterial invasive disease. Vaccination coverage was 93% against pneumococcus and 95% against haemophilus influenzae type B. Regard to meningococcus C the coverage rate was 90.1% In children, 81% at 6 years of age and 78.2% at 15 years. The preliminary data of an active surveillance of invasive bacterial diseases show that the Streptoccoccus pneumoniae was the main agent involved and that its consequences were particularly serious in elderly subjects. With regard to Neisseria meningitidis, we observed a substantial reduction in the number of cases due to serogroup C and a concomitant rise in the percentage of cases due to serogroup B. The suspension of mandatory vaccination should be maintained, the monitoring of vaccination coverage and the active surveillance proved to be a very good assessment tools.

An immunization strategy can take advantage of various tools, among which the pediatrician and family practitioner These figures, have been assigned the role of accompanying the child and his/her family throughout development. One of the objectives of this role is also to take a major part in the support of immunization coverage of infants, especially in light of the sospension of required immunizations in the Veneto Region. For this reason it is necessary to open dialogue on immunizations together with pediatricians and family physicians. In addition, training of these professional figures, together with healtcare operators who work in the immunization clinics, has allowed the formation and standardization of the network, as the persons who attend the immunization clinics are no longer passive users but persons who require information exchange in order to make an informed choice about immunizations for their children. Surveillance of vaccination coverage is a useful tool for evaluating the trend in vaccination refusals, and in particular it takes into consideration the motivation behind the refusal to adhere to the polio vaccine recommendations even if for now the coverage is maintained above 95%. Concluding, another strong point for the immunization program is "Genitori Più" which finds its continuity with the Regional Prevention Plan.

In 2005, universal varicella vaccination was introduced in the Veneto region, Italy. We examined trends in varicella incidence and hospitalization rates before and after vaccine introduction, and applied statistical models to assess vaccine effectiveness. Varicella incidence rates for 2000-2008 were calculated from the mandatory regional surveillance data and from a special surveillance system based on reports from a sample of family pediatricians that during the study period followed more than 40,000 children. To evaluate hospital admission rates, we analyzed the regional hospital discharge registry. The vaccine coverage rate was 6.8% in the 2004 birth-cohort and 78.6% in the 2008 cohort. Varicella incidence in 0-14 year-olds was 6136.8/100,000 person-years in 2000 and 4004.8 in 2008; hospitalization rates were 18.7 and 8.4. Incidence rates significantly decreased 2.5 years after beginning the universal vaccination, while hospitalization rates showed a significant decrease one year earlier. There was a remarkable decline of both varicella incidence and hospitalizations especially in 1-4 year-old children. This study confirms the positive impact of universal vaccination., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The protein kinase Akt/protein kinase B (PKB) is implicated in insulin signaling in mammals and functions in a pathway that regulates longevity and stress resistance in Caenorhabditis elegans. We screened for long-lived mutants in nondividing yeast Saccharomyces cerevisiae and identified mutations in adenylate cyclase and SCH9, which is homologous to Akt/PKB, that increase resistance to oxidants and extend life-span by up to threefold. Stress-resistance transcription factors Msn2/Msn4 and protein kinase Rim15 were required for this life-span extension. These results indicate that longevity is associated with increased investment in maintenance and show that highly conserved genes play similar roles in life-span regulation in S. cerevisiae and higher eukaryotes.

Epidermal growth factor receptor (EGFR) is a potentially useful new biological prognostic and predictive indicator in human breast cancer. Additional research on EGFR is warranted to enhance our information on: i) the method of choice for its detection and quality control issues; ii) its association with novel pathobiological markers of prognosis; iii) its prognostic value in multivariate analysis; and iv) its capability to predict response to hormone therapy and, in the future, to biological treatments using antibodies against the specific receptor or its ligands. In the present study we update previous data on EGFR status, determined immunocytochemically, by prolonging the period of observation up to 5 years and by including, in the multivariate analysis, several new biological indicators. The main results obtained are: i) EGFR is weakly associated with Ki-67 score (p = 0.073) and with p53 expression (p = 0.06); ii) EGFR is a significant indicator for recurrence (p < 0.01 and odds ratio of 2.82) but not for death (p = 0.27 and odds ratio of 1.49); iii) the prognostic power of EGFR is enhanced when combined with the knowledge of S-phase fraction; and iv) in multivariate analysis on relapse-free survival, EGFR and S-phase fraction (likelihood ratio test = 26.40; p < 0.01), c-erB-2 protein and p53 mutant protein expression (likelihood ratio test = 5.94; p = 0.05), cathepsin D (likelihood ratio test = 9.78; p < 0.01), and nodal status (likelihood ratio test = 7.32: p < 0.01) are significant and independent prognostic factors in early-stage breast carcinoma. This new information could be of help for a more rational approach in the use of EGFR as a marker in future clinical research.

One hundred eighty patients affected by cerebral arteriovenous malformations (AVMs) underwent radiosurgical treatment in our department. One hundred fifty-three patients have been treated with complete irradiation of the entire AVM nidus. In 27 patients (with large and/or three-dimensional irregular target volumes), only part of the nidus was covered with a dose adequate for obliteration. Follow-up ranged from 88 to 1 months (mean, 43.1 mo). Angiographic control was performed at 12, 24, and 36 months until complete obliteration was attained. The complete obliteration rate was 46% at 1 year and 80% at 2 years. We observed 15 hemorrhages after treatment, and five patients died from them. No bleeding took place after complete angiographic obliteration. The aim of this study is to evaluate the effect of irradiation on bleeding risk after radiosurgery and before complete obliteration. Inclusive parameters of patients considered at risk were as follows: 1) all patients in the time lapse between irradiation and demonstrated complete angiographic obliteration; 2) all patients in the time lapse between irradiation and definitive treatment either by surgery or embolization; and 3) all patients in the time lapse between irradiation and death. These groups include all irradiated patients who still had incompletely obliterated AVMs. They were stratified starting from 0 time (the date of radiosurgery), and the hemorrhages were evaluated every 6 months. In totally irradiated cases, the bleeding risk decreased from 4.8% in the first 6 months after radiosurgery to 0% starting from the 12th month of the follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Squamous-cell carcinoma of the head and neck includes a heterogeneous group of tumours of the upper air and food passages for which prognosis is difficult to assess. In fact, patients in comparable stages may have diverse clinical courses and responses to similar treatments. In order to better define the prognosis of each patient there is therefore a need to identify novel biological markers which reflect more accurately growth rate, progression and metastatic potential of each tumour. We assessed whether metastases correlate with microvessel counts (i.e. intratumoral vascularity) using the CD-31 monoclonal antibody (MAb) and p53 mutant protein expression, determined in the primary by immunocytochemical methods in 70 patients with locally advanced head and neck cancer. Patients were treated with concurrent chemo-radiotherapy; 50 of these presented loco-regional node metastasis at diagnosis whereas 3 cases, initially node-negative, developed distant metastasis during the period of observation. No feature was predictive for objective response to treatment. The overall mean and median blood vessel density at "hot spots" was 37.42 and 36, respectively, and 57% of the tumours expressed p53 mutant proteins. These 2 biological markers were significantly associated. Patients with metastases (loco-regional and distant) had a significantly higher mean blood-vessel density than those without tumour spread. Also, patients with p53-positive (+/++) tumours had a significantly higher incidence of metastasis than those with negative ones. Multivariate analysis showed that both vascularity and stage, but not p53 expression, are significant and independent predictors of metastasis in this series.

The incidence of breast cancer is increasing in all Western countries. Due both to a more widespread public education and to early diagnosis by mammography screening programs, the percentage of patients with node-negative breast cancer has gone up to 70%. Thus, node-negative breast cancer is a major public health problem and, consequently, clinical research in this setting is an expanding field. A recent overview analysis confirmed the results of five prospective randomized clinical trials suggesting that systemic adjuvant therapy can benefit node-negative breast cancer patients. Because of the heterogeneity of node-negative breast cancer, it is reasonable to attempt to avoid excessive treatment morbidity and costs by using selective prognostic markers to identify patients at high risk for disease recurrence who are eligible for postsurgical systemic adjuvant therapy. It is also desirable to use predictive markers in selecting the therapy to which each patient is more likely to respond. The need for additional prognostic and predictive factors has led to identification of a plethora of potentially useful markers. As a result, the selection of patients at different risks of developing node-negative breast cancer and the choice for appropriate therapy remain difficult and confusing for the clinician. Moreover, the majority of studies have examined new markers individually rather than by multivariate analysis and retrospectively rather than prospectively. Thus, there are also important methodologic biases in such studies. This analysis consists of (a) defining the clinical "problem," (b) defining the terms of prognostic and predictive factors, (c) suggesting more appropriate laboratory and clinical approaches to properly evaluate a new indicator, (d) identifying the subsets of patients in whom the use of new prognosticators is warranted and of particular importance, and (e) providing some direction for future research on this topic. Our ultimate goals are to facilitate the understanding of node-negative breast cancer prognostic markers among clinicians, to help them select the most appropriate indicator for specific situations, and to recommend methodology for future research.

Primary soft tissue sarcoma of the retroperitoneum is a rare disease. A series of 11 evaluable adult patients with retroperitoneal soft tissue sarcomas is reported. These patients were treated with complete surgery and adjuvant radiation therapy (total dose from 50 to 64 Gy) using an 18 MeV linear accelerator. After a median follow-up of 48 months (range, 6-84), 4 patients had a local-regional recurrence, 3 had distant metastases, and 4 died of progressive disease. Four-year estimated disease-free survival was 54.5% and overall survival was 70%. Treatment was well tolerated by most patients: 7 patients experienced moderate gastrointestinal toxicity, mainly nausea and diarrhea, during radiotherapy; 2 cases had weight loss > 15% at the end of the therapy; and chronic ileitis was observed in 2 cases. We conclude that adjuvant radiotherapy seems to reduce the incidence of local-regional recurrences in these patients. No radiation-induced irreversible injury was observed, but one young woman had amenorrhea after radiotherapy. Controlled clinical trials are warranted to define the role and effectiveness of adjuvant radiotherapy and/or chemotherapy in retroperitoneal soft tissue sarcomas.

Background: Axillary lymph node status has been the most important prognostic factor in operable breast carcinoma, but it does not fully account for the varied disease outcome. More accurate prognostic indicators would help in selection of patients at high risk for disease recurrence and death who are candidates for systemic adjuvant therapy. Our recent findings indicated that microvessel density (count or grade) in invasive breast carcinoma (a measure of tumor angiogenesis) is associated with metastasis and thus may be a prognostic indicator., Purpose: This study was designed to further define the relationship of microvessel density with overall and relapse-free survival and with other reported prognostic indicators in breast carcinoma., Methods: In a prospective, blinded study of 165 consecutive patients, the microvessels within primary invasive breast carcinoma were highlighted by immunocytochemical staining to detect factor VIII-related antigen. Using light microscopy, we counted microvessels per 200x field in the most active areas of neovascularization and graded microvessel density. These findings were correlated, by univariate and multivariate analyses, with overall and relapse-free survival, axillary node status, and other prognostic indicators (median follow-up, 51 months)., Results: There was a highly significant (P < or = .001) association of microvessel density with overall survival and relapse-free survival in all patients, including node-negative and node-positive subsets. All patients with breast carcinomas having more than 100 microvessels per 200x field experienced tumor recurrence within 33 months of diagnosis, compared with less than 5% of the patients with breast carcinoma having 33 or fewer microvessels per 200x field. Moreover, microvessel density was the only statistically significant predictor of overall survival among node-negative women (P < .001). Only microvessel density (P < .001) and histologic grade (P = .04) showed statistically significant correlations with relapse-free survival in the node-negative subset., Conclusions: Microvessel density in the area of the most intense neovascularization in invasive breast carcinoma is an independent and highly significant prognostic indicator for overall and relapse-free survival in patients with early-stage breast carcinoma (I or II by International Union Against Cancer criteria)., Implications: Such an indicator would be useful in selection of those node-negative patients with breast carcinoma who are at high risk for having occult metastasis at presentation. These patients could then be given systemic adjuvant therapy.

The PC-10 monoclonal antibody to PCNA was employed to analyze proliferative grade in conventionally-formalin fixed, paraffin-embedded tumour samples of 162 patients with primary breast carcinoma. To perform the immunocytochemical method, sections were not heated, were de-waxed using alcohol, and then immersed in a phosphate-buffered saline solution and in methanol with 0.5% hydrogen peroxide to block endogenous peroxidase activity. Immunostaining was performed by a streptavidin-biotin peroxidase substrate. A semiquantitative scoring system was used to evaluate the fraction of nuclei that were PCNA-positive. The score ranged from 0% to 75% with a median value of 25%, mean of 27.8 +/- 1.5. PCNA staining was significantly associated with oestrogen receptor-negativity (p = 0.011) and correlated, but not at a statistically significant level, with tumour size (p = 0.08). No significant association was observed between PCNA and node status, grading, DNA ploidy, progesterone receptor or menopausal status. Prognostic indices such as number of positive lymph nodes and DNA ploidy were significantly associated with relapse-free survival (RFS) and overall survival (OS). No significant correlation between PCNA nuclear immunostaining and RFS or OS was observed after a median follow-up of 4 years. Our results indicate that analysis of PCNA alone does not seem to be a useful marker in identifying patients at different prognosis in human breast cancer.

A synergism between cisplatin and radiotherapy has been demonstrated in in vitro and in vivo studies. To improve the locoregional control of disease and the survival rate in patients affected by locally advanced or recurrent squamous cell carcinoma of the head and neck, we planned a Phase II study of concurrent radiotherapy, 2 Gy for 5 days every week for a total dose of 60-70 Gy with cisplatin 80 mg/m2 every 21 days for 2 or 3 doses (on days 1, 21, 42). Fifty-one patients were entered in the study; 48 were evaluable for response and toxicity; 18 (37.5%) had untreated Stage III disease; 25 (52%) had Stage IV disease; 5 (10.5%) had recurrent disease. The complete response rate in Stage III-IV patients was 63% (27 of 43) with 95% confidence limits from 48 to 77% (+/- 14.5%). In the group of five patients with recurrent disease, only one (20%) achieved a complete response. In patients with Stage III-IV disease, a significantly higher complete response rate was observed for those younger than 58.5 years (p = 0.05). The overall estimated 1- and 2-year survival was 59% and 37%, respectively, and a significantly better survival was observed in complete responders compared to partial responses or patients with stable disease (p = 0.037). Disease-free survival was 46% and 36% at 1 and 2 years, respectively. Distant failure occurred only in 12.5% of the patients. Overall, the treatment was well tolerated, and only three patients refused to complete the planned therapy. Gastrointestinal and hematological toxicity were the most common side effects. Data from present trial were compared with that of 50 patients with comparable characteristics treated with radiotherapy alone from 1985 to 1987 as a historical control. The complete response rate, the disease-free survival, and the overall survival appear to be better in the patients treated with chemoradiotherapy. It was concluded that the combination of chemoradiotherapy in patients with Stage III-IV head and neck squamous cell carcinoma is an effective and safe treatment with an apparent better locoregional control than radiotherapy alone. Survival results need to be evaluated in a Phase III randomized trial.

In 164 breast carcinomas the presence of peritumoral lymphatic vessel invasion (PLVI) was evaluated and correlated with other known indicators of prognosis and with the clinical outcome of the patients. Overall 22% of tumors were PLVI-positive. The presence of PLVI was significantly associated with axillary node involvement (p less than 0.0001) and tumor size (p = 0.005), and tended toward an association with grading (p = 0.065). No significant association was found between PLVI and steroid hormone receptors, DNA ploidy, or proliferative activity. Univariate analysis shows that peritumoral vessel invasion was significantly associated with a higher risk of recurrence (p = 0.012) and with a trend toward shorter survival (p = 0.074). Besides the presence of PLVI, prognosis was significantly worse also for patients with high proliferative aneuploid tumors and with axillary node metastases. Moreover, within the subsets of patients generally considered to have good prognosis, the presence of PLVI identified patients with a trend for higher risk such as those with PLVI-positive diploid tumors, PLVI-positive low-proliferative tumors, and PLVI-positive node-negative tumors. Adopting multivariate analysis, PLVI failed to retain prognostic importance when adjusted for node status, DNA ploidy, and proliferative activity. In conclusion, we found that the presence of PLVI has prognostic significance when singly evaluated. Multivariate analysis shows that PLVI is not an independent prognostic factor in stage I-II breast cancer.

Immunocytochemical assay (ICA) of the progesterone receptor (PgR) was performed on 152 patients with stage I-II breast cancer. We employed the rat monoclonal antibody KD-68 and a peroxidase/antiperoxidase displaying system. The results obtained by ICA (Pg(RICA)) were compared with those by the biochemical dextran-coated charcoal assay (PgRDCC). Comparing the two methods we found an overall agreement (accuracy) of 77.5%, a PgR(ICA) sensitivity of 83.5% and a specificity of 73%. Both methods were significantly associated with oestrogen receptor expression, detected by DCC (P less than 0.001 for PgRDCC and P = 0.0014 for PgR(ICA)). No significant association was found between PgR(ICA) or PgRDCC and the other clinicopathological features analysed. After a median follow-up of 36 months, the overall survival probability was 91% in PgRDCC-positive versus 81.5% in PgRDCC-negative patients (log-rank test, chi 2 = 0.91) compared to 87.5% in PgR(ICA)-positive versus 82% in PgR(ICA)-negative ones (log-rank test, chi 2 = 0.93). Disease-free survival probability was 74.5% in both PgRDCC-positive and PgRDCC-negative patients (log-rank test, chi 2 = 0.02) compared to 78% in PgR(ICA)-positive versus 71.5% in PgR(ICA)-negative cases (log-rank test, chi 2 = 0.37). The present study demonstrates that ICA is a reliable method to detect PgR, correlating well with the DCC assay. Moreover, the ICA assay seems to provide clinical information complementary to the biochemical method. The definition of its prognostic value in operable breast cancer needs additional studies, particularly in node-negative patients.

In operable breast cancer, cell kinetics can be utilized in the prediction of the clinical outcome of patients. The discovery of monoclonal antibodies recognizing antigens related to cell proliferation has permitted the assessment of cell kinetics by rapid and practical immunocytochemical methods. It is claimed that the Ki-67 mouse monoclonal antibody recognizes an antigen expressed in proliferating cells but not present in quiescent (G0) cells. To study the relationship between Ki-67 score and DNA flow cytometric S-Phase Fraction (SPF), the latter being one of the most widely used methods to assess cell kinetics, we compared these two techniques of measurement in 122 breast carcinomas using both for each specimen. In this series 90% of tumors were Ki-67 positive, with a median value of 7.5% (range 1% to 70%). DNA flow cytometric analysis revealed that 69 tumors (57%) were aneuploid, whereas 53 were diploid. The median SPF value was 8% for diploid and 15% for aneuploid tumors (range 2% to 32%). Ki-67 scores were significantly higher in the DNA aneuploid compared to the diploid carcinomas (p = 0.015). Overall, a good correlation was found between Ki-67 and SPF values both in diploid (r = 0.60) and in aneuploid (r = 0.38) tumors. High Ki-67 scores were associated with the presence of axillary lymph node metastases (p = 0.0023) and poor histologic differentiation (p = 0.0028). Menopausal status, tumor size and peritumoral vessel invasion were unrelated to the Ki-67 score. Over-expression of the Epidermal Growth Factor receptor (EGF-r) and the c-erbB-2 oncogene were not correlated with Ki-67 staining. In conclusion, in this study Ki-67 immunostaining correlated with other indices of cell proliferation (SPF and Grade) and with some features of tumor aggressiveness (DNA aneuploidy and lymph node metastases) but seemed to be independent of some biological markers (EGR-r and c-erbB-2). Since the major objective for assessing proliferative status in Stage I-II breast carcinoma is to determine prognosis, it will have to be evaluated whether the determination of the Growth Fraction has comparable or even greater prognostic value than other cell kinetics markers.

In vitro and preclinical in vivo data have shown a synergistic antitumor activity between alpha-interferon and some antiproliferative agents. A phase I study of the concurrent administration of interferon-alpha 2 and mitoxantrone was initiated, to determine the maximum tolerated dose of mitoxantrone given i.v. every 3 weeks in escalating doses combined with a fixed dose of s.c. interferon alpha 2 (6 x 10(6) IU three times per week 3), in patients with advanced solid tumors resistant to conventional chemotherapy. At least three evaluable patients were entered in each dose level of mitoxantrone starting at 4 mg/m2, with no escalations allowed in the same patient. Twenty-seven patients received a total of 101 cycles and five dose-levels were explored (4-6-8-10-12 mg/m2 of mitoxantrone). The dose-limiting toxicities were leukopenia and granulocytopenia at 12 mg/m2 of mitoxantrone, at which dose hematological toxicity occurred in greater than 50% of cases, with one patient presenting grade 4 leuko-granulocytopenia. No severe thrombocytopenia occurred. In the majority of patients transient hepatic enzyme elevations and a flu-like syndrome due to interferon alpha 2 were observed in all dose-levels explored. These observations suggest that the hepatotoxic effects of interferon alpha 2 do not emphasize mitoxantrone side-effects if given simultaneously. When mitoxantrone is administered with 6 x 10(6) IU of interferon alpha 2, the recommended dose for future phase II studies is 10 mg/m2/weeks 3 with escalation up to 12 mg/m2 in selected patients if such a combination is well tolerated in terms of myelosuppression. Regarding therapeutic activity, four out of 25 (16%) cases evaluable for response achieved a partial response.(ABSTRACT TRUNCATED AT 250 WORDS)

From 1980 to 1987, 243 evaluable patients with pT1, pT2 (less than 3 centimeters in diameter), N0, M0, invasive breast cancer were treated with "quadrantectomy" with axillary dissection followed by electron beam radiation therapy (QUART) at the St. Bortolo Hospital, Vicenza. Stage II patients received adjuvant chemotherapy (CMF) if preperimenopausal or hormonotherapy (tamoxifen) if postmenopausal. The median follow-up was 54 months (26 to 116 months). The 4.5-year overall survival (OS) and disease-free survival (DFS) were respectively 91% and 85%; the 10-year actuarially estimated OS and DFS was 77%. Thirty-three patients relapsed, 11 of whom had local recurrence, and 23 developed distant metastases. A significantly longer OS and DFS were observed in stage I versus stage II (p = 0.0008) and in pT1 versus pT2 (p = 0.001) tumors. No difference was found regarding menopausal status and histotype. The local control of disease was very high (95.5%), with a significantly higher local recurrence rate in premenopausal women compared to postmenopausal (10/117 versus 1/126; p = 0.009). Tumor size did not influence the frequency of local recurrence. No major complications occurred but a significantly higher rate of reversible radiation-pneumonitis occurred in patients treated with higher energies of electrons (17 to 20 MeV) compared with lower (6 to 13 MeV) (33/177 versus 7/66; p less than 0.05). Cosmetic results were judged as excellent in 20%, satisfactory in 68%, unsatisfactory in 6% and not evaluable in 6% of cases. We conclude first, that small pT2 breast carcinomas may also be safely treated with QUART, second, that the electron beam is a radiotherapeutic technique able to produce a good cosmetic result and to assure a satisfactory local control and, finally, that the use of tamoxifen in postmenopausal stage II breast carcinomas is safe and easy to combine with radiotherapy in the conservative management of early breast cancer due to the lower toxic effects, compared to those observed in premenopausal women treated with chemotherapy.

Epidermal growth factor (EGF) has been shown to have a mitogenic effect on some breast cancer cells lines in vitro. The growth of the subclass of human breast tumors which expresses the specific receptor for EGF seems to be mediated by autocrine mechanisms rather than steroid hormones. The expression of EGF-receptor, as detected by an immunocytochemical method, was compared with the Growth Fraction (GF) by the Ki-67 monoclonal antibody and the S-phase content as tumor proliferative activity indexes, and with DNA ploidy and some pathologic features in 86 stage I-II breast carcinomas. Overall 52 out of 86 (60%) of the tumors were EGF-receptor positive. There was no correlation between the cell kinetics parameters and the EGF-receptor status, suggesting that its expression may be unrelated to the proliferative activity of the tumor in these clinical stages and that the EGF-receptor GF and S-phase may be independent variables in breast cancer. In our series 57% of tumors were DNA aneuploid and only a trend was found towards EGF-receptor positivity (P = 0.08). There was no correlation between EGF-receptor expression and grading or node-status. The overall picture is that of an independent relationship between EGF-receptor with the cell kinetics parameters and ploidy, confirming the complex and heterogeneous biology of breast carcinoma. These results suggest the possibility of better recognition of subsets of patients with diverse tumor aggressiveness, combining together EGF-receptor status, cell kinetics and ploidy, with a better stratification for treatment options.

Forty-nine patients with advanced breast cancer who had failed from first-line cyclophosphamide, methotrexate, and 5-fluorouracil (CMF regimen) chemotherapy, were randomized to treatment with either epirubicin (Epi) or doxorubicin (Dox) at a dose of 20 mg/m2 given intravenously (i.v.) weekly to compare the efficacy and toxicity of these two anthracyclines given in such a schedule. Of 43 evaluable patients 36% (eight of 22) treated with Epi and 38% (eight of 21) treated with Dox achieved a complete plus partial response rate (95% confidence limits 16-56% +/- 20% and 18-58% +/- 20%, respectively). Patients who obtained a major therapeutic response to previous CMF exhibited a significantly higher response rate with both the drugs: seven of eight (87.5%) compared with one of 13 (8%); p less than 0.05 for Epi and six of seven (86%) compared with two of 15 (13%); p less than 0.05 for Dox. The median duration of response was 4.5 months with Epi compared with 7 months with Dox, and the median survival of the two groups of patients were superimposable (12 months with Epi versus 11 months with Dox). The median cumulative dose was 220 mg/m2 (range 160-620) and 240 mg/m2 (range 160-860) for Epi and Dox, respectively. Gastrointestinal and hematological toxicities were moderate for both the drugs, with fewer episodes of nausea and vomiting, stomatitis, and leukopenia following Epi administration. A very low incidence of alopecia was recorded for both the drugs. Regarding cardiac evaluation, no significant differences were evident; however, the only case that developed symptomatic congestive heart failure was in the Dox arm, after a cumulative dose of 820 mg/m2 at 11.5 months. Epi given weekly at low doses preserves efficacy in the treatment of patients with advanced breast cancer, and given at equimolar doses, has a slightly better therapeutic index than the parent compound.

A synergism between cis-platinum (CDDP) and radiotherapy (RT) has been demonstrated both in culture systems and in clinical studies. On the above basis, we planned, in patients with locally advanced or unresectable squamous cell carcinoma of the head and neck, a concomitant treatment with CDDP 80 mg/m2 i.v. every 3 weeks for three doses (days 1, 21 and 42) and RT in the primary and in the neck nodes bilaterally, for a total dose of 60-70 Gy. Thirty-five untreated patients with poor prognosis unresectable stage II and stages III-IV disease were entered in the study and 32 were evaluable. Complete response (CR) rate was 75% (24/32) with 95% confidence limits from 60 to 90% (+/- 15%): 8 cases (25%) achieved a partial response, for an overall response rate of 100%. A significantly higher CR rate and a longer survival rate was observed in patients with good performance status (PS = 90-100) and stages II-III. The overall estimated 2-year survival is 46%; 59% for patients who obtained a CR versus 0% for those who achieved only a partial response. Overall the treatment was well tolerated and gastrointestinal and hematologic toxicities were the most common side effects. In conclusion, the combination of CDDP plus RT is a very effective and safe treatment and we recommend such an approach in head and neck squamous cell carcinoma, particularly in those patients with good PS and with unresectable stage II or stage III disease.

A series of 14 eyes (11 patients) with choroidal metastases from breast cancer were reported. The lesions were classified into three grades according to the severity and extent of involvement. Eleven eyes (9 patients) were treated by radiotherapy with two opposed lateral fields using a 4 MeV linear accelerator. The contralateral eye received a prophylactic irradiation. An average dose of 42 Gy was delivered (range, 30-50). Results of radiotherapy were the following: 5 CR and 2 PR in grade II (9 eyes) and 2 PR in grade III (2 eyes). We conclude that radiotherapy is useful to control choroidal metastases of breast cancer. No contralateral metachronous involvement was found. Quality of life of responders showed a marked improvement. Radiation-induced injury was not seen.