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Understanding the consequences of exposure to low dose ionizing radiation is an important public health concern. While the risk of low dose radiation has been estimated by extrapolation from data at higher doses according to the linear non-threshold model, it has become clear that cellular responses can be very different at low compared to high radiation doses. Important phenomena in this respect include radioadaptive responses as well as low-dose hyper-radiosensitivity (HRS) and increased radioresistance (IRR). With radioadaptive responses, low dose exposure can protect against subsequent challenges, and two mechanisms have been suggested: an intracellular mechanism, inducing cellular changes as a result of the priming radiation, and induction of a protected state by inter-cellular communication. We use mathematical models to examine the effect of these mechanisms on cellular responses to low dose radiation. We find that the intracellular mechanism can account for the occurrence of radioadaptive responses. Interestingly, the same mechanism can also explain the existence of the HRS and IRR phenomena, and successfully describe experimentally observed dose-response relationships for a variety of cell types. This indicates that different, seemingly unrelated, low dose phenomena might be connected and driven by common core processes. With respect to the inter-cellular communication mechanism, we find that it can also account for the occurrence of radioadaptive responses, indicating redundancy in this respect. The model, however, also suggests that the communication mechanism can be vital for the long term survival of cell populations that are continuously exposed to relatively low levels of radiation, which cannot be achieved with the intracellular mechanism in our model. Experimental tests to address our model predictions are proposed.

Neutral mutations play an important role in many biological processes including cancer initiation and progression, the generation of drug resistance in bacterial and viral diseases as well as cancers, and the development of organs in multicellular organisms. In this paper we study how neutral mutants are accumulated in nonlinearly growing colonies of cells subject to growth constraints such as crowding or lack of resources. We investigate different types of growth control which range from "division-controlled" to "death-controlled" growth (and various mixtures of both). In division-controlled growth, the burden of handling overcrowding lies with the process of cell-divisions, the divisions slow down as the carrying capacity is approached. In death-controlled growth, it is death rate that increases to slow down expansion. We show that division-controlled growth minimizes the number of accumulated mutations, and death-controlled growth corresponds to the maximum number of mutants. We check that these results hold in both deterministic and stochastic settings. We further develop a general (deterministic) theory of neutral mutations and achieve an analytical understanding of the mutant accumulation in colonies of a given size in the absence of back-mutations. The long-term dynamics of mutants in the presence of back-mutations is also addressed. In particular, with equal forward- and back-mutation rates, if division-controlled and a death-controlled types are competing for space and nutrients, cells obeying division-controlled growth will dominate the population., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Primary heart tumors are rare with an estimated incidence ranging 0.0017-0.19%. Myxoma is the most prevalent primary heart tumor. The right atrium is an unusual location, occurring only in the 15-20% of myxoma cases. We describe the case of a massive right atrial myxoma causing right ventricular inflow and tricuspid valve obstruction. The tumor was detected by echocardiography and confirmed by abdomen-thoracic tomography. It was resected along with a section of tricuspid septal leaflet, followed by primary repair. In 2-year follow-up the patient is asymptomatic., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background. Perception remains that brachytherapy-based regimens are inappropriate for patients having increased risk of extracapsular extension (ECE). Methods. 321 consecutive intermediate and high-risk disease patients were treated between 1/92 and 2/97 by one author (M. Dattoli) and stratified by NCCN guidelines. 157 had intermediate-risk; 164 had high-risk disease. All were treated using the combination EBRT/brachytherapy ± hormones. Biochemical failure was defined using PSA >0.2 and nadir +2 at last followup. Nonfailing patients followup was median 10.5 years. Both biochemical data and original biopsy slides were independently rereviewed at an outside institution. Results. Overall actuarial freedom from biochemical progression at 16 years was 82% (89% intermediate, 74% high-risk) with failure predictors: Gleason score (P = .01) and PSA (P = .03). Hormonal therapy did not affect failure rates (P = .14). Conclusion. This study helps to strengthen the rationale for brachytherapy-based regimens as being both durable and desirable treatment options for such patients. Prospective studies are justified to confirm these positive results.

Higher plasma concentrations of the N-terminal fragment of brain natriuretic peptide (NT-pro-BNP) and the tumor necrosis factor-alpha (TNF-alpha) have been observed in patients affected by chronic heart failure (CHF). Recent clinical studies have tried to correlate the plasma levels of these biomarkers with severity of the disease. To evaluate the role of NT-pro-BNP, TNF-alpha and C-reactive protein (CRP) in a population of geriatric patients affected by CHF, and to assess their different plasma levels in diabetics and in normoglycemic patients, we enrolled 57 patients affected by CHF: 29 patients were diabetic and 28 were normoglycemic. Clinical and echocardiographic examinations were performed in all patients, in order to evaluate the NYHA-class and the left ventricular ejection fraction (EF). All of them had been stabilized with medical therapy from at least 3 weeks. Plasma NT-pro-BNP, TNF-alpha and CRP levels were measured in each recruited patient. In the whole population we observed a linear correlation between NT-pro-BNP levels, EF and NYHA-class (p<0.05) but there was no significant correlation between TNF-alpha or CRP and the clinical or echocardiographic data (p=0.588 and p=0.9, respectively). Finally we evaluated, if there were significant differences in the biomarker concentrations between diabetics and normoglycemics. Both the clinical and the echocardiographic parameters of systolic dysfunction were comparable in these two groups. We observed a significant difference in CRP levels between the two groups (3.76+/-2.85 in diabetics vs. 1.42+/-2.35 in normoglycemics; p<0.001). The NT-pro-BNP levels were also higher in diabetics than in normoglycemic patients (12867.8+/-18042.0 vs. 6400.89+/-5655.0; p=0.07). Plasma TNF-alpha levels (23.03+/-11.52 vs. 23.31+/-12.0; p=0.93) and left ventricular EF (35.65+/-4.03 vs. 35.18+/-3.55; p=0.63) were similar in the two groups. In agreement with recent studies, we confirm a linear correlation between NT-pro-BNP, EF and the severity of disease in CHF patients. We also observed a greater cytokine activation in diabetics than in normoglycemic patients, demonstrating probably that in this group a greater inflammatory reaction is present.

Despite being treated with antiresorptive drugs, the severe osteoporosis (SO) is being considered as a condition in which patients are still subject to one or more vertebral or femoral fractures, or non-vertebral or non-femoral fractures, i.e., of other parts of the body such as the wrist, shoulder, tibia, ribs or hip. These patients are defined as non-responders (NRs) to the antiresorptive therapy, and recent research has shown that they represent 10-25% of all SO patients. During the last almost 3 years a new drug has become available in Italy, called teriparatide (rh-PTH-1-34), produced in Escherichia coli using the recombinant-DNA technique. It shows remarkable trophic and anabolic actions on the bones, and proved to be very useful for treating the osteoporosis in general. This study describes our experience in using teriparatide for the treatment of SO in a sample of 141 elderly women of mean age 73.4+/-5.8 years, with a mean number of fractures of 3.0+/-0.85, with a spine deformity index (SDI) of 5.92+/-1.27 and a mean vertebral T-Score (L1-L4) of -3.15+/-0.39, and a mean femoral T-Score of -2.50+/-0.28. All these patients had been treated with antiresorptive drugs for at least 1 year: specifically 70 of them with Alendronate, 42 of them with Risedronate and 29 of them with Raloxifene. For 18 months, all these patients were injected subcutaneously with 20 microg of teriparatide, with the daily addition of 1 g of calcium and 880 IU of vitamin D. The study was continued for 24 months, at the end of which the patients continued to take only calcium and vitamin D. The patients underwent a CBM-DEXA control of vertebral column and femur every 6 months, and they were also administered a Quality-of-Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO). The QUALEFFO (41 items) questionnaire to evaluate the changes in the quality-of-life (QoL) and the consumption of non-steroidal anti-inflammatory drugs (NSAIDs) was also recorded. The results showed that teriparatide protected 96.5% against new fractures (only five new fractures occurred), bone mineral density (BMD) increased approximately by 12% in the vertebral column and by 11% in the femur, consumption of NSAIDs was reduced at the early stage approximately 80%, the QoL improved considerably and remained so during the 18 months of teriparatide treatment, with only a slight decrease during the 6 subsequent months.

Objectives: To perform a retrospective analysis to assess the utility of pretreatment serum prostatic acid phosphatase (PAP) as a predictor of cause-specific survival (CSS) in patients with higher risk prostate cancer treated with palladium-103 (103Pd) brachytherapy and supplemental external beam radiotherapy (EBRT)., Methods: From 1992 to 1996, 193 patients with clinically localized prostate adenocarcinoma, a pretreatment PAP level, and Gleason score 7 or more, and/or a prostate-specific antigen (PSA) level of 10 ng/mL or more were treated with 103Pd brachytherapy and supplemental EBRT. The patients underwent EBRT of 41.4 Gy to a limited pelvic field and 103Pd brachytherapy with a prescribed minimum 103Pd dose of 80 Gy. Multivariate analysis was performed to analyze the predictive value of PAP, PSA, and Gleason score on CSS., Results: The 10-year CSS rate for patients with a PAP level of less than 1.5, 1.5 to 2.4, and 2.5 U/L or more was 93%, 87%, and 75%, respectively (P = 0.013). The 10-year CSS rate for patients with a PSA level of less than 10, 10 to 20, and greater than 20 ng/mL was 92%, 76%, and 83%, respectively (P = 0.393). The 10-year CSS rate for patients with a Gleason score of 6, 7, 8, and 9 was 90%, 89%, 70%, and 68%, respectively (P = 0.002). On Cox multivariate regression analysis, PAP (hazard ratio 1.31, P <0.0001) and Gleason score (hazard ratio 2.37, P = 0.0007) were associated with CSS. PSA was not predictive of CSS (P = 0.393)., Conclusions: The results of this study demonstrated that PAP is a stronger predictor of CSS than PSA or Gleason score in men with higher risk prostate cancer treated with 103Pd brachytherapy and EBRT. Given the findings of this analysis, the use of PAP should be reconsidered in these patients.

Background: This study summarizes long-term outcomes from treatment of prostate cancer with increased risk of extracapsular cancer extension (ECE) using brachytherapy-based treatment., Methods: A total of 282 consecutive patients were treated from 1992-1996 by 1 author (M.D.). Two hundred forty-three patients had at least 1 higher risk feature for ECE including Gleason Score 7-10 (172), prostate-specific antigen (PSA) above 10 (166), and clinical stages T(2c) (109) and T(3) (107). Using National Comprehensive Cancer Network (NCCN) guidelines, 119 patients had intermediate-risk disease and 124 had high-risk disease. Patients received pelvic 3-dimensional conformal external beam radiation followed by a palladium (Pd)-103 boost. Generous brachytherapy margins were utilized. Biochemical failure was defined using ASTRO Consensus Definition, nadir +2 and PSA >0.2 ng/mL at last follow-up. The nonfailing patient follow-up period was 1-14 years (median, 9.5 years). Biochemical data and original biopsy slides were independently re-reviewed at the University of Washington (by K.W. and L.T., respectively)., Results: Overall actuarial freedom from biochemical progression at 14 years was 81%, including 87% and 72% having intermediate and high-risk disease, respectively. Absolute risk of failure decreased progressively, falling to 1% beyond 6 years after treatment. All failing patients had prostate biopsies without evidence of local recurrence. The strongest predictor of failure was Gleason score (P = .03) followed by PSA (P = .041). Treatment morbidity was limited to temporary RTOG grade 1-2 urinary and gastrointestinal symptoms., Conclusions: High tumor control rates are possible with beam radiation followed by Pd-103 brachytherapy. Despite perceptions that brachytherapy is inappropriate for patients at higher risk for ECE, this series strengthens the rationale that brachytherapy-based treatment may be a desirable modality for such patients., ((c) 2007 American Cancer Society.)

Objectives: To report the long-term biochemical control rates with brachytherapy-based treatment for patients with prostate cancer at high risk of extracapsular cancer extension., Methods: A total of 243 consecutive patients with at least one higher risk factor (Gleason score of 7 or worse, prostate-specific antigen [PSA] level greater than 10 ng/mL, or elevated prostatic acid phosphatase level greater than 2.5 U) who were treated with palladium-103 plus supplemental external beam radiotherapy from 1992 through 1996 were included in this study. Patients received 41 Gy external beam radiotherapy to a limited pelvic field, followed 4 weeks later by a palladium-103 boost. The prescribed minimal palladium-103 dose to the prostate was 80 to 90 Gy. Freedom from biochemical failure was defined as a serum PSA level of 0.2 ng/mL or less at the last follow-up visit., Results: Of the 243 patients, 41 developed biochemical failure. The overall actuarial freedom from biochemical progression rate at 13 years was 81%, with 198 patients followed up for longer than 5 years. The overall actuarial freedom from failure rate for the 93 patients with a PSA level of 10 ng/mL or greater and Gleason score of 7 or greater was 74% at 5 years and 72% at 10 years. The overall actuarial freedom from failure rate for the 66 patients with elevated prostatic acid phosphatase was 65% at 10 years. The absolute risk of failure decreased progressively with time, falling to 1% by 6 years after treatment. On Cox proportional hazard multivariate analysis, considering each factor as a continuous variable, the strongest predictor of failure was the acid phosphatase level (P <0.0001), followed by Gleason score (P = 0.42) and PSA level (P = 0.15)., Conclusions: The evidence from this patient group at high risk of extracapsular cancer extension suggests that the relatively high tumor control rates with brachytherapy-based therapy are durable.

Background: The objective of this study was to define the long-term prognostic significance of prostatic acid phosphatase (PAP) levels in patients with higher risk, early-stage prostate carcinoma., Methods: One hundred sixty-one consecutive patients with Stage T1-T3 prostate carcinoma (according to the 1992 criteria of the American Joint Committee on Cancer) were treated from 1992 through 1996. Each patient had a Gleason score > or = 7 and/or a prostate specific antigen (PSA) level > 10 ng/mL. The original biopsy slides for 130 of 161 patients were retrieved and rereviewed by a single pathologist (L.T.). Enzymatic PAP measurements were determined using a standard method. Values up to 2.5 Units were considered normal. Patients received 41 grays (Gy) of external beam radiation therapy to a limited pelvic field followed 4 weeks later by a palladium 103 (Pd-103) boost using transrectal ultrasound and fluoroscopic guidance as described previously. The prescribed minimum Pd-103 dose to the prostate was 80 Gy (pre-National Institute of Standards and Technology [NIST]-99). Freedom from biochemical failure was defined as a serum PSA level < or =0.2 ng/mL at last follow-up., Results: There was little correlation between pretreatment PSA levels, Gleason scores, and PAP measurements. Thirty-eight patients developed biochemical failure. The overall actuarial freedom from biochemical progression at 10 years is 79%, with 118 patients followed for > 5 years. In a multivariate Cox proportional hazards analysis that considered each factor as a continuous variable, the strongest predictor of failure was PAP (P = 0.0001), followed by Gleason score (P = 0.13), and PSA (P = 0.04). PAP was especially helpful in stratifying patients with pretreatment PSA levels between 4 ng/mL and 20 ng/mL, for whom the prognosis does not different when they are subdivided into PSA categories. When the PAP subgroup analysis was limited to this relatively favorable group, there was a wide range of prognoses., Conclusions: The biochemical cure rate was remarkably high among the 161 patients evaluated. The fact that the PAP was the strongest predictor of long-term biochemical failure in patients with otherwise higher risk features reported here suggests that it may be a more accurate indicator of micrometastatic disease compared with the Gleason score and the PSA level. This report adds to the rationale for reintroducing PAP measurement into general practice., (Copyright 2003 American Cancer Society)

Background: The objective of this study is to evaluate the oxidative stress status in patients affected by Alzheimer's disease, considering the role played by the free radicals in the progression and determination of this disease., Methods: We have studied 13 patients aged between 65 and 84 years and diagnosed with Alzheimer's disease on the basis of Brain CT scan or MRI results, PTEA (uditive mapped slow potential waves), EEG analysis, evaluation questionnaire (MMSE, ADAS), free radicals levels., Results: This study proved the presence of an oxidative stress status in all patients studied, showing an interaction between the disease and oxidative status. A reduction of the free radicals levels after therapy with determinable anti radicals has also been observed., Conclusions: The existence between Alzheimer's disease and oxidative stress has already been demonstrated. This study is a contribution to this orientation. Further studies are suggested on the preventive effects, but particularly to demonstrate if the use of antioxidants may be able to decrease or stop the evolution of this disease.

Purpose: To establish the prognostic role of serum enzymatic prostatic acid phosphatase (PAP) in patients treated with palladium (103Pd) and supplemental external beam irradiation (EBRT) for clinically localized, high-risk prostate carcinoma., Methods and Materials: One hundred twenty-four consecutive patients with Stage T2a-T3 prostatic carcinoma were treated from 1992 through 1995. Each patient had at least one of the following risk factors for extracapsular disease extension: Stage T2b or greater (100 patients), Gleason score 7-10 (40 patients), pretreatment prostate specific antigen (PSA) >15 ng/ml (32 patients), or elevated serum PAP (25 patients). Patients received 41 Gy conformal EBRT to a limited pelvic field, followed 4 weeks later by a 103Pd boost (prescription dose 80 Gy). Biochemical failure was defined as a PSA greater than 1 ng/ml (normal <4 ng/ml)., Results: The overall, actuarial freedom from biochemical failure at 4 years after treatment was 79%. In Cox-proportional hazard multivariate analysis, the strongest predictor of failure was elevated pretreatment acid phosphatase (p = 0.02), followed by Gleason score (p = 0.1), and PSA (p = 0.14)., Conclusion: PAP was the strongest predictor of long-term biochemical failure. It may be a more accurate indicator of micrometastatic disease than PSA, and as such, we suggest that it be reconsidered for general use in radiation-treated patients.

Purpose: To summarize biochemical failure rates and morbidity of external beam irradiation (EBRT) combined with palladium (103Pd) boost for clinically localized high-risk prostate carcinoma., Methods and Materials: Seventy-three consecutive patients with stage T2a-T3 prostatic carcinoma were treated from 1991 through 1994. Each patient had at least one of the following risk factors for extracapsular disease extension: Stage T2b or greater (71 patients), Gleason score 7-10 (40 patients), prostate specific antigen (PSA) > 15 (32 patients), or elevated prostatic acid phosphatase (PAP) (17 patients). Patients received 41 Gy EBRT to a limited pelvic field, followed 4 weeks later by a 103Pd boost (prescription dose: 80 Gy). Biochemical failure was defined as a PSA greater than 1.0 ng/ml (normal < 4.0 ng/ml). Patients whose PSA was still decreasing at the last follow-up were censored at that time. Patients whose PSA plateaued at a value greater than 1.0 were scored as failures at the time the PSA first plateaued., Results: The overall, actuarial freedom from biochemical failure at 3 years after treatment was 79%. In Cox proportional hazard multivariate analysis, the strongest predictor of failure was elevated acid phosphatase (p = 0.04), followed by PSA (p = 0.17), Stage (p = 0.23), and Gleason score (p = 0.6). Treatment-related morbidity was usually limited to temporary, RTOG Grade 1-2 urinary symptoms. One patient, who had both a transurethral incision of the prostate (TUIP) and a transurethral resection of the prostate (TURP), developed low-volume urinary incontinence. The actuarial potency rate at 3 years after implantation was 77% for 46 patients who were sexually potent prior to implant., Conclusion: Biochemical freedom from failure rates following combined EBRT and 103Pd brachytherapy for clinically localized, high-risk prostate cancer compare favorably with that reported after conventional dose EBRT alone. Morbidity has been acceptable.

The binding of [14C]ellipticine to native calf thymus DNA was studied using equilibrium dialysis. A Scatchard polt revealed the presence of high-and low-affinity binding sites in DNA, the former having a K of 4.0 X 10(7) M(-1) and an n (saturation limiting of binding) of 0.078 (1mol ellipticine/13 mol of DNA nucleotides). The forces involved in stabilizing the high-affinity binding, which has been equated with intercalative binding, were due to a combination of hydrophobic interactions and hydrogen bonding. Difference spectra of ellipticine in the presence of the polydeoxynucleotides, poly d(A-T) or poly d(G-C), showed that there was no base specificity involved in the high-affinity binding. Ellipticine binding to the low-affinity sites, which has been equated with surface binding, was due primarily to the participation of electrostatic interactions of ellipticine with the anionic phosphate groups on the double helical surface of DNA.

Fifty-one patients with stage IIIA or IIIB locally advanced breast cancer received primary induction chemotherapy (hormonal synchronization, 46 patients) to a maximum objective clinical response before proceeding to local therapy. Patients achieving a pathological complete response (CR) received radiation therapy, while patients with residual disease, partial response (PR), or stable disease (NC) received debulking surgery prior to radiation therapy; in all patients, 6 additional months of chemotherapy were administered. Chemotherapy consisted of cyclophosphamide (500 mg/m2 iv) and doxorubicin (30 mg/m2 iv) on day 1; tamoxifen (40 mg/m2 orally) on days 2-6; Premarin (0.625 mg/m2 orally) every 12 hours for three doses, beginning on day 7; and methotrexate (300 mg/m2 iv) followed in 1 hour by 5-fluorouracil (500 mg/m2 iv) on day 8 and leucovorin rescue (10 mg/m2 orally) every 6 hours for six doses, beginning 24 hours after methotrexate. Fifty patients are evaluable with respect to response, time to disease progression, and survival. The rate of objective response to chemotherapy was 90%; 52% of the patients had CR, 38% had PR, and 10% had NC. The median numbers of chemotherapy cycles to achieve CR, PR, and NC were five, four, and four, respectively. Twenty-four patients with CR to chemotherapy were pathologically assessed, 22 by multiple biopsies and 2 by mastectomy. Seventy-one percent of the patients were proven to have pathological CR. All patients completing combined therapy thus far are disease free. Nine of 29 patients with stage IIIB disease have relapsed; 7 of 23 with inflammatory histology have relapsed; and 2 of 20 with stage IIIA disease have relapsed.(ABSTRACT TRUNCATED AT 250 WORDS)

We have treated 76 patients with locally advanced breast cancer, 31 with stage IIIA, 41 with stage IIIB, and 4 with stage IV disease, with primary induction chemotherapy including an attempted hormonal synchronization in 70 patients. All were treated to maximum objective clinical response before proceeding to any local therapy. Patients achieving a complete response with a negative repeat biopsy generally received radiation therapy while patients with residual disease, partial response (PR) or no change (NC) status received debulking surgery prior to radiation therapy. Regardless of response to induction chemotherapy, patients received at least 6 additional months of chemotherapy following local therapy. Initial doses of combination chemotherapy were escalated to targeted myelosuppression. The objective response rate to induction chemotherapy was 93% with 49% complete response (CR), 44% PR, and 7% NC. The median numbers of cycles of chemotherapy to achieve a CR, PR, or NC were 5, 3, and 5, respectively. Three patients who currently have PRs are still on chemotherapy with continued tumor regression. Of 37 patients achieving a CR to chemotherapy, 35 were assessed by biopsies to determine pathological evidence of response. Twenty-three of the 37 patients (62%) were proven to be complete responders with negative biopsies. Twenty-four patients have relapsed, 6 with stage IIIA, 16 with stage IIIB, and 2 with stage IV. Five patients have had locoregional relapses alone, 4 locoregional and distant, and 15 distant alone. Median time to progression is 35.9 months for stage IIIA and 34.2 months for stage IIIB. Median survival is 35.3 months for stage IIIB and is indeterminate for stage IIIA. This aggressive primary chemotherapy regimen with hormonal synchronization followed by local therapy appears to provide excellent local control and encouraging early results on systemic disease control.