Sick leave and disability pension among Swedish testicular cancer survivors according to clinical stage and treatment.

PURPOSE: To investigate if testicular cancer survivors (TCSs) have a higher incidence of work loss compared with the population, accounting for stage, treatment and relapse. MATERIAL AND METHODS: A cohort of 2146 Swedish TCSs diagnosed 1995-2007 (seminoma n = 926, non-seminoma n = 1220) was identified in the SWENOTECA (Swedish-Norwegian Testicular Cancer Group) register, and matched 1:4 to population comparators. Prospectively recorded work loss data (both before and after diagnosis) were obtained from national registers through September 2013. Adjusted relative risks (RR) and 95% confidence intervals (CI) of sick leave and/or disability pension were calculated annually and overall with Poisson- and Cox regression, censoring at relapse. The mean number of annual work days lost was also estimated. RESULTS: TCSs were at a modestly increased annual risk of work loss up to the third year of follow-up (RR3rd year 1.25, 95% CI 1.08, 1.43), attributed to a more pronounced risk among extensively treated patients (4 chemotherapy courses: RR3rd year 1.60, 95% CI 1.19, 2.15; > 4 courses: RR3rd year 3.70, 95% CI 2.25, 6.11). Patients on surveillance or limited treatment (radiotherapy, 1-3 chemotherapy courses) did not have an increased risk of work loss beyond the first year. TCSs receiving > 4 chemotherapy courses had higher mean number of annual days of work loss up to the 10th year post-diagnosis, and a five-fold risk of disability pension (RR 5.16, 95% CI 2.00, 10.3). CONCLUSION: Extensively treated TCSs, but not those on surveillance or limited treatment, are at increased risk of work loss long-term, not explained by relapse. These patients may benefit from early rehabilitation initiatives.

Treatment of oral mucositis pain following radiation therapy for head-and-neck cancer using a bioadhesive barrier-forming lipid solution.

PURPOSE: CAM2028, a vehicle that forms a bioadhesive lipid barrier when applied to the oral mucosa, was developed as a carrier system for local delivery of benzydamine, an NSAID used for pain relief in oral mucositis. This trial compared the analgesic effect of CAM2028 plus benzydamine (CAM2028-benzydamine) with unmedicated CAM2028 (CAM2028-control) for the treatment of oral mucositis in patients with head-and-neck cancer. METHODS: Thirty-eight study participants were enrolled during their 3rd to 4th week of radiation therapy. Participants were required to have symptomatic oral mucositis (WHO Grade 2 or above) at screening and pain scores of at least 6 on an 11-point Likert scale at screening and on each day before treatment with study medication. After undergoing radiation, patients were administered a single dose of CAM2028-control or CAM2028-benzydamine 2 days apart, in a randomized crossover fashion. Pain was assessed over the following 8 h. RESULTS: With both treatments, patients experienced a mean 40 % decrease in pain intensity at 6 h (the primary study endpoint). Both treatments resulted in significant pain relief within 5 min of application that was evident during the entire 8-h assessment period. There was no difference in pain relief between the two interventions at any time point. Both treatments were safe and well tolerated. CONCLUSIONS: CAM2028-benzydamine and CAM2028-control were both efficacious in reducing pain in patients with oral mucositis related to radiation therapy for head-and-neck cancer. Analgesic effects of both medications were immediate, clinically significant, and persistent for up to 8 h.

High-dose chemotherapy with autologous stem cell support in patients with metastatic non-seminomatous testicular cancer - a report from the Swedish Norwegian Testicular Cancer Group (SWENOTECA).

BACKGROUND: The SWENOTECA IV protocol from 1995 is a prospective population-based study in metastatic non-seminomatous germ cell testicular cancer (NSGCT), designed for early identification of patients with poor response to standard cisplatin-based chemotherapy. A slow tumor marker decline (HCG T(½) > 3 days, AFP T(½) > 7 days) after BEP or BEP plus ifosfamide was regarded as poor response. The aim of this study was to present survival and toxicity data for patients treated with high-dose chemotherapy (HDCT) within the SWENOTECA IV cancer care program. MATERIAL AND METHODS: In total 882 adult men diagnosed with metastatic NSGCT between July 1995 and June 2007 in Sweden and Norway (except one center) were included in SWENOTECA IV and treated accordingly. Among these, 55 men (6.2%) were treated with HDCT according to three different indications in the protocol: A) poor response to standard-dose intensified chemotherapy (BEP plus ifosfamide); B) vital cancer at surgery after intensified chemotherapy; and C) selected relapses after previous chemotherapy. In situation A and C two HDCT cycles and in situation B one HDCT cycle was recommended. Situation A was the reason for HDCT in 36 patients, B in seven and C in 12 patients. The first HDCT cycle consisted of carboplatin 28 × (GFR + 25) mg, cyclofosfamide 6000 mg/m(2) and etoposide 1750 mg/m(2), administered over four days. In cycle two, etoposide was replaced by tiotepa 480 mg/m(2). RESULTS: After a median follow-up of 7.5 years, overall survival was 72%, 100% and 58%, while failure-free survival was 64%, 71% and 42% in situation A, B and C, respectively. Three patients (5.5%) died during HDCT (renal failure or intracerebral hemorrhage). Nephrotoxicity was the most common non-hematological grade 4 toxicity (n = 5, 9%). CONCLUSION: The population-based SWENOTECA strategy, selecting patients who do not respond adequately to primary standard-dose chemotherapy for immediate treatment intensification with HDCT, is feasible and might be advantageous.

Testicular-cancer survivors experience compromised language following chemotherapy: findings in a Swedish population-based study 3-26 years after treatment.

BACKGROUND: Studies suggest an increased risk for compromised cognitive function among cancer survivors. It is unclear to what extent chemotherapy is the cause and how the dysfunction, when present, affects everyday life. The objective was to study self-reported behaviours that may depend on cognitive function, among testicular-cancer survivors who received various cycles of cisplatin-based chemotherapy by comparing them with those who did not. MATERIAL AND METHODS: We identified 1173 eligible men diagnosed with non-seminomatous testicular cancer treated according to the national cancer-care programs SWENOTECA I-IV between 1981 and 2004. During an 18-month qualitative phase we constructed a study-specific questionnaire including questions about specific activities and behaviour in everyday life. RESULTS: We obtained information from 960 of 1173 (82%) testicular-cancer survivors diagnosed on average 11 years previously. The prevalence of "saying similar but incorrect words" at least once a week was 5% among those having received no chemotherapy versus 16% among those having received five or more cycles, giving a prevalence ratio ("relative risk", RR) of 3.3 with a 95% confidence interval of 1.5 to 7.1. The corresponding figure for "saying words in the wrong order" was 3.1 (1.7-5.8), for "difficulties understanding what other people mean" 3.1 (1.3-7.7), for "saying words other than planned" 2.2 (1.1-4.5) and for "difficulties completing sentences" 2.0 (1.0-3.6). The relative risks for those with a low level of education ranged between 4.9 (1.6-14.9) and 15.3 (1.9-120.5). CONCLUSION: Testicular-cancer survivors in Sweden who have received five or more cycles of cisplatin-based chemotherapy experience an increased incidence of long-term compromised language; the effect is primarily seen among men with a low level of education.

Estrogen receptor α single nucleotide polymorphism modifies the risk of azoospermia in childhood cancer survivors.

OBJECTIVE: Cancer treatment in childhood leads to permanent azoospermia in a significant number of boys and those who are diagnosed with cancer before puberty do not have the option of pretreatment cryopreservation of spermatozoa. However, there is an interindividual variation in the sensitivity to gonadotoxic effects of cancer therapy, which probably is due to genetic factors. Identification of genetic markers for the risk of azoospermia in childhood cancer survivors may help in identifying boys to whom testicular cryopreservation should be offered. METHODS: Fifty-one single nucleotide polymorphisms (SNPs) being markers of 12 different haplotype blocks in the androgen receptor, estrogen receptor (ER) α and ER ß genes were examined in 127 adult childhood cancer survivors. RESULTS: In ERα, markers of one specific haplotype block (rs2207396, rs9340958, rs9340978) were associated with an increased risk of azoospermia. Compared with those with the GG genotype, patients being heterozygous for the A allele in rs2207396 had a significantly increased risk of azoospermia [odds ratio (OR): 3.8; 95% confidence interval: 1.5-9.5; P=0.008], this OR being even higher in the subgroup treated with alkylating drugs (OR: 8.8; 95% confidence interval: 2.1-36; P=0.004). In this subgroup, 48% of the patients carried the A allele of rs2207396, this proportion being 70% among the azoospermic patients. CONCLUSION: Use of genetic markers of high risk of posttreatment azoospermia may, in the future, prove an important clinical tool in selection of boys to whom preservation of testicular tissue before cancer therapy should be offered.

Sexual function in men treated for testicular cancer.

INTRODUCTION: Testicular germ cell cancer (TGCC) patients may be at risk of developing sexual dysfunction after treatment. AIM: The aim of this study was to assess the prevalence of sexual dysfunctions in TGCC patients 3 to 5 years after treatment, and relate findings to biochemical hypogonadism, treatment intensity, and the expected prevalence in the Swedish male population. METHODS: A questionnaire study on 129 consecutive TGCC patients 3 to 5 years post-treatment was performed. Comparators were an age-matched nationally representative group of men (N = 916) included in a study on sexual life in Sweden. MAIN OUTCOME MEASURES: Sexual functions (including erectile dysfunctional distress), time since last intercourse, sexual satisfaction, and experience of sexological treatment seeking were assessed using the same questions used in the epidemiological study on sexual life in Sweden. The findings in TGCC patients were correlated to biochemical signs of hypogonadism and type of oncological treatment: Surveillance, adjuvant chemotherapy, adjuvant radiotherapy, or standard doses of chemotherapy. RESULTS: A higher proportion of TGCC patients than comparators were likely to report low sexual desire (odds ratio [OR] 6.7 [95% confidence interval {CI} 2.1-21]) as well as erectile dysfunction (OR 3.8 [95% CI 1.4-10]). No significant differences were observed regarding erectile dysfunctional distress, change of desire over time, interest in sex, premature or delayed ejaculation, time since last intercourse, need for or receiving sexual advice, or sexual satisfaction. Hypogonadism did not predict erectile dysfunction (OR 1.1 [95% CI 0.26-4.5]) or low sexual desire (OR 1.2 [95% CI 0.11-14]). Treatment modality had no obvious impact on sexual function. CONCLUSION: Men treated for testicular cancer had higher risk of having low sexual desire and erectile dysfunction 3 to 5 years after completion of therapy than comparators. These sexual dysfunctions were not significantly associated with treatment intensity or hypogonadism.

Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) study.

BACKGROUND: The definition and role of bulky disease in young patients (ie, aged 18-60 years) with good-prognosis diffuse large-B-cell lymphoma (DLBCL), who have been treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-like chemotherapy with or without rituximab, remain controversial. We aimed to assess the effect of maximum tumour diameter (MTD) in these patients. METHODS: Patients from the MInT (Mabthera International Trial Group) study were eligible. We analysed event-free (EFS) and overall survival (OS) after CHOP-like chemotherapy with or without rituximab, according to MTD, by Martingale residual analyses and Cox regression models. Radiotherapy was given to sites of primary bulky disease according to national standards, and to primary extranodal disease at physician discretion. The primary endpoint was EFS and the secondary endpoint was OS. Analyses were by intention to treat. FINDINGS: Of the 824 patients enrolled in the MInT study, the informed-consent form of one patient was missing, leaving 823 patients evaluable for intention-to-treat analysis. Data on MTD of involved sites were available for 802 patients. Martingale residual analysis showed an adverse prognostic effect of MTD on EFS and OS, which increased linearly. In a multivariable analysis with MTD as a linear regression variable, the effect of MTD was significant after CHOP-like treatment alone for EFS (hazard ratio 1.090 [95% CI 1.051-1.130], p < 0.0001) and OS (1.119 [1.057-1.184], p = 0.0001), and after CHOP-like treatment and rituximab for OS (1.089 [1.003-1.183], p = 0.043), but not for EFS (1.044 [0.991-1.099], p=0.103). For CHOP-like treatment alone, 3-year EFS ranged from 78.2% (MTD < 5.0 cm, 95% CI 68.3-85.4) to 41.3% (MTD > or = 10.0 cm, 31.8-50.4). For CHOP-like treatment and rituximab, 3-year EFS ranged from 83.2% (MTD < 5.0 cm, 72.8-89.9) to 72.7% (MTD > or = 10.0 cm, 63.8-79.7). With CHOP-like treatment alone, 3-year OS decreased from 92.9% (MTD < 5.0 cm, 84.9-96.8) to 73.5% (MTD > or = 10.0 cm, 63.9-81.0); for CHOP-like treatment and rituximab, 3-year OS decreased from 98.0% (MTD < 5.0 cm, 92.2-99.5) to 85.2% (MTD > or = 10.0 cm, 77.0-90.6). For CHOP-like treatment, any cut-off point between 5.0 cm and 10.0 cm separated two populations with a significant EFS difference (p < 0.0001 for all log-rank tests) and OS difference (p < or = 0.003 for all log-rank tests). For CHOP-like treatment and rituximab, only a cut-off point of 10.0 cm separated two populations with a significant EFS difference (log-rank p = 0.047), but any cut-off point of 6.0 cm or more separated two populations with a significant OS difference (log-rank p values 0.0009-0.037). INTERPRETATION: Rituximab decreased, but did not eliminate the adverse prognostic effect of MTD in young patients with good-prognosis DLBCL. Due to the linear prognostic effect of MTD on outcome, arbitrary cut-off points for bulky disease can be set between 5.0 cm and 10.0 cm, depending on clinical considerations. Based on this study, a cut-off point of 10.0 cm might be a suitable margin in the rituximab era to delineate those patients with bulky disease.

Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma.

In order to identify genes associated with primary chemotherapy-resistance, gene expression profiles (GEP) in tumour tissue from 37 patients with de novo diffuse large B-cell lymphoma (DLBCL), stage II-IV, either in continuous complete remission (n = 24) or with progressive disease during primary treatment (n = 13), were examined using spotted 55K oligonucleotide arrays. Immunohistochemistry was used for confirmation at the protein level. The top 86 genes that best discriminated between the two cohorts were chosen for further analysis. Only seven of 86 genes were overexpressed in the refractory cohort, e.g. RABGGTB and POLE, both potential targets for drug intervention. Seventy-nine of 86 genes were overexpressed in the cured cohort and mainly coded for proteins expressed in the tumour microenvironment, many of them involved in proteolytic activity and remodelling of extra cellular matrix. Furthermore, major histocompatibility complex class I molecules, CD3D and ICAM1 were overexpressed, indicating an enhanced immunological reaction. Immunohistochemistry confirmed the GEP results. The frequency of tumour infiltrating lymphocytes, macrophages, and reactive cells expressing ICAM-1, lysozyme, cathepsin D, urokinase plasminogen activator receptor, signal transducer and activator of transcription 1, and galectin-3 was higher in the cured cohort. These findings indicate that a reactive microenvironment has an impact on the outcome of chemotherapy in DLBCL.

A subset of CD5- diffuse large B-cell lymphomas expresses nuclear cyclin D1 with aberrations at the CCND1 locus.

In 231 diffuse large B-cell lymphomas, the expression of cyclin D1 and CD5 was evaluated. All cases were CD5-. Ten (4.3%) were positive for cyclin D1 and were subjected to fluorescence in situ hybridization at the CCND1 locus. One case showed the t(11;14). In another case, the telomeric probe signal for cyclin D1 was lost in most tumor cells, and in a small proportion of the cells, there were fluorescence signals indicative of the t(11;14). Two other cases displayed additional cyclin D1 signals in the absence of the t(11;14). All cases but 1 were positive for bcl-6 or MUM1, disfavoring the possibility of misdiagnosed blastoid variants of CD5- mantle cell lymphomas. Thus, contrary to the current view, there seems to exist a certain number of cyclin D1+ and CD5- diffuse large B-cell lymphomas, some of which have structural aberrations at the CCND1 locus, including the t(11;14).

CD40 expression identifies a prognostically favourable subgroup of diffuse large B-cell lymphoma.

In order to confirm our earlier findings of the prognostic effects of CD23 and CD40 expression in diffuse large B-cell lymphoma (DLBCL), possibly due to association with the germinal center (GC) phenotype and/or an increased autologous tumour response, tumour specimens from 125 patients with de novo DLBCL were investigated for immunohistochemical expression of CD23, CD40, BCL6, CD10, MUM1, CD4 and CD8. CD40 was positive in 64% and was associated with improved overall survival (p = 0.03). A GC phenotype was present in 47%, and was also associated with a better overall survival (p = 0.006) but did not correlate with CD40-expression. There was no correlation between amount of tumour infiltrating T-cells and CD40-positivity. CD23 was positive in 10% and expression did not correlate with prognosis. In conclusion, the prognostic effect of CD40 expression was confirmed, but did not correlate with GC-phenotype or T-cell infiltration.

Androgen receptor gene CAG and GGN repeat lengths as predictors of recovery of spermatogenesis following testicular germ cell cancer treatment.

Spermatogenesis is an androgen-regulated process that depends on the action of androgen receptor (AR). Sperm production may be affected in men treated for testicular cancer (TC), and it is important to identify the factors influencing the timing of spermatogenesis recovery following cancer treatment. It is known that the CAG and GGN repeat numbers affect the activity of the AR; therefore, the aim of this study is to investigate if the CAG and GGN polymorphisms in the AR gene predict recovery of sperm production after TC treatment. TC patients (n = 130) delivered ejaculates at the following time points: postorchiectomy and at 6, 12, 24, 36, and 60 months posttherapy (T0, T6, T12, T24, T36, and T60). The CAG lengths were categorized into three groups, <22 CAG, 22-23 CAG, and >23 CAG, and the GGN tracts were also categorized into three groups, <23 GGN, 23 GGN, and >23 GGN. At T12, men with 22-23 CAG presented with a statistically significantly (P = 0.045) lower sperm concentration than those with other CAG numbers (8.4 × 106 ml-1 vs 16 × 106 ml-1 ; 95% CI: 1.01-2.65). This association was robust to omitting adjustment for treatment type and sperm concentration at T0 (P = 0.021; 3.7 × 106 ml-1 vs 10 × 106 ml-1 ; 95% CI: 1.13-4.90). The same trends were observed for total sperm number. The least active AR variant seems to be associated with a more rapid recovery of spermatogenesis. This finding adds to our understanding of the biology of postcancer therapy recovery of fertility in males and has clinical implications.

Dose-fractionated radioimmunotherapy in non-Hodgkin's lymphoma using DOTA-conjugated, 90Y-radiolabeled, humanized anti-CD22 monoclonal antibody, epratuzumab.

PURPOSE: Fractionated radioimmunotherapy may improve therapeutic outcome by decreasing heterogeneity of the dose delivered to the tumor and by decreasing hematologic toxicity, thereby allowing an increased amount of radionuclide to be administered. Because humanized anti-CD22 epratuzumab can be given repeatedly, a single-center study was conducted to establish the feasibility, safety, optimal dosing, and preliminary efficacy of weekly administrations of 90Y-labeled 1,4,7,10-tetra-azacyclodecane-N,N',N'',N'''-tetraacetic acid-conjugated epratuzumab. EXPERIMENTAL DESIGN: Cohorts of three to six patients with B-cell lymphoma received 185 MBq/m2 [90Y]epratuzumab with unconjugated epratuzumab (total protein dose 1.5 mg/kg) once weekly for two to four infusions, with [(111)In]epratuzumab coadministered at first infusion for scintigraphic imaging and dosimetry. RESULTS: Sixteen patients received treatment without significant infusional reactions. The overall objective response rate was 62% (95% confidence interval, 39-86%) in both indolent (75%) and aggressive disease (50%). Complete responses (CR/CRu) occurred in 25% of patients and were durable (event-free survival, 14-41 months). Two patients receiving four infusions had hematologic dose-limiting toxicity. Serum epratuzumab levels increased with each weekly dose. Of 13 patients with tumor cell CD22 expression determined by flow cytometry, seven of eight with strongly positive results had objective responses, versus one of five with negative or weakly positive results (P = 0.032). CONCLUSIONS: Radioimmunotherapy with weekly 185 MBq/m2 [90Y]epratuzumab achieved a high objective response rate (62%) across lymphoma subtypes, including durable CRs. The findings that three weekly infusions (555 MBq/m2, total dose) can be administered safely with only minor toxicity, that antibody levels increased during treatment weeks, and that therapeutic response predominantly occurs in patients with unequivocal CD22 tumor expression provide guidance for future studies.

The SWENOTECA group: A good example of continuous binational and multidisciplinary collaboration for patients with testicular cancer in Sweden and Norway.

OBJECTIVE: The aim of this article is to present the Swedish and Norwegian Testicular Cancer Group (SWENOTECA), with an emphasis on the history of SWENOTECA, organization, results and current status. MATERIALS AND METHODS: SWENOTECA was founded in 1981 as a binational organization open to hospitals in Sweden and Norway treating testicular cancer. It has since published treatment protocols for testicular cancer and prospectively registered patients with testicular cancer. Today, all hospitals in Norway and Sweden involved in the care of testicular cancer participate in SWENOTECA, and all patients with testicular cancer are prospectively registered in a population-based database. RESULTS: Nine protocols with standardized guidelines on the diagnosis, treatment and follow-up of testicular cancer have been published. In addition to the guidelines, several studies have been performed or initiated within the scope of SWENOTECA. The details are presented in this article. CONCLUSIONS: SWENOTECA has been a very fruitful binational collaboration and has thoughtfully evolved over time. The group's continuous work and dedication have provided an example for other national and international cancer networks. The binational implementation of standardized guidelines has resulted in excellent patient outcomes, regardless of place of residence. Although testicular cancer is a relatively rare disease, the population-based binational organization of SWENOTECA has made it possible to publish some of the largest studies in the field of testicular cancer.

Immunohistochemical expression of CD23 and CD40 may identify prognostically favorable subgroups of diffuse large B-cell lymphoma: a Nordic Lymphoma Group Study.

PURPOSE: In search for subgroups of diffuse large B-cell lymphoma (DLBCL) with different histogenetic origin and prognosis, as has been described by gene expression profiling, we examined tumor specimens from 125 patients with DLBCL, uniformly treated by either cyclophosphamideAdriamycin-vincristine-prednisone or methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin in a multicenter trial set by the Nordic Lymphoma Group 1989-1994. EXPERIMENTAL DESIGN: Bcl-6, CD10, and CD40 were chosen as markers for a germinal center phenotype, CD23 as a marker of pre/early germinal center origin, and CD138 as a marker for postgerminal center origin. In addition, expression of the apoptotic regulators bcl-2 and bax was analyzed. Immunohistochemical analysis was performed using the EnVision method. RESULTS: CD10 was positive in 51%, bcl-6 in 97%, and CD138 only in 2% of the cases. No prognostic conclusions could be drawn from analysis of these factors. CD40 was positive in 76% of the cases. This group was associated with superior time to treatment failure (P = 0.027) and overall survival (OS; P = 0.0068). By Cox regression analysis, positivity for CD40 was shown to be a prognostic factor for OS, independent of International Prognostic Index. CD23 was positive in 16% of the cases (all CD5 negative and all CD40 positive). This group showed a strong tendency for better OS (P = 0.033). CD40 expression correlated with bax but not with bcl-2 expression. CONCLUSIONS: CD23 and CD40 expression seems to be prognostically favorable in DLBCL. This may be secondary to a germinal center origin or attributable to increased apoptosis via induction of bax and/or enhanced T-cell interaction, resulting in improved autologous tumor response. Confirmatory studies are necessary.

A novel platform for radioimmunotherapy: extracorporeal depletion of biotinylated and 90Y-labeled rituximab in patients with refractory B-cell lymphoma.

Radioimmunotherapy is limited by the absorbed dose to radiosensitive organs. Removal of circulating radiolabeled MAbs after tumor tissue has been optimally targeted and should permit the administration of higher radioactivity to patients, resulting in a higher absorbed tumor dose. A novel "extracorporeal affinity adsorption treatment" (ECAT) device (MitraDep)was tested, with which biotinylated and radiolabeled MAbs can be removed from the circulation by passing whole blood over a filter coated with avidin. The antibodies were simultaneously radiolabeled and biotinylated using a trifunctional moiety comprising DOTA and biotin. Eight patients--all but 1 of whom with aggressive or mantle cell B-cell lymphoma-- who had failed to respond to standard therapies received infusions of 250 mg/m(2) cold rituximab and 150 MBq (111)In-rituximab-biotin for immunoscintigraphy. A week later, the patients were treated with another 250 mg/m(2) rituximab followed by (111)In/-(90)Y-rituximab-biotin (11 or 15 (90)Y MBq/kg). ECAT was performed 48 hours later. All 8 patients receiving (111)In-rituximab-biotin showed tumor uptake. Seven patients received radioimmunotherapy and subsequent ECAT. The mean depletion of (90)Y-rituximab-biotin in whole blood after ECAT was 96%, in the whole body 49%, in the lungs 62%, and in the liver and kidneys 40%. No effects on patients' vital signs and no adverse effects on hematological or coagulation parameters was observed during the ECAT procedure. A dose-escalation study is initiated.

Growth hormone deficiency predicts cardiovascular risk in young adults treated for acute lymphoblastic leukemia in childhood.

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and until recently prophylactic cranial radiotherapy (CRT) was important for achieving long-term survival. Hypothalamic-pituitary hormone insufficiency is a well-recognized consequence of CRT for childhood cancer. Another problem is increased cardiovascular risk, which has been shown in long-term survivors of other childhood cancers. In the only previously reported study on cardiovascular risk after childhood ALL, obesity and dyslipidemia were recorded in a small subgroup treated with CRT, compared with patients treated with chemotherapy. The mechanisms behind the increase in cardiovascular risk in survivors of childhood cancer are not clarified. The aim of the present study was to elucidate mechanisms of increased cardiovascular risk in former childhood ALL patients. A group of 44 ALL survivors (23 males, median age 25 yr, range 19-32 yr at the time of study) treated with CRT (median 24 Gy, 18-30 Gy) at a median age of 5 yr (1-18 yr) and chemotherapy were investigated for prevalence of GH deficiency and cardiovascular risk factors. Comparison was made with controls randomly selected from the general population and individually matched for sex, age, smoking habits, and residence. All patients and controls underwent a GHRH-arginine test, and patients with a peak GH 3.9 microg/liter or greater were further investigated with an additional insulin tolerance test. Significantly higher plasma levels of insulin (P = 0.002), blood glucose (P = 0.01), and serum levels of low-density lipoprotein cholesterol, apolipoprotein (Apo) B, triglycerides, fibrinogen, and leptin (all P

Linkage between androgen receptor gene CAG trinucleotide repeat length and testicular germ cell cancer histological type and clinical stage.

Sex hormones and/or gonadotropins may play a crucial role in the development of testicular germ cell cancer (TGCC). A direct link between this malignancy and endocrine factors has not been confirmed. We tested whether CAG and GGN repeats of the androgen receptor gene (AR) play a role in the aetiology or pathogenesis of TGCC. Eighty-three TGCC patients and 220 controls were included. Mean CAG or GGN lengths did not differ between the TGCC cases and controls. The proportion of males with CAG lengths above 25, indicative of reduced androgen sensitivity, was significantly lower among patients with pure seminomas and in the combined group of seminomas and mixed tumours compared with non-seminomas and controls. The median CAG length was higher if the tumour was metastasing at diagnosis. This is the first study showing an association between the AR polymorphism and histological type as well as the progression rate of TGCC.

Gene expression profiling indicates that immunohistochemical expression of CD40 is a marker of an inflammatory reaction in the tumor stroma of diffuse large B-cell lymphoma.

Immunohistochemical expression of CD40 is seen in 60-70% of diffuse large B-cell lymphoma (DLBCL) and is associated with a superior prognosis. By using gene expression profiling we aimed to further explore the underlying mechanisms for this effect. Ninety-eight immunohistochemically defined CD40 positive or negative DLBCL tumors, 63 and 35 respectively, were examined using spotted 55K oligonucleotide arrays. CD40 expressing tumors were characterized by up-regulated expression of genes encoding proteins involved in cell-matrix interactions: collagens, integrin αV, proteoglycans and proteolytic enzymes, and antigen presentation. Immunohistochemistry confirmed that CD40 positive tumors co-express the proinflammatory proteoglycan biglycan (p = 0.005), which in turn correlates with the amount of infiltrating macrophages and CD4 and CD8 positive T-cells. We postulate that immunohistochemical expression of CD40 mainly reflects the inflammatory status in tumors. A high intratumoral inflammatory reaction may correlate with an increased autologous tumor response, and thereby a better prognosis.

Risk of birth abnormalities in the offspring of men with a history of cancer: a cohort study using Danish and Swedish national registries.

BACKGROUND: The potential mutagenic effects of cancer therapies and the growing number of young male cancer survivors have given rise to concern about the health of their offspring. METHODS: We identified all singleton children born alive in Denmark between 1994 and 2004 and in Sweden between 1994 and 2005 (n = 1,777,765). Of the 8670 children with a paternal history of cancer, 8162 were conceived naturally and 508 were conceived using assisted reproductive technologies (ARTs) (in vitro fertilization or intracytoplasmatic sperm injection). Of the 1,769,095 children without a paternal history of cancer, 25,926 were conceived using ARTs. Associations between paternal history of cancer and risk of adverse birth outcomes of children conceived naturally or by ARTs were investigated using log-linear binomial models, yielding risk ratios (RRs) with 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: The offspring of male cancer survivors were more likely to have major congenital abnormalities than the offspring of fathers with no history of cancer (RR = 1.17, 95% CI = 1.05 to 1.31, P = .0043, 3.7% vs 3.2%). However, the mode of conception (natural conception or ARTs) did not modify the association between paternal history of cancer and risk of congenital abnormalities (natural conception, RR = 1.17, 95% CI = 1.04 to 1.31; ARTs, RR = 1.22, 95% CI = 0.80 to 1.87, P(interaction) = .84). CONCLUSION: We observed a statistically significant but modest increase in the risk of major congenital abnormalities among offspring of males with a history of cancer, independent of the mode of conception.

Management of seminomatous testicular cancer: a binational prospective population-based study from the Swedish norwegian testicular cancer study group.

PURPOSE: A binational, population-based treatment protocol was established to prospectively treat and follow patients with seminomatous testicular cancer. The aim was to standardize care for all patients with seminoma to further improve the good results expected for this disease. PATIENTS AND METHODS: From 2000 to 2006, a total of 1,384 Norwegian and Swedish patients were included in the study. Treatment in clinical stage 1 (CS1) was surveillance, adjuvant radiotherapy, or adjuvant carboplatin. In metastatic disease, recommended treatment was radiotherapy in CS2A and cisplatin-based chemotherapy in CS2B or higher. RESULTS: At a median follow-up of 5.2 years, 5-year cause-specific survival was 99.6%. In CS1, 14.3% (65 of 512) of patients relapsed following surveillance, 3.9% (seven of 188) after carboplatin, and 0.8% (four of 481) after radiotherapy. We could not identify any factors predicting relapse in CS1 patients who were subjected to surveillance only. In CS2A, 10.9% (three of 29) patients relapsed after radiotherapy compared with no relapses in CS2A/B patients (zero of 73) treated with chemotherapy (P = .011). CONCLUSION: An international, population-based treatment protocol for testicular seminoma is feasible with excellent results. Surveillance remains a good option for CS1 patients. No factors predicted relapse in CS1 patients on surveillance. Despite resulting in a lower rate of relapse than with adjuvant carboplatin, adjuvant radiotherapy has been abandoned in the Swedish and Norwegian Testicular Cancer Project (SWENOTECA) as a recommended treatment option because of concerns of induction of secondary cancers. The higher number of relapses in radiotherapy-treated CS2A patients when compared with chemotherapy-treated CS2A/B patients is of concern. Late toxicity of cisplatin-based chemotherapy versus radiotherapy must be considered in CS2A patients.