Predictive value of DNA repair gene expression for response to neoadjuvant chemotherapy in breast cancer.

Genome-wide analysis using microarrays has revolutionized breast cancer (BC) research. A substantial body of evidence supports the clinical utility of the 21-gene assay (Oncotype DX) and 70-gene assay (MammaPrint) to predict BC recurrence and the magnitude of benefit from chemotherapy. However, there is currently no genetic tool able to predict chemosensitivity and chemoresistance to neoadjuvant chemotherapy (NACT) during BC treatment. In this study, we explored the predictive value of DNA repair gene expression in the neoadjuvant setting. We selected 98 patients with BC treated with NACT. We assessed DNA repair expression in 98 formalin-fixed, paraffin-embedded core biopsy fragments used at diagnosis and in 32 formalin-fixed, paraffin-embedded post-NACT residual tumors using quantitative reverse transcription-polymerase chain reaction. The following genes were selected: BRCA1, PALB2, RAD51C, BRCA2, ATM, FANCA, MSH2, XPA, ERCC1, PARP1, and SNM1. Of 98 patients, 33 (33.7%) achieved pathologic complete response (pCR). The DNA expression of 2 genes assessed in pre-NACT biopsies (PALB2 and ERCC1) was lower in pCR than in non-pCR patients (P=0.005 and P=0.009, respectively). There was no correlation between molecular subtype and expression of DNA repair genes. The genes BRCA2 (P=0.009), ATM (P=0.004), FANCA (P=0.001), and PARP1 (P=0.011) showed a lower expression in post-NACT residual tumor samples (n=32) than in pre-NACT biopsy samples (n=98). The expression of 2 genes (PALB2 and ERCC1) was lower in pCR patients. These alterations in DNA repair could be considered suitable targets for cancer therapy.

Predictive value of DNA repair gene expression for response to neoadjuvant chemotherapy in breast cancer

Genome-wide analysis using microarrays has revolutionized breast cancer (BC) research. A substantial body of evidence supports the clinical utility of the 21-gene assay (Oncotype DX) and 70-gene assay (MammaPrint) to predict BC recurrence and the magnitude of benefit from chemotherapy. However, there is currently no genetic tool able to predict chemosensitivity and chemoresistance to neoadjuvant chemotherapy (NACT) during BC treatment. In this study, we explored the predictive value of DNA repair gene expression in the neoadjuvant setting. We selected 98 patients with BC treated with NACT. We assessed DNA repair expression in 98 formalin-fixed, paraffin-embedded core biopsy fragments used at diagnosis and in 32 formalin-fixed, paraffin-embedded post-NACT residual tumors using quantitative reverse transcription-polymerase chain reaction. The following genes were selected: BRCA1, PALB2, RAD51C, BRCA2, ATM, FANCA, MSH2, XPA, ERCC1, PARP1, and SNM1. Of 98 patients, 33 (33.7%) achieved pathologic complete response (pCR). The DNA expression of 2 genes assessed in pre-NACT biopsies (PALB2 and ERCC1) was lower in pCR than in non-pCR patients (P=0.005 and P=0.009, respectively). There was no correlation between molecular subtype and expression of DNA repair genes. The genes BRCA2 (P=0.009), ATM (P=0.004), FANCA (P=0.001), and PARP1 (P=0.011) showed a lower expression in post-NACT residual tumor samples (n=32) than in pre-NACT biopsy samples (n=98). The expression of 2 genes (PALB2 and ERCC1) was lower in pCR patients. These alterations in DNA repair could be considered suitable targets for cancer therapy.

Outcome of EGFR inhibitors treatment in advanced NSCLC patients, not enrolled in clinical trials.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become a treatment after first-line chemotherapy in patients with advanced NSCLC. We assessed the predictive and prognostic role of EGFR and Kras mutations in NSCLC patients treated with TKIs after progression, not included in clinical trials. Gefitinib 250 mg or Erlotinib 150 mg per os were administered to 70 patients. Radiological assessment was performed every six weeks. EGFR and Kras mutations were found in 21.4% and 24.3% of patients, respectively. At multivariate analysis, Kras mutation was positively associated with progression-free survival (PFS; HR=0.71, 95% CI: 0.53-0.96; p=0.027) and, less clearly, with response (OR=1.84, 95% CI: 0.98-3.45; p=0.057) and survival (HR=0.74, 95% CI:0.54-1.02; p=0.066). EGFR mutation influenced positively PFS (HR=0.69, 95% CI: 0.47-1.02; p=0.06), but not survival. In conclusion, in our unselected patients mutation of Kras correlated with a better outcome. The small number of patients may explain some discrepancies with data in literature.

Age and comorbidities deeply impact on clinical outcome of patients with myelodysplastic syndromes.

BACKGROUND: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders, with very different prognosis in given individuals; age and comorbidities are emerging as relevant patient-related factors influencing clinical outcome in MDS. Our aim was to evaluate the impact of age, comorbidities and disease severity (IPSS and IPSS-R prognostic scores) in a "real-life" series of MDS patients. METHODS: 318 patients with available assessment of comorbidities at diagnosis and consecutively registered into the Registro Ligure delle Mielodisplasie were analyzed. Comorbidities were evaluated according to HCT-CI and MDS-CI comorbidity indexes. Overall survival (OS) and the probability of death among patients who did not develop acute myeloid leukemia (NLD cumulative incidence) were analyzed. RESULTS: Comorbidities were seen in 177 (55.7%) patients. An older age (>75 y) had a significant negative impact on OS (p=0.008). HCT-CI was not associated with OS. MDS-CI was of prognostic significance (p=0.001), but the association was limited to pts with IPSS or IPSS-R "lower-risk". In multivariate analysis, MDS-CI remained an independent factor associated with OS and with an increased risk of NLD both when controlling for IPSS (p=0.019 and p=0.001, respectively) and for IPSS-R (p=0.048 and p=0.002, respectively). CONCLUSIONS: Evaluation of age and comorbidities according to a tailored tool such is MDS-CI helps to predict survival in patients with MDS and should be incorporated to current prognostic scores.

Multiple chemical sensitivity and the workplace: current position and need for an occupational health surveillance protocol.

Multiple chemical sensitivity, commonly known as environmental illness, is a chronic disease in which exposure to low levels of chemicals causes correlated symptoms of varying intensity. With the continuous introduction of new substances, people with MCS suffer significant limitations to their living environment and frequently to their workplace. This paper describes the current situation as regards MCS and the critical points in its case definition, which is still not generally agreed upon; this makes it difficult to recognize with certainty, especially, its precise relationship with work. Other problems arise in relation to the occupational physician's role in diagnosing and managing the worker with the disorder, the question of low levels of exposure to chemicals, and the best measures possible to prevent it. A diagnostic "route" is proposed, useful as a reference for the occupational physician who is often called in first to identify cases suspected of having this disease and to manage MCS workers. Work-related problems for people with MCS depend not only on occupational exposure but also on the incompatibility between their illness and their work. More occupational physicians need to be "sensitive" to MCS, so that these workers are recognized promptly, the work is adapted as necessary, and preventive measures are promoted in the workplace.

Blood reduced glutathione (GSH) concentrations in healthy and ill subjects.

BACKGROUND: Recently blood reduced glutathione (GSH), an important cellular antioxidant, has been proposed as an indicator of health, particularly in the elderly. To date, a gold standard unit for the expression of GSH concentrations is not known. The aim of the study is to define the most sensitive laboratory expression of GSH. EXPERIMENTAL DESIGN: a comparative study among some laboratory expressions of GSH. SETTING: Geriatric and Internal Medicine Units; General Community. PATIENTS AND PARTICIPANTS: forty-eight inpatients from Geriatric and Internal Medicine Units and 82 healthy subjects recruited among medical students and residents, people from preventive medicine services and from local senior centres. EXCLUSION CRITERIA FOR HEALTHY SUBJECTS: use of drugs in the year prior to the study. INTERVENTIONS: neither treatment nor interventions. MEASURES: the laboratory expression of GSH, compared in this study, were mg/dl, packed cell volume (PCV), mg/1010 RBC, mM/gHb. RESULTS: We noted statistically significant differences only if GSH was calculated as mg/1010 RBC; higher values were found in healthy subjects than in inpatients, apart from age. This modality of expression is minimally affected by haematological parameters; the low sensibility of the other modalities may be due to variations of MCV and Hb. Instead, the ratio GSH mg/1010 RBC expresses the true GSH concentrations inside each erythrocyte. This modality of expression is minimally affected by haematological parameters; the low sensibility of the other modalities may be due to variations of MCV and Hb.

New hematological indices in the healthy elderly.

BACKGROUND: Recently, new indices related to erythrocytes and platelet counts have been provided by hematological analysers. The purpose of the study is to investigate these new parameters in the elderly to define their normal values and to compare them with the range provided by the manufacturer. EXPERIMENTAL DESIGN: a comparative study. SETTING: general community, geriatric and internal medicine ambulatories. PATIENTS: sixty healthy free-living elderly (cut-off: 65 years) and 66 healthy young-adults, as a control group. MEASURES: we measured the common and the new hematological parameters by H.1 Bayer technology. The new hematological parameters are red diameter width-RDW, hemoglobin distribution width-HDW, mean platelet volume-MPV, platelet diameter width-PDW, platelet hematocrit-Pct. We then compared the values of our population with the Bayer range. RESULTS: The confidence interval width of the new indices define very faster limits than the Bayer range. Statistical differences were significant only in male groups: young-adults (Y) versus elderly (E) with higher values in Y than E in RBC p=0.002, in Platelet count p=0.050 and in MPV p=0.026; and higher values in E in MCV p=0.008, MCH p=0.006 and PDW p=0.004. CONCLUSIONS: In the literature a wide range of common hematological parameters are reported in the elderly, while the new hematological values have not been discussed till now. Our results may contribute to define the laboratory limits of the new hematological values in the healthy elderly.

Using the essential services as a foundation for performance measurement and assessment of local public health systems.

Efforts are under way to develop a performance measurement monitoring system for state and local public health systems and to develop a strategic planning tool for local public health systems. The development of these measures is being based on the Essential Public Health Services. This article provides the rationale for why the Essential Services offer a good framework for identifying, analyzing, and evaluating public health activities. The article also reviews the history of local public health and the development and application of the Essential Public Health Services and their predecessor frameworks such as the core functions, the organizational practices, and the essential elements.

Simple and safe method to prepare patients with prosthetic heart valves for surgical dental procedures.

Temporary discontinuation of high-intensity oral anticoagulant treatment is not recommended in patients undergoing dental surgery. This policy is not based on solid data from randomized clinical trials but on expert consensus. The alternative, i.e., to continue treatment and treat patients with tranexamic acid mouthwash, often is not applicable. A prospective cohort study was carried out to evaluate bleeding and thromboembolic complications in patients bearing prosthetic heart valves and registering International Normalized Ratio (INR) values between 2.0 and 4.5, who underwent dental procedures after a 2-day suspension of warfarin treatment. One hundred four consecutive patients receiving high-intensity anticoagulation underwent 123 dental procedures after 2 days' warfarin withdrawal. No major bleeding complications occurred in the week after the procedure; minor bleeding requiring local measures occurred in two patients. No thromboembolic events and no cases of bacterial endocarditis were recorded in the 3 months after the procedure. A mean decrease in INR by approximately 1.0 U (from 2.95+/-0,59 to 1.87+/-0,46) occurred after 2 days' warfarin suspension. Seven days after reinitiation of warfarin, INR values returned to the therapeutic range in 90% of cases. The calculated average time spent at INR less than 2.0 (critical value) was 28 hours. Two days' warfarin suspension is a simple and safe policy for patients with prosthetic heart valves undergoing dental surgery.

Blood zinc, copper and magnesium in aging. A study in healthy home-living elderly.

BACKGROUND: Blood concentrations of copper, zinc and magnesium were determined in healthy elderly to assess whether aging interferes with mineral and micronutrient status. EXPERIMENTAL DESIGN: case series. SETTING: Internal Medicine and Geriatrics ambulatories in a University Hospital in Pisa, a city of Central Italy. PARTICIPANTS: 143 healthy outpatients of both sexes, who underwent a cardiological examination. INTERVENTION: no treatment and intervention were performed. MEASURES: copper (Cu), zinc (Zn) and magnesium--both intraerythrocytic (iMg) and extracellular (eMg)--were measured. RESULTS: The concentrations of Cu and eMg were found significantly higher in the elderly: Cu 117.5 +/- 17.0 micrograms/dl in the elderly vs 102.5 +/- 19.6 micrograms/dl in the younger (p < 0.001); eMg 1.8 +/- 0.2 in the elderly vs 1.7 +/- 0.2 mEq/l in the younger (p < 0.05). On the other hand, the levels of Zn and iMg did not differ in the two groups: Zn 113.3 +/- 14.9 micrograms/dl in the elderly vs 118.0 +/- 17.3 micrograms/dl in the younger, p = n.s.; iMg 4.3 +/- 0.4 mEq/l in the elderly vs 4.2 +/- 0.4 mEq/l in the younger, p = n.s. No correlation was found between age and single elements. CONCLUSIONS: These results suggest that the healthy free-living elderly have an adequate mineral intake. Nutrient supplements may by useful in the elderly with chronic diseases, comorbidities, and polypharmacy to prevent further age dysfunctions.

Congenital hypopituitarism in a 48-year old adult. Natural course, hormonal study and MRI evidence.

A case of Congenital Hypopituitarism (CH) in an untreated 48 yr-old-man is reported. The hormonal studies demonstrated a panhypopituitarism and MR imaging revealed absence of pituitary stalk, small anterior pituitary remnant on the sella floor and ectopic neurohypophysis at the tuber cinereum. The pattern of hormonal responsiveness suggests that CH encompasses findings typical of primary anterior pituitary disease and those of hypothalamic dysfunction.

Congenital hypopituitarism in a 48-year old adult. Natural course, hormonal study and MRI evidence.

A case of Congenital Hypopituitarism (CH) in an untreated 48 yr-old-man is reported. The hormonal studies demonstrated a panhypopituitarism and MR imaging revealed absence of pituitary stalk, small anterior pituitary remnant on the sella floor and ectopic neurohypophysis at the tuber cinereum. The pattern of hormonal responsiveness suggests that CH encompasses findings typical of primary anterior pituitary disease and those of hypothalamic dysfunction.

Takayasu's arteritis on steroid therapy. Seven years follow-up.

The authors report a 7 year follow-up of Takayasu's arteritis (TA) type III, group 1, in a young Italian woman. At diagnosis, at the age of 25, the echotomographic and angiographic studies showed narrow subclavian arteries, narrow abdominal aorta (diameter of 0.6-0.8 cm) below the renal arteries, stenotic left common carotid and renal arteries, and occluded upper mesenteric artery. With steroid therapy, (prednisone 50 mg/day per os), the erythrocyte sedimentation rate (ESR) normalized within 12 days. With a maintenance dosage of 7.5 mg/day per os, the patient achieved remission as documented by the absence of symptoms, the persistent normalization of ESR, and the improving of the diameter of the abdominal aorta (1.3-1.4 cm). On steroid therapy, the patient had a normal pregnancy and delivered a healthy baby girl. The disease has been stable for seven years. Recently, diabetes mellitus occurred and it has been treated with insulin therapy. The rising of ESR after tapering of steroid therapy (prednisone 5 mg per os on alternate days) suggests an alternative treatment with a cytotoxic agent.

[Occult stromal tumour of the small intestine: a cause of chronic intestinal blood loss in a 70 year-old woman]. / Tumore stromale occulto del tenue causa di sanguinamento intestinale cronico in 70enne.

The case of a 70 year-old woman with a chronic gastrointestinal blood loss due to a stromal tumor located in the middle third of the small intestine is reported. The peculiarities of the case are the characteristic immunohistochemistry of the neoplasm and, particularly, the mimetic clinical presentation, a kind of ''phantom tumor'' confirmed only with celiotomy and surgical excision.

Assessing the impact of Medicaid managed care on TB activities in local health departments.

Three in-depth case studies were conducted to explore the impact of Medicaid managed care on local health department prevention activities. Tuberculosis (TB) was selected as a sentinel issue because TB includes both clinical treatment and population-based public health considerations (such as surveillance and contact tracing). Overall, study results indicated that there has been a minimal impact on TB prevention and control services, primarily because few TB patients are served by managed care. However, the sites offer many suggestions for areas to monitor, possible collaborative opportunities, and mechanisms to assure continued TB prevention and control.

[Why regular physical activity favors longevity]. / Perché l'attività fisica abitudinaria favorisce la longevità.

Regular physical exercise is useful at all ages. In the elderly, even a gentle exercise programme consisting of walking, bicycling, playing golf if performed constantly increases longevity by preventing the onset of the main diseases or alleviating the handicaps they may have caused. Cardiovascular diseases, which represent the main cause of death in the elderly, and osteoporosis, a disabling disease potentially capable of shortening life expectancy, benefit from physical exercise which if performed regularly well before the start of old age may help to prevent them. Over the past few years there has been growing evidence of the concrete protection offered against neoplasia and even the ageing process itself.

Tortuosity, kinking, and coiling of the carotid artery: expression of atherosclerosis or aging?

The etiology of carotid abnormalities is both congenital than acquired. The aim of this study was to clarify the role of aging and atherosclerosis in the acquired cases, and the role of these abnormalities in hemodynamic alterations and neurologic symptoms. Over a 1-year period the authors studied all the subjects undergoing carotid examination by continuous-wave and color-coded Doppler sonography at an Angiology Unit. They evaluated neurologic symptoms; risk factors for atherosclerosis; number, sites, and kinds of carotid abnormalities; atherosclerotic lesions; stenosis; hemodynamic alterations of the carotid; and other localizations of atherosclerotic diseases. There were 469 subjects: 272 (58%) with abnormalities (group 1) and 197 (42%) without abnormalities (group 2). The total number of abnormalities was 479 (104 tortuosities, 262 kinkings, and 113 coilings). The abnormalities were more prevalent in the elderly (P<0.001) and in women (P<0.001). In group 1 they found significant prevalences of hyperlipemia (P<0.001), hypertension (P<0.01), chronic cigarette smoking (P<0.01), and ischemic heart disease (P<0.05). Carotid atherosclerotic lesions were more prevalent in group 1 than in group 2 (P<0.001); among the patients with atherosclerotic carotid lesions, those in group 1 were older than those in group 2 (P<0.001). Tortuosity seemed to be associated with fewer hemodynamic alterations. The authors conclude that atherosclerosis, hypertension, and aging may play an important role in producing carotid abnormalities. The aging seemed more important than atherosclerosis. Only a prospective study of patients with carotid abnormalities and no atherosclerotic lesion will clarify the role of hemodynamics and neurologic symptomatology.

[Fever of unknown origin in the elderly of the 90's]. / La febbre di origine sconosciuta nell'anziano degli anni '90.

MATERIALS AND METHODS: Eighteen elderly patients (mean age 76.3 +/- 6.9 years) with fever of unknown origin (FUO) are studied sequentially and prospectively from January 1994 to December 1996. The classic Petersdori's criteria of FUO are no more valid for the elderly. The fever of more than 3-4 weeks duration is the only criterion to be considered, the fever is frequently under 38.5 degrees C and the elderly patient is often studied for more than 1 week outside the hospital. RESULTS: The most frequent underlying conditions were: malignancies in particular haematological diseases, followed by multisystem diseases and infections, tuberculosis "in primis". CONCLUSIONS: Selected investigations directed to the most frequent underlying conditions of FUO in the aged individuals overcome the financial cost and the patient discomfort of the tests since an identified curable disease can improve the life expectancy and quality.

[Cardiac myxoma in the elderly. Clinical study]. / I mixomi cardiaci nell'anziano. Studio clinico.

Cardiac mixoma in the elderly. A clinical study. The clinical features of 13 cardiac myxomas surgically resected are presented. The mean age at presentation was 68 years. Ten were in the left atrium, 5 near the fossa ovalis, 3 at the base of the atrial septum, 1 at the inferior wall and 1 on the anterior leaflet of mitral valve, 3 were in the right atrium, 1 of these was accompanied with a myxoma at the apex of left ventricle. The ECG and the chest X-ray were normal in 9 and in 8 patients, respectively. In 3 patients, the diagnosis was occasionally made by routine 2-dimensional echocardiography. 5 patients presented with fever of unknown origin, arthralgias, weakness, weight loss. None had intracardiac or extracardiac recurrence in the 73 months follow-up. The presentation with constitutional symptoms only like fever of UO, may mimic collagen and neoplastic diseases, vasculitis, lymphomas: the 2-dimensional echocardiography is mandatory to esclude a cardiac myxoma in the elderly.