Monitoring radiotherapy induced tissue changes in localized prostate cancer by multi-parametric magnetic resonance imaging (MP-MRI).

PURPOSE: To evaluate the utility of multi-parametric magnetic resonance imaging (MP-MRI), including dynamic contrast-enhanced MRI and diffusion-weighted MRI, for monitoring tumor tissue changes after volumetric-modulated arc radiotherapy in localized prostate cancer (PCa), and to compare the radiotherapy induced tumor tissue changes between conventional, moderate and extreme hypofractionated groups. Furthermore, we aimed to evaluate if follow-up by MRI has an incremental value compared to the standard care by prostate-specific antigen (PSA) serum level measurement. MATERIALS AND METHODS: Fifty-five men (mean age: 70±5 [SD] years; range: 60-79 years) with biopsy-proven PCa underwent MRI examination before radiotherapy, and at 3 and 12 months after radiotherapy. Pharmacokinetic analysis post-processing platform with dedicated software (Tissue 4D) was used to generate colorized parametric maps of enhancing tumors. The volume transfer constant (Ktrans), reflux constant (Kep), and initial area under curve (iAUC) were calculated from the tumors. Tumor apparent diffusion coefficient (ADC) value was measured on the ADC map. The patients were allocated into three radiotherapy groups: 17 conventional (39×2Gy), 16 moderate (20×3Gy) and 22 extreme hypofractionated (5×7.25Gy) regimen. RESULTS: Sixty lesions were detected in the prostates of the 55 patients. Follow-up MRI showed decreases in tumor size and degree of enhancement. Ktrans, Kep, and iAUC all decreased at 3 months (P<0.001, respectively) and decreased further at 12 months (P<0.001, respectively). ADC increased at 3 months (P<0.001) and increased further at 12 months (P<0.001). There were no significant differences in the percentage changes of the measured MP-MRI parameters of the tumors from baseline to 12 months between the conventional, moderate and extreme hypofractionated regimen groups. CONCLUSION: MP-MRI is a reliable tool for lesion detection and follow-up, providing both qualitative and quantitative data.

Intravenous but not intrathecal central nervous system-directed chemotherapy improves survival in patients with testicular diffuse large B-cell lymphoma.

BACKGROUND: Testicular lymphoma is a rare malignancy affecting mainly elderly men, the majority representing diffuse large B-cell lymphoma (DLBCL). Its relapse rate is higher than that of nodal DLBCL, often affecting the central nervous system (CNS) with dismal prognosis. PATIENTS AND METHODS: We searched for patients with testicular DLBCL (T-DLBCL) involvement from the pathology databases of Southern Finland University Hospitals and the Danish Lymphoma Registry. Clinical information was collected, and outcomes between treatment modalities were evaluated. Progression-free survival (PFS), disease-specific survival (DSS) and overall survival (OS) were assessed using Kaplan-Meier and Cox proportional hazards methods. RESULTS: We identified 235 patients; of whom, 192 were treated with curative anthracycline-based chemotherapy. Full survival data were available for 189 patients. In univariate analysis, intravenous CNS-directed chemotherapy, and irradiation or orchiectomy of the contralateral testis translated into favourable PFS, DSS and OS, particularly among the elderly patients (each p ≤ 0.023). Intrathecal chemotherapy had no impact outcome. In multivariate analyses, the advantage of intravenous CNS-directed chemotherapy (hazard ration [HR] for OS, 0.419; 95% confidence interval [CI], 0.256-0.686; p = 0.001) and prophylactic treatment of contralateral testis (HR for OS, 0.514; 95% CI, 0.338-0.782; p = 0.002) was maintained. Rituximab improved survival only among high-risk patients (International Prognostic Index≥3, p = 0.019). The cumulative risk of CNS progression was 8.4% and did not differ between treatment modalities. CONCLUSION: The results support the use of CNS-directed chemotherapy and prophylactic treatment of the contralateral testis in patients with T-DLBCL involvement. Survival benefit appears resulting from better control of systemic disease rather than prevention of CNS progression.

Correlation between apparent diffusion coefficient value on diffusion-weighted MR imaging and Gleason score in prostate cancer.

OBJECTIVES: To investigate whether diffusion-weighted imaging (DWI) apparent diffusion coefficient (ADC) correlates with prostate cancer aggressiveness and further to compare the diagnostic performance of ADC and normalized ADC (nADC: normalized to non-tumor tissue). PATIENTS AND METHODS: Thirty pre-treatment patients (mean age, 69years; range: 59-78years) with prostate cancer underwent magnetic resonance imaging (MRI) examination, including DWI with three b values: 50, 400, and 800s/mm2. Both ADC and nADC were correlated with the Gleason score obtained through transrectal ultrasound-guided biopsy. RESULTS: The tumor minimum ADC (ADCmin: the lowest ADC value within tumor) had an inverse correlation with the Gleason score (r=-0.43, P<0.05), and it was lower in patients with Gleason score 3+4 than in those with Gleason score 3+3 (0.54±0.11×103mm2/s vs. 0.64±0.12×10-3mm2/s, P<0.05). Both the nADCmin and nADCmean correlated with the Gleason score (r=-0.52 and r=-0.55, P<0.01; respectively), and they were lower in patients with Gleason score 3+4 than those with Gleason score 3+3 (P<0.01; respectively). Receiver operating characteristic (ROC) analysis showed that the area under the ROC curve was 0.765, 0.818, or 0.833 for the ADCmin, nADCmin, or nADCmean; respectively, in differentiating between Gleason score 3+4 and 3+3 tumors. CONCLUSION: Tumor ADCmin, nADCmin, and nADCmean are useful markers to predict the aggressiveness of prostate cancer.

Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial.

BACKGROUND: We have previously shown the prognostic importance of tumor-infiltrating lymphocytes (TILs) in newly diagnosed triple-negative breast cancer (TNBC) using tumor samples from a large clinical trial cohort. In this study, we aimed to validate these findings and also investigate associations with trastuzumab benefit in HER2-overexpressing disease (HER2+). PATIENTS AND METHODS: A prospective-retrospective study was conducted using samples from the FinHER adjuvant, phase III trial that enrolled 1010 early-stage BC patients, 778 of whom were HER2-nonamplified. Those with HER2+ disease (n = 232) were randomized to 9 weeks of trastuzumab or no trastuzumab in addition to chemotherapy. Two pathologists independently quantified stromal TILs in 935 (92.6%) available slides. The primary end point of distant disease-free survival (DDFS) and interactions with trastuzumab were studied in Cox regression models. RESULTS: Confirming our previous findings, in TNBC (n = 134) each 10% increase in TILs was significantly associated with decreased distant recurrence in TNBC; for DDFS the hazard ratio adjusted for clinicopathological factors: 0.77; 95% confidence interval (CI) 0.61-0.98, P = 0.02. In HER2+ BC (n = 209), each 10% increase in lymphocytic infiltration was significantly associated with decreased distant recurrence in patients randomized to the trastuzumab arm (DDFS P interaction = 0.025). CONCLUSIONS: Higher levels of TILs present at diagnosis were significantly associated with decreased distant recurrence rates in primary TNBC. These results confirm our previous data and further support that TILs should be considered as a robust prognostic factor in this BC subtype. We also report for the first time an association between higher levels of TILs and increased trastuzumab benefit in HER2+ disease. Further research into why some TN and HER2+ BCs can or cannot generate a host antitumor immune response and how trastuzumab can favorably alter the immune microenvironment is warranted.

The quality of life and social support in significant others of patients with breast cancer--a longitudinal study.

The purpose of this study was to evaluate prospectively the quality of life (QOL) and received social support from the network and nurses in significant others of breast cancer patients and identify factors predicting negative changes in their QOL within 6 months. The quasi-random longitudinal study conducted for the breast cancer patients and their significant others. Patients were quasi-randomised to supportive intervention group (via telephone at baseline and face-to-face at follow-up) and control group. This paper reports results of significant others (N = 165). The QOL data were collected using the Quality of Life Index - Cancer Version (QLI-CV). Support from network in aid increased the risk of negative changes in health and functioning. Retired significant others had a greater risk of more negative changes in their global and in socio-economic QOL than other. Relatives had a smaller risk to negative changes both in their global and in their family QOL than spouses/partners/boyfriends of patients with breast cancer. QOL of the significant others should be supported more intensively and enhanced by the use of individually tailored methods on the basis of significant others and their family needs.

Effect of exercise on bone structural traits, physical performance and body composition in breast cancer patients--a 12-month RCT.

In this 12-month RCT, we examined whether aerobic impact exercise training (3x/week) could facilitate breast cancer survivors' recovery by enhancing their bone structural strength, physical performance and body composition. After the adjuvant chemo- and/ or radiotherapy, 86 patients were randomly assigned into the training or control group. Structural bone traits were assessed with pQCT at the tibia and with DXA at the femoral neck. Agility (figure-8 running), jump force and power (force platform), grip strength and cardiovascular fitness (2-km walk test) were also assessed. Training effects on outcome variables were estimated by two-way factorial ANCOVA using the study group and menopausal status as fixed factors. Bone structural strength was better maintained among the trainees. At the femoral neck, there was a small but significant 2% training effect in the bone mass distribution (p=0.05). At the tibial diaphysis, slight 1% to 2% training effects (p=0.03) in total cross-sectional area and bone structural strength were observed (p=0.03) among the postmenopausal trainees. Also, 3% to 4% training effects were observed in the figure-8 running time (p=0.03) and grip strength (p=0.01). In conclusion, vigorous aerobic impact exercise training has potential to maintain bone structural strength and improve physical performance among breast cancer survivors.

Toxicity in patients receiving adjuvant docetaxel + hormonal treatment after radical radiotherapy for intermediate or high-risk prostate cancer: a preplanned safety report of the SPCG-13 trial.

BACKGROUND: Radical radiotherapy (RT) combined with androgen deprivation therapy is currently the standard treatment for elderly patients with localized intermediate- or high-risk prostate cancer (PC). To increase the recurrence-free and overall survival, we conducted an adjuvant, randomized trial using docetaxel (T) in PC patients (Scandinavian Prostate Cancer Group trial 13). METHODS: The inclusion criteria are the following: men >18 and ≤75 years of age, WHO/ECOG performance status 0--1, histologically proven PC within 12 months before randomization and one of the following: T2, Gleason 7 (4+3), PSA >10; T2, Gleason 8--10, any PSA; or any T3 tumors. Neoadjuvant/adjuvant hormone therapy is mandatory for all patients. The patients were randomized to receive six cycles of T (75 mgm(-2) d 1. cycle 21 d) or no docetaxel after radical RT (with a minimum tumor dose of 74 Gy). This study identifier number is NTC 006653848 (http://www.clinicaltrials.org). RESULTS: In this preplanned safety analysis of 100 patients, T treatment induced grade (G) 3 adverse events (AEs) in 15 patients (30%) and G4 AEs in 30 patients (60%), mainly due to bone marrow toxicity. Neutropenia G3--4 was observed in 72% of the patients, febrile neutropenia was found in 24% of patients, neutropenic infection in 10% of patients and G3 infection without neutropenia in 4% of patients. Nonhematological G3 AEs were rare: anorexia, diarrhea, mucositis, nausea, pain (1 patient each) and fatigue (5). Other severe serious AEs related to T were pulmonary embolism and renal failure. However, only three patients discontinued T before completing the planned six cycles. No deaths had occurred. No patients in the control arm experienced G3--4 toxicities at 12 weeks after the randomization. CONCLUSIONS: Adjuvant docetaxel chemotherapy after radiotherapy has a higher frequency of neutropenia than previous studies on patients with metastatic disease. Otherwise, the treatment was quite well tolerated.

Very high quantitative tumor HER2 content and outcome in early breast cancer.

BACKGROUND: It is unknown how a very high tumor total HER2 (human epidermal growth factor receptor-2) content (H2T) influences outcome in early breast cancer treated with adjuvant trastuzumab plus chemotherapy. PATIENTS AND METHODS: H2T was measured using a novel quantitative assay (HERmark(®)) from formalin-fixed tumor tissue of 899 women who participated in the FinHer trial (ISRCTN76560285). In a chromogenic in situ hybridization (CISH) test, 197 (21.9%) patients had HER2-positive cancer and were randomly assigned to receive trastuzumab or control. RESULTS: Cancer H2T levels varied 1808-fold. High H2T levels were correlated with a positive HER2 status by CISH (P < 0.0001). A nonlinear association was present between H2T and the hazard of distant recurrence in a subpopulation treatment effect pattern plot analysis in CISH-positive disease. Patients with very high H2T (defined by ≥22-fold the median of HER2-negative cancers; 13% of CISH-positive cancers) did not benefit from adjuvant trastuzumab [hazard ratio (HR) 1.23; 95% confidence interval (CI) 0.33-4.62; P = 0.75], whereas the rest of the patients with HER2-positive disease by CISH (87%) did benefit (HR 0.52; 95% CI 0.28-1.00; P = 0.050). CONCLUSION: Patients with HER2-positive breast cancer with very high tumor HER2 content may benefit less from adjuvant trastuzumab compared with those whose cancer has more moderate HER2 content.

Texture analysis on MRI images of non-Hodgkin lymphoma.

The aim here is to show that texture parameters of magnetic resonance imaging (MRI) data changes in lymphoma tissue during chemotherapy. Ten patients having non-Hodgkin lymphoma masses in the abdomen were imaged for chemotherapy response evaluation three consecutive times. The analysis was performed with MaZda texture analysis (TA) application. The best discrimination in lymphoma MRI texture was obtained within T2-weighted images between the pre-treatment and the second response evaluation stage. TA proved to be a promising quantitative means of representing lymphoma tissue changes during medication follow-up.

Soluble immunological parameters and early prognosis of renal cell cancer patients.

In local or metastatic cancer, a prognostic tumour marker could be a valuable tool in the selection of different treatments. In renal cell cancer (RCC) no such markers have been available. We therefore evaluated the association between several pretreatment serum markers, tumour classification and short term survival in RCC patients. Serum samples were collected before surgery and three months thereafter from 24 RCC patients. Interleukin-6 (IL-6), IL- 12, soluble IL-2 receptor (sIL-2R) and intercellular adhesion molecule-1 (sICAM-1) were measured in serum samples using specific commercial enzyme immunoassay kits. Serum IL-6, sIL-2R and sICAM-1 levels before nephrectomy were significantly higher in non-local tumours than in local ones (mean IL-6 53 pg/ml versus 6.3 pg/ml, and sICAM-1 443 ng/ml versus 290 ng/ml, sIL-2R 3779 pg/ml versus 1796 pg/ml). In contrast, IL-12 levels were higher in local tumours (148 versus 102 pg/ml) and the levels increased significantly (P < 0.005) after removal of the primary tumour in patients with local disease. All patients with local tumours had normal IL-6 values, while only one with a non-local tumour had IL-6 levels below 10 pg/ml. In addition, IL-6 and sICAM-1 levels before operation were significantly higher in patients with short (less than one year) survival (p=0.007 to IL-6 and p=0.006 to sICAM-1). In contrast, patients with shorter survival had significantly lower IL-12 (p=0.03) levels. Our findings suggest that RCC induces changes in several immunological parameters. These soluble immunological factors, IL-6, IL-12, sIL-2R and sICAM-1, might have a role as prognostic factors in RCC.

Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer.

PURPOSE: The combination of interferon alfa-2a (IFNalpha2a) plus vinblastine (VLB) induces objective tumor responses in patients with advanced renal cell cancer. However, no prospective randomized trial has shown that this treatment prolongs overall survival. We compared overall survival after treatment with IFNalpha2a plus VLB versus VLB alone in patients with advanced renal cell cancer. PATIENTS AND METHODS: We prospectively randomized 160 patients with locally advanced or metastatic renal cell cancer to receive either VLB alone or IFNalpha2a plus VLB for 12 months or until progression of disease. In both groups, VLB was administered intravenously at 0.1 mg/kg every 3 weeks, and in the combination group IFNalpha2a was administered subcutaneously at 3 million units three times a week for 1 week, and 18 million units three times a week thereafter for the second and subsequent weeks. For patients unable totolerate IFNalpha2a at 18 million units per injection, the dose was reduced to 9 million units. RESULTS: Median survival was 67.6 weeks for the 79 patients receiving IFNalpha2a plus VLB and 37.8 weeks for the 81 patients treated with VLB (P =.0049). Overall response rates were 16. 5% for patients treated with IFNalpha2a plus VLB and 2.5% for patients treated with VLB alone (P =.0025). Treatment with the combination was associated with constitutional symptoms and abnormalities in laboratory parameters, but no toxic deaths were reported. CONCLUSION: The combination of IFNalpha2a plus VLB is superior to VLB alone in the treatment of patients with locally advanced or metastatic renal cell carcinoma. This is the first study to demonstrate that survival can be prolonged by using IFNalpha2a for these patients.

Single-agent gemcitabine: an active and better tolerated alternative to standard cisplatin-based chemotherapy in locally advanced or metastatic non-small cell lung cancer.

This randomized study was designed to determine the response rates, survival and toxicities of single-agent gemcitabine (GEMZAR) and a combination of cisplatin/etoposide in chemonaive patients with non-resectable, locally advanced or metastatic non-small cell lung cancer (NSCLC). Gemcitabine 1000 mg/m2 was given as a 30-min intravenous infusion on days 1, 8, 15 of a 28-day cycle, cisplatin 100 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1 (following cisplatin), 2 and 3. Major eligibility criteria included histologically confirmed non-small cell lung cancer, measurable disease, Zubrod performance status 0-2, no prior chemotherapy, no prior radiation of the measured lesion, and no CNS metastases. One hundred and forty-seven patients were enrolled, 72 in the gemcitabine and 75 in the cisplatin/etoposide arm. Patient characteristics were well-matched across both arms. Sixty-seven gemcitabine and 72 cisplatin/etoposide patients were qualified for efficacy analysis. There were no complete responses, but 12 partial responses in the gemcitabine arm and 11 in the cisplatin/etoposide arm, for protocol-qualified response but 12 partial responses in the gemcitabine arm and 11 in the cisplatin/etoposide arm, for protocol-qualified response rates of 17.9% (95%, CI: 9.6-29.2%,) and 15.3% (95% CI: 7.9-25.7%,), respectively. Median survival times were 6.6 months (95% CI: 4.9-7.3 months) for gemcitabine and 7.6 months (95% CI: 5.4-9.3 months) for cisplatin/etoposide. The 1-year survival probability estimate was 26% for gemcitabine and 24% for cisplatin/etoposide. There were no statistically significant between-group differences in time-to-event measures, but patients in the gemcitabine arm had a greater probability of achieving a tumour response after 2 months (probability estimate: 8 vs. 0%,) and of the response lasting at least 6 months (73 vs. 45%,). Clinical and haematologic toxicity was more pronounced in the cisplatin/etoposide arm. Quality-of-life measures indicated a significant worsening of symptomatology in the cisplatin/etoposide arm for hair loss, nausea and vomiting, and appetite loss. This randomized study provides further evidence that single-agent gemcitabine is an active and effective therapy for patients with non-resectable. locally advanced or metastatic NSCLC and good performance status, and that it is better tolerated than the combination cisplatin/ etoposide.

Evaluating the response to antioestrogen toremifene treatment in DMBA induced rat mammary carcinoma.

Evaluation of the treatment response to hormonal therapy in experimental mammary carcinoma models usually consists of recording the changes in tumour volume or in number of tumours. We performed quantitative histology on dimethylbenz[a]anthracene(DMBA) induced rat mammary carcinoma treated with the antioestrogen toremifene. The inhibition of growth of the treated regressing tumours was not only associated with inhibition of mitosis and reduction of the neoplastic epithelium, but toremifene seemed to reduce all main tissue components. The percentual area fractions of epithelium and stroma were equal in the untreated and the treated tumours. The estimated absolute volumes of epithelium, stroma and glandular luminae as well as the mitotic index were significantly reduced during toremifene treatment in those tumours which were responding by regression to the treatment. The findings indicate growth inhibiting effect on both epithelium and stroma or on interactions between epithelium and stroma. Adding quantitative histology to the gross response analysis in experimental animal models is feasible and may elucidate the mechanisms of action of a novel hormonal treatment.

Correlation between lectin binding and clinical factors in seminoma patients.

The binding of a panel of lectins to histological sections of seminomas was studied. The findings were correlated with different clinical parameters. Concanavalin A and wheat germ agglutinin stained all seminomas whereas horse gram (DBA) and peanut agglutinin did not stain the tumor cells. A varying staining pattern was found with lectins from castor bean (RCA I), soy bean (SBA) and gorse (UEA I) indicating a heterogeneity of the tumor cell population. In the seminomas that were derived from undescended testis there were more cases that showed positive staining with soy bean agglutinin, which shows that the intra-abdominal location of the seminoma might cause changes in the cellular metabolism resulting in glycoconjugates different from those in descended tumors. No correlation was found between the lectin staining and the prognosis, stage or metastasis of the tumor.

Tumor localization with 18F-2-fluoro-2-deoxy-D-glucose: comparative autoradiography, glucose 6-phosphatase histochemistry, and histology of renally implanted sarcoma of the rat.

Rous sarcoma cells were implanted into the kidney of rats. After 5 days of growth the renal tumor was used for comparing histology with glucose 6-phosphatase (G6Pase) enzyme histochemistry (EHC) and 18F-fluoro-2-deoxyglucose (FDG) auroradiography (ARG). It was found that the regions of the kidney tumor that had retained normal kidney structures were devoid of FDG, whereas there was histochemical staining of normal cortical areas. Regions of tumor growth, on the other hand, retained FDG and lacked G6Pase. Necrotic areas did not accumulate FDG. There was a dramatic decrease in the areas of G6Pase activity as a result of tumor infiltration in the kidney. The results show that FDG, currently being evaluated as a tumor detecting radiopharmaceutical indeed accumulates into areas of vital malignant growth, and they indicate that FDG positron emission tomographic (PET) images reveal the true anatomic location of malignant tissue.

Occurrence of nuage in fetal human germ cells.

Germ cells of human fetuses aged 7-13 weeks were studied. Dense fibrous material called nuage was found in the cytoplasm of human fetal germ cells. The nuage increased in frequency in the germ cells during the interval studied. In oogonia the nuage occurred much more frequently than in spermatogonia and the frequency of nuage in oogonia increased earlier than in spermatogonia. The number of nuage was continuously at a higher level in oogonia than in spermatogonia. It is suggested that these findings support the theory that the nuage may act as a germ cell determinant.