Treatment of stage I seminoma, with one course of adjuvant carboplatin or surveillance, risk-adapted recommendations implementing patient autonomy: a report from the Swedish and Norwegian Testicular Cancer Group (SWENOTECA).

BACKGROUND: The purpose of the protocol was to reduce the treatment burden in clinical stage I (CSI) seminoma by offering risk-adapted treatment. The protocol aimed to prospectively validate the proposed risk factors for relapse, stromal invasion of the rete testis and tumor diameter >4 cm, and to evaluate the efficacy of one course of adjuvant carboplatin. PATIENTS AND METHODS: From 2007 to 2010, 897 patients were included in a prospective, population-based, risk-adapted treatment protocol implementing one course of adjuvant carboplatin AUC7 (n = 469) or surveillance (n = 422). In addition, results from 221 patients receiving carboplatin between 2004 and 2007 are reported. RESULTS: At a median follow-up of 5.6 years, 69 relapses have occurred. Stromal invasion of the rete testis [hazard ratio (HR) 1.9, P = 0.011] and tumor diameter >4 cm (HR 2.7, P < 0.001) were identified as risk factors predicting relapse. In patients without risk factors, the relapse rate (RR) was 4.0% for patients managed by surveillance and 2.2% in patients receiving adjuvant carboplatin. In patients with one or two risk factors, the RR was 15.5% in patients managed by surveillance and 9.3% in patients receiving adjuvant carboplatin. We found no increased RR in patients receiving carboplatin <7 × AUC compared with that in patients receiving ≥7 × AUC. CONCLUSION: Stromal invasion in the rete testis and tumor diameter >4 cm are risk factors for relapse in CSI seminoma. Patients without risk factors have a low RR and adjuvant therapy is not justified in these patients. The efficacy of adjuvant carboplatin is relatively low and there is need to explore more effective adjuvant treatment options in patients with high-risk seminoma. The data do not support the concept of a steep dose response for adjuvant carboplatin.

One course of adjuvant BEP in clinical stage I nonseminoma mature and expanded results from the SWENOTECA group.

BACKGROUND: SWENOTECA has since 1998 offered patients with clinical stage I (CS I) nonseminoma, adjuvant chemotherapy with one course of bleomycin, etoposide and cisplatin (BEP). The aim has been to reduce the risk of relapse, sparing patients the need of toxic salvage treatment. Initial results on 312 patients treated with one course of adjuvant BEP, with a median follow-up of 4.5 years, have been previously published. We now report mature and expanded results. PATIENTS AND METHODS: In a prospective, binational, population-based risk-adapted treatment protocol, 517 Norwegian and Swedish patients with CS I nonseminoma received one course of adjuvant BEP. Patients with lymphovascular invasion (LVI) in the primary testicular tumor were recommended one course of adjuvant BEP. Patients without LVI could choose between surveillance and one course of adjuvant BEP. Data for patients receiving one course of BEP are presented in this study. RESULTS: At a median follow-up of 7.9 years, 12 relapses have occurred, all with IGCCC good prognosis. The latest relapse occurred 3.3 years after adjuvant treatment. The relapse rate at 5 years was 3.2% for patients with LVI and 1.6% for patients without LVI. Five-year cause-specific survival was 100%. CONCLUSIONS: The updated and expanded results confirm a low relapse rate following one course of adjuvant BEP in CS I nonseminoma. One course of adjuvant BEP should be considered a standard treatment in CS I nonseminoma with LVI. For patients with CS I nonseminoma without LVI, one course of adjuvant BEP is also a treatment option.

Incorporation of (3H)uridine by the chromatoid body during rat spermatogenesis.

The in vitro incorporation of tritiated uridine into RNA by the spermatogenic cells of the rat has been analyzed by high-resolution autoradiography. Special attention has been focused on the unique cytoplasmic organelle, the chromatoid body. After a short labeling time (2 h), this organelle remains unlabeled in the vast majority of the early spermatids although the nuclei are labeled. When the 2-h incubation with (3H)uridine is followed by a 14-h chase, the chromatoid body is seen distinctly labeled in all spermatids during early spermiogenesis from step 1 to step 8. Very few grains are seen elsewhere in the cytoplasm of these cells. When RNA synthesis in the spermatid ceases, the chromatoid body also remains unlabeled. It is likely that the chromatoid body contains RNA which is synthesized in the nuclei of the spermatids. The function of this RNA as a stable messenger RNA needed for the regulation of late spermiogenesis is discussed.

The synaptic impact of the host immune response in a parkinsonian allograft rat model: Influence on graft-derived aberrant behaviors.

Graft-induced dyskinesias (GIDs), side-effects found in clinical grafting trials for Parkinson's disease (PD), may be associated with the withdrawal of immunosuppression. The goal of this study was to determine the role of the immune response in GIDs. We examined levodopa-induced dyskinesias (LIDs), GID-like behaviors, and synaptic ultrastructure in levodopa-treated, grafted, parkinsonian rats with mild (sham), moderate (allografts) or high (allografts plus peripheral spleen cell injections) immune activation. Grafts attenuated amphetamine-induced rotations and LIDs, but two abnormal motor syndromes (tapping stereotypy, litter retrieval/chewing) emerged and increased with escalating immune activation. Immunohistochemical analyses confirmed immune activation and graft survival. Ultrastructural analyses showed increases in tyrosine hydroxylase-positive (TH+) axo-dendritic synapses, TH+ asymmetric specializations, and non-TH+ perforated synapses in grafted, compared to intact, striata. These features were exacerbated in rats with the highest immune activation and correlated statistically with GID-like behaviors, suggesting that immune-mediated aberrant synaptology may contribute to graft-induced aberrant behaviors.

Lymphocyte homing and clinical behavior of non-Hodgkin's lymphoma.

Lymphocyte homing receptors (HRs) defined by Hermes antibodies (anti-CD44) and lymphocyte function associated antigen-1 (LFA-1, CD11a/CD18) are involved in lymphocyte binding to endothelial cells of high endothelial venules (HEVs) at sites where lymphocytes exit the blood. Their expression was correlated to the clinical behavior of 245 non-Hodgkin's lymphomas followed up for the median of 87 mo after the diagnosis. Lymphomas that showed no or weak staining intensity for HRs were more often of stage I (P = 0.005), disseminated less frequently hematogenously (P = 0.003), and had more favorable prognosis than lymphomas with intensive staining for HRs (P less than 0.0001) despite that they were more often histologically of high grade malignancy (P = 0.002). Expression of LFA-1 beta chain (CD18) did not correlate significantly with stage or survival, but had prognostic value in a subgroup of HR expression negative lymphomas (P = 0.03). HR staining intensity was an independent prognostic factor in a multivariate analysis. These findings indicate that Hermes/CD44 molecule is associated to the determination of the metastatic potential and prognosis of non-Hodgkin's lymphomas. They also reveal a new entity among non-Hodgkin's lymphomas, because lymphomas that express low levels of HR have favorable prognosis despite their often highly malignant histological appearance.

Effect of treatment on the prognostic value of S-phase fraction in non-Hodgkin's lymphoma.

PURPOSE: To investigate the prognostic value of cell proliferation rate in non-Hodgkin's lymphoma, study its association with histologic classification, and investigate whether its predictive value is influenced by the type of treatment given. PATIENTS AND METHODS: The S-phase fraction (SPF) size was determined by DNA flow cytometry from paraffin-embedded tissue obtained at diagnosis from 490 patients with non-Hodgkin's lymphoma, diagnosed in a defined geographic area from 1970 to 1991. Clinical data were collected from hospital records and the files of the Finnish Cancer Registry. RESULTS: SPF size correlated well with histologic grading performed either according to the Working Formulation or Kiel classification (P < .0001 for both). The mean SPFs of low-, intermediate-, and high-grade malignant lymphomas were 4.9% (95% confidence interval [CI], 4.2% to 5.5%), 10.3% (95% CI, 9.3% to 11.4%), and 15.5% (95% CI, 14.0% to 16.9%), respectively. Lymphomas with an SPF lower than the median (7.9%) had a 58% 5-year and 44% 15-year survival rate, whereas those with an SPF larger than the median had a 44% 5-year and 40% 15-year survival rate (P < .0001). SPF size was not significantly associated with prognosis in some subgroups, such as among patients treated primarily with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (n = 114) or cyclophosphamide, vincristine, and prednisone (COP) (n = 124) with or without radiotherapy (P > .05), whereas a stronger association was found among patients with stage I or II lymphoma treated with radiotherapy only (n = 100; P = .003) and among patients with stage III or IV lymphoma who did not receive chemotherapy (n = 44; P < .0001). In multivariate analyses that included the factors used to construct the International Prognostic Index, SPF had independent prognostic value both in low-grade and intermediate- or high-grade lymphomas, but not in the subset of patients treated with combination chemotherapy with or without radiotherapy. CONCLUSION: Cell proliferation rate measured as SPF is closely associated with histologic grading in non-Hodgkin's lymphoma, and it has independent prognostic value. The treatment given influences considerably the prognostic value of SPF.

Relation of antipsoriatic and Langerhans cell depleting effects of systemic psoralen photochemotherapy: a clinical, enzyme histochemical, and electron microscopic study.

The possible relation between the therapeutic action and Langerhans cell (LC) depleting effect of psoralen photochemotherapy (PUVA) was investigated in 9 psoriatic patients by parallel recording of the clinical status, using the psoriasis area and severity index ( PASI ), and the epidermal LC counts of uninvolved skin, using light (ATPase staining) and electron microscopy (EM). Both light and electron microscopically recorded LC numbers decreased significantly during the PUVA course of, on the average, 21 exposures and a mean cumulative UVA dose of 77 J/cm2. At the end of the treatment period, both the PASI score and the light microscopically recorded LC density had reduced to about one-tenth of original, i.e., from 7.5 +/- 5.7 to 0.8 +/- 0.8 points and from 787 +/- 70 to 60 +/- 48 cells/mm2, respectively. After cessation of the PUVA course, the PASI scores remained low during the 3-7 week follow-up period, while the LC counts returned to normal, and even exceeded the starting value by 12%. Although a possible functional impairment of LC in the post-PUVA period cannot be excluded, the data are interpreted as speaking against the hypothesis that the therapeutic action of PUVA would be mediated through its LC effects.

Detection of residual tumours in postchemotherapy testicular cancer by FDG-PET.

The aim of this study was to investigate whether 2-(F-18)-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) could reliably detect testicular cancer in patients following chemotherapy. Twenty FDG-PET studies were performed on 15 patients with metastatic seminoma or non-seminoma. Tracer uptake in the PET study was measured by calculating the standardised uptake value (SUV) for the tracer. Nine lesions out of 20 were judged to be positive based on high FDG uptake. Three proved to represent inflammatory changes in non-cancerous tissue. Eleven PET studies were negative. In one of these, viable tumour was found at retroperitoneal lymphadenectomy. The median SUV values of metastatic tumours and benign residual tumours were 2.7 (range 1.6-9.5, n = 10) and 1.7 (range 0.7-5.5, n = 15), respectively. The large overlap of SUVs between these groups was due to the relatively high FDG uptake in inflammatory tissue (median 4.2, range 2.0-5.5, n = 4). The results indicate that FDG imaging of metastatic testicular cancer after chemotherapy has limited value because of a potentially high accumulation of FDG in inflammatory tissues.

Identification of the nonclassical HLA molecules, mica, as targets for humoral immunity associated with irreversible rejection of kidney allografts.

BACKGROUND: A substantial portion of kidney allografted patients experience early acute rejection episodes and even irreversible rejections in the early posttransplantation period. The presence of HLA alloantibodies before grafting is associated with early immunological complications, but in many patients rejections and graft loss occur even in the absence of such antibodies. METHODS: In this study, 748 serum samples taken before and at various time points after kidney transplantation from 139 patients were investigated for the presence, frequency, and specificity of kidney microvascular endothelial cell (KMEC)-reactive antibodies using major histocompatability class (MHC) I-related chain A (MICA) transfected cells and flow cytometry, antibody blocking experiments, and Western blotting. The ability of MICA-specific antibodies to fix complement and to induce a prothrombotic phenotype in KMECs was investigated. RESULTS: A polymorphic, 62 kDa nonclassical HLA class I molecule is identified as a new target molecule for reactivity in sera from patients with irreversible rejections. Specific blocking and transfection experiments verified the target molecule as MICA. A significant correlation was established for pre- or posttransplantation MICA humoral immunity and graft loss (P<0.001). MICA-specific antibody titers increased in the posttransplantation period and were present before any signs of clinical rejection. MICA antibody-containing patient sera induced a prothrombotic phenotype in KMECs. CONCLUSION: The increasing polymorphism detected at the MIC loci combined with the results of this study suggest that typing for the MIC loci and crossmatching for the detection of anti-MIC antibodies before transplantation should be used routinely. A better recipient-donor selection based on a negative crossmatch for both anti-donor HLA and MICA antibodies will decrease early graft rejections and losses.

RNA synthesis in different stages of rat seminiferous epithelial cycle.

In vitro RNA synthesis has been analyzed using autoradiographic and electrophoretic methods in isolated 1-2 mm segments of rat seminiferous tubules. The cellular composition of each segment was accurately identified using microscopic analysis of the transillumination pattern of the freshly isolated, unstained, seminiferous tubules combined with phase-contrast microscopy of the living spermatogenic cells. The RNA synthesized in the seminiferous tubules was found to be mostly heterogenous nuclear RNA (HnRNA), which appeared to have a long lifetime. It was most actively formed in the stages which contain mid-pachytene spermatocytes. Formation of rRNA was slow in all stages and it was first observed when a 2-h pulse with [3H]uridine was followed by a 6-h chase. A very low RNA synthetic rate was observed in the stage containing the meiotic reduction divisions. The function of the meiotic RNA in regulation of spermiogenesis is discussed.

Post-transcriptional regulation of zenk expression associated with zebra finch vocal development.

In the male zebra finch, highly variable juvenile song and stereotyped adult song induce mRNA expression of the immediate early gene zenk in telencephalon. However, the functional consequences of this behavior-driven gene expression remain unknown. Here we characterize the developmental expression of zenk mRNA and protein in two forebrain song regions (HVC, the higher vocal center, and RA, the robust nucleus of the archistriatum). In HVC, singing results in similar percentages of cells producing zenk mRNA and zenk protein at different stages of vocal development. Similarly, song behavior at all stages of vocal development induces a comparable percentage of RA cells expressing zenk mRNA. However, the percentage of RA zenk immunoreactive cells is low during early vocal learning, increasing only as the vocal pattern matures. Early induction of a stereotyped vocal pattern in juvenile birds is associated with increased zenk immunoreactivity in RA, indicating that it is the form of the behavior (and not the age of the bird) that correlates with changes in zenk immunoreactivity. Together, our findings reveal a previously unrecognized relationship between behavioral development and post-transcriptional gene regulation.

Lectin histochemistry of embryonal carcinoma.

Histological tissue sections of human testicular embryonal carcinoma from 13 patients and of a xenograft tumour in nude mice, as well as cell lines of human embryonal carcinoma, were investigated with eight different lectins to characterize the distribution of glycoconjugates in embryonal carcinoma. In all cases the malignant cells showed binding with Con A, WGA and RCA I conjugates, whereas other lectins were bound to some, but never to all, tumour cells in each group, revealing the heterogeneity of the malignant cells. A polarization of cancer cells was shown particularly with WGA and RCA I labelling, which was most intense on the luminal borders of the carcinoma cells, where pseudotubular structures were formed. The sugar staining properties were retained in cell culture and in the xenograft tumour. Regardless of the germ cell origin, embryonal carcinoma cells differed from normal germ cells. The distribution of glycoconjugates was also different from that of testicular carcinoma-in-situ germ cells, which share morphological features and the pattern of glycosylation with seminoma cells. However, the similarities in lectin binding pattern of seminomas and embryonal carcinomas suggest the close relationship between the two types of testicular malignancy, without excluding the possibility that embryonal carcinomas were derived from seminomas. Although lectins seem to be less important for differential diagnostic use in testicular cancer, our findings showed the usefulness of lectin histochemistry for characterization of embryonal carcinoma.

Borrelial lymphocytoma--a historical case.

We here describe a patient with a tick bite in the areola mammae in 1953 followed by erythema migrans. Twenty years later, after another tick bite in the axillary skin, also followed by erythema migrans, a large lymphatic infiltrate developed in the mammary skin, when the margin of the erythema reached the areola. The infiltrate resolved within a year without any therapy. Borrelial DNA was detected by polymerase chain reaction in the paraffin blocks of the lymphatic skin infiltrate. The patient died 9 years later of generalized lymphoma. A similar monoclonal immunoglobulin heavy chain gene rearrangement was detected both in the mammary skin lesion and in the lymphoma specimen.

Autologous stem cell transplantation in adult patients with peripheral T-cell lymphoma: a nation-wide survey.

Limited experience is available on the feasibility and efficacy of high-dose therapy (HDT) supported by autologous stem cell transplantation (ASCT) in patients with peripheral T-cell lymphoma (PTCL). Therefore, a nation-wide survey was conducted in adult patients transplanted for PTCL in Finland during 1990-2001. After histopathology review, 37 patients were identified. The median age was 46 years (16-68) at the time of ASCT. Histology included PTCL not otherwise specified in 14 patients, anaplastic large cell lymphoma (ALCL) in 14 patients, and other in nine patients. Disease status at the time of ASCT was CR/PR1 in 18 patients; CR/PR2 in 14 patients, and other in five patients. HDT consisted of either BEAC (N=22) or BEAM (N=15), supported by blood stem cells in 34 patients (92%). Early transplant-related mortality was 11%. With a median follow-up of 24 months from HDT, 16 patients (43%) have relapsed or progressed. The estimated 5-year overall survival (OS) was 54%. Patients with ALCL had superior OS when compared with other subtypes (85 vs 35%, P=0.007). OS at 5 years was 63% in patients transplanted in CR/PR1 vs 45% in those transplanted in other disease status (P=NS). Prospective studies are needed to define the role of ASCT in this lymphoma type.

Should i.m. injections be avoided during cancer chemotherapy?

The intravascular transit of malignant tumor cells constitutes an important step in the formation of distant metastases. The development of tumors in extravascular tissues depends upon the exit of these cells from the circulation by crossing the barriers formed by endothelium and basement membrane and their growth in the extravascular environment. Cytostatic drugs may disturb the function of these barriers and some of them, as well as antiemetic drugs, are given as i.m. injections. Thus these both mechanically and chemically induced endothelial and extravascular tissue changes might facilitate tumor cell transit to extravascular tissues. These aspects are discussed in this case report of a young female patient with a mediastinal germ cell tumor. At 4 years after complete remission induced with chemotherapy and radiotherapy she developed recurrent germ cell tumor in the form of a s.c. gluteal abscess. This gluteal region is the most common site of i.m. injections during or after cancer chemotherapy.

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.

Primary Hodgkin's disease of the stomach.

A case of primary Hodgkin's disease of the nodular sclerosis type in the stomach is described. The patient was a 71-year-old woman, who had an ulcerating tumor 4 cm in diameter in the wall of the stomach. The restriction of the disease to the stomach was confirmed by laparotomy and staging examinations, and the patient has been free of any malignancy during a follow-up period, of eight years. Histologically the tumor consisted of fibrous strands between which mostly small lymphocytes but also some plasma cells, eosinophils, lacunar cells, and binucleated Reed-Sternberg cells were seen. The Reed-Sternberg cells were also identified with Leu-M1 and peanut agglutinin-staining. The present case confirms that Hodgkin's disease may--although rarely--arise in the lymphatic tissue of the stomach.

Lectin binding to serous ovarian tumours.

Sections of normal ovarian surface epithelium, benign serous cystadenomas, borderline serous cystadenomas and serous cyst-adenocarcinomas were stained with a pattern of lectins (Con A, WGA, SBA, DBA, UEA I, PNA and RCA I) to determine the different glycoproteins and their cellular changes. The epithelial cells stained with Con A, WGA, UEA I and RCA, although the intensity of the staining was generally higher in the malignant tumours. PNA stained only the malignant cells of the cystadenocarcinoma and DBA only the benign epithelial cells. These findings show that ovarian epithelial cells contain different glycoconjugates and that malignant transformation is accompanied by changes in the composition of these glycoconjugates.

Effect of etoposide on experimental testicular teratoma in 129/SvJ mice.

To study the effects of etoposide on experimental testicular teratoma in 129/SvJ mouse we analysed the tumour growth, differentiation, apoptosis and the localisation of mdr1 P-glycoprotein (mdr1-Pgp). In this model the implanted gonadal ridges developed into testicular teratomas in 17 out of 56 implanted testes (30%) and in 14 out of 28 mice (50%). The tumour-bearing mice were treated with etoposide on 4 successive days either 4 weeks or 6 weeks after implantation, and killed 7 days after the last dose. The mice in the control groups did not receive etoposide. The teratomas consisted mainly of neural tissue. The etoposide-treated 4-week teratomas, but not the 6-week teratomas, were significantly smaller than those in the corresponding control groups. The density of apoptotic cells and the distribution of the mdr1-Pgp were not altered by etoposide. The decreased proportion of immature neuroectodermal tissue components was observed in all treated teratomas, converting the histology towards that of a mature teratoma. In addition, a low proportion of immature tissue components was frequently combined with a low density of apoptotic cells. In conclusion, etoposide decreased the immature tissue components of teratomas, while mature tissues remained unaffected. These results may have clinical relevance in man, since they confirm that postchemotherapy mature teratomas cannot be treated with chemotherapy. Despite benign histology, the human residual tumours have a significant malignant potential and require complete surgical excision and close surveillance.