A Retrospective Analysis of the First 41 mCRPC Patients with Bone Pain Treated with Radium-223 at the National Institute of Oncology in Hungary.

Radium-223 dichloride is an alpha-emitting radiopharmaceutical which significantly prolongs overall survival in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases. This was a retrospective analysis of the efficacy and safety of Radium-223 in the first 41 patients treated at a single center in Hungary. Radium-223 was given at a dose of 50 kBq/kg intravenously every 4 weeks for up to 6 cycles. Between 23rd July 2014 and 23rd February 2016, 41 patients were treated. Patient demographics, laboratory values, treatment outcomes and adverse events were collected from medical records. The mean age was 72.2 years (SD: 7.1). 24 patients received Radium-223 as first-line treatment (58%), 7 patients as second (17%), 3 as third (7.3%), 6 as (14.6%), and 1 as fifth-line therapy (2.4%). The mean number of cycles administered was 5.5 (SD: 1.1). The most common side effects were anemia (32% grade 1-3), nausea (28%, grade 1), diarrhea (4%, grade 2), thrombocytopenia (4%, grade 3). The mean baseline PSA level was 307.2 ng/ml (SD: 525.7), which increased to a mean value of 728.5 ng/ml (SD: 1277) by the end of treatment. The baseline mean ALP of 521.1 U/L (SD: 728) decreased to 245.1 U/L (SD: 283.5). The majority of patients experienced a decrease (37%) or complete cessation (43%) of bone pain intensity. In our symptomatic prostate cancer patient population, Radium-223 proved to be efficient in terms of pain relief, with moderate side effects. No PSA response was detected, while alkaline phosphatase levels significantly decreased.

Do metallothioneins affect the response to treatment in testis cancers?

PURPOSE: Data on the involvement of elevated metallothionein (MT) expression in resistance to some of the commonly used anticancer treatments are scattered and conflicting. This encouraged us to examine further the contribution of metallothionein expression to the development of this resistance phenotype. PATIENTS AND METHODS: Formalin-fixed, paraffin-embedded blocks of primary untreated germ cell testicular tumor specimens, obtained from 77 patients following radical orchiectomy, were examined for their MT expression using monoclonal antibody and immunohistochemistry. Clinical staging, the chemotherapeutic schedule and evaluation of response to treatment (defining objective response) were performed according to UICC criteria. RESULTS: All tumor types, including seminomas and nonseminomas, expressed MT, regardless of their histology and clinical stage. The immunoreactivity of MT showed a significant positive correlation with the clinical sensitivity of cancer to antitumor therapy (P = 0.0001). CONCLUSION: In patients with germ cell testicular tumors, high MT expression, as detected by immunohistochemistry, predicts a better response rate to chemotherapy whereas tumors lacking or demonstrating low MT expression show a worse prognosis. These data do not support the hypothesis that MT overexpression contributes to cisplatinum resistance, at least in this tumor type.

mdm-2 expression in human testicular germ-cell tumors and its clinical value.

BACKGROUND: In germ cell testicular tumors (GCTT) mdm-2 gene was analyzed for amplification and transcripts but not for protein. The purpose of this study is to determine whether mdm-2 protein level is aberrant in GCTT and if so, what is the relationship between mdm-2 overexpression and other disease parameters including histologic subtypes, p53 status, metastatic potential and clinical stage. METHODS: 81 testicular germ-cell tumors were screened for their mdm-2 expression at the protein levels using immunohistochemistry (IHC) and Western blot (WB) analysis. RESULTS: Of 81 GCTTs 45 (55.55%) showed mdm-2 nuclear immunoreactivity, 34 (41.97%) of which were strongly positive. The incidence of mdm-2 immunostaining was significantly higher (P = 0.0007) in non-seminomas (NSGCT) than in seminomas (SGCT). The frequency of positive tumor was higher in tumors from metastatic patients than in tumors from metastatic-free patients (P = 0.011). mdm-2 expression was detected significantly more frequently in tumors of advanced stages, i.e. IIB, IIC and III versus tumors of early stages (I and II/A) (P = 0.0098). A significant difference between the three stages of disease as to the expression of mdm-2 (chi 2 = 0.0386) could be established, namely the incidence of mdm-2 expression increased with an increase in stage. Using Westem blotting 22 (68.75%) out of 32 tumors overexpressed the mdm-2 oncoprotein of 90 kd (p90). CONCLUSIONS: mdm-2 expression as detected by immunohistochemistry may provide a reliable prognostic tool to isolate subgroups of patients with more aggressive GCTT.

Is p53 expression, detected by immunohistochemistry, an important parameter of response to treatment in testis cancer?

BACKGROUND: Several prior studies revealed positive p53 expression via immunohistochemistry (IHC) in a large percentage of germ cell testicular cancers (GCTTs). However, the predicting and prognostic value of this protein remains to be defined. Therefore, the aim of our study was to further clarify the role of p53 protein in GCTTs and to look for correlations between its gene expression and other disease parameters, including histological subtype, stage and clinical resistance sensitivity. Furthermore, we correlated p53 protein expression with that of MDRI gene product protein (Pgp) in order to examine the interrelationship between these two markers. PATIENTS AND METHODS: 77 untreated patients with GCTTs were investigated for their p53 expression using monoclonal antibody and immunohistochemistry in paraffin-embedded specimens. There were 34 patients with stage I, 16 with stage II, 27 with stage III disease. RESULTS: All tumor types, except differentiated teratomas, were immunoreactive for p53 to a various extent ranging from scarcely positive to homogeneously stained tumor cells. Seminomas (S) and embryonal carcinoma (EC) components showed the most positive nuclear staining. p53 expression showed a significant inverse correlation with the stage of disease (P < 0.0003). There was a significant positive relationship between p53 immunoreactivity and response to treatment (P = 0.0012), i.e. high levels of p53 expression correlated with clinical sensitivity of the tumors to chemotherapy. We could demonstrate a statistically significant opposite relationship between p53 and Pgp immunoreactivity (P < 0.0005). CONCLUSION: Our results show that p53 status in tumor cells may be a strong determinate of susceptibility to chemotherapy and that p53 overexpression has a favorable prognosis in terms of response to treatment in GCTTs. Moreover, the findings provide clinical evidence for the presense of significant relationship between p53 and MDR1/Pgp immunoreactivity. They also suggest that patients resistant to chemotherapy and lacking p53 expression might benefit from an alternative appropriately designed chemotherapeutic regimen to achieve further successful treatment in GCTTs.

Drug resistance and sensitivity of germ cell testicular tumors: evaluation of clinical relevance of MDR1/Pgp, p53, and metallothionein (MT) proteins.

BACKGROUND: Although in vitro and clinical studies indicate that overexpression of P-glycoprotein (Pgp), p53, or metallothionein (MT) is involved in modulating drug resistance/sensitivity of cancer cells, the clinical relevance of the overexpression remains to be elucidated. MATERIALS AND METHODS: In this paper the expression and clinical value of Pgp, p53, and MT were evaluated immunohistochemically in 77 specimens of germ cell testicular tumors (GCT). We also studied the interrelationship(s) between the investigated markers. RESULTS: Pgp positivity correlated with cancers of advanced stages (P = 0.000). p53 and MT immunostaining does not predict a poor response to chemotherapy, but rather is correlated to a favorable clinical outcome (P = 0.001, P = 0.00006 respectively). We obtained an inverse association between Pgp and p53 (P = 0.0005), and positive strong association between p53 and MT immunoreactivity (P = 0.0002). CONCLUSIONS: Based on our results in patients with germ cell testicular tumors we assume that the poor clinical outcome seen in certain Pgp positive tumors is the consequence of Pgp association with a more progressive malignant phenotype, rather than its role in multidrug resistance (MDR). p53 and MT immunoreactivity predicts a better response rate to chemotherapy, wheres tumors lacking or demonstrating low MT and or p53 expression show a worse prognosis.

[Review of drugs used in the neutropenic period following cytostatic therapy and comparative study of doxycycline and ofloxacin in the treatment of patients with testicular cancer]. / Citosztatikus kezelést követö neutropeniás idöszakban alkalmazott gyógyszerek ismertetése és tapasztalataink doxycyclin és ofloxacin összehasonlító vizsgálatáról heredaganatos betegek kezelése során.

The authors compared the effectivity of doxycyclin or ofloxacin after combined chemotherapy of testicular cancer patients during the leukopenic periods. Between 1988 and 1991 200 patients were randomized and 194 were evaluated. One hundred and fifty two patients had been treated by cytostatic treatment earlier 2.5 or 2.9 times and 17 by irradiation. The average age was 30.1 in the doxycyclin group and 31.5 years in ofloxacin group. The patients characteristics in average age and previous treatments were not significant in the two groups. Doxycyclin was applied at the first day 200 mg and the following days 100 mg for 6.8 days and ofloxacin was given 2 times 100 mg day for 8.0 days. The preventive antibiotic treatment was insufficient in 16 or 6 cases requiring the the new antibiotic therapy. The development of the new infectional lesions was significantly higher in doxycyclin group and it needed the other antibiotic therapy. The condition of the patients did not require systemic antimycotic or antiviral therapy. The toxicity was lower in oflaxacin group. Tarivid is suitable for preventing the infection in neutropenic periods after the cytostatic therapy. The number of infections are decreased the completion with some penicillins. Regarding to previous cytostatic drugs the cephalosporins are suggested for prevention during the neutropenic periods.

[Treatment of germ cell tumors at the threshold of the third millennium]. / Csírasejt típusú daganatok kezelése a harmadik évezred küszöbén.

The aim of the authors is to present the risk factors and the risk factors based treatment strategy of germ cell tumors. They review the risk adapted treatment strategy of germ cell tumors using the treatment policy of the Léon Bérard Oncological Center and the current findings published. More than of 80% germ cell tumors may be cured by standard treatment. The treatment of stage I seminoma is lumboaortic radiotherapy and that of stage I non seminoma is either surveillance, retroperitoneal lymph node dissection or chemotherapy depending on the risk factors of extratesticular involvement (pure embryonal carcinoma, vascular invasion). The treatment of metastatic cases is chemotherapy: three cycles of bleomycin, etoposid, cisplatin of four cycles of the similar components without bleomycin for good risk patients, and four cycles bleomycin, etoposid and cisplatin in poor risk cases. The overall five year survival rates are 90 and 50% in cases of good and poor prognosis groups respectively. The indication of retroperitoneal lymph node dissection depends on the size of retroperitoneal spreading prior to chemotherapy and on the efficacy of chemotherapy. The second line salvage treatment is four cycles of a combination of vinblastin, ifosfamide and cisplatin. After salvage chemotherapy the resection of all residual masses is recommended. New drugs, such as gemcitabine, taxotere, oxaliplatin and high dose chemotherapy may bring further success, however these new treatment modalities are not available for clinical practice in Hungary. Risk adapted treatment for germ cell tumors decreasing the early and late toxicity's of conventional treatment may improve the patients quality of life, and may decrease the cost of standard treatment in Hungary. The said new medication and the use of high dose chemotherapy may further improve the chances of patients with poor and intermediate prognosis and of those who are resistant to the cisplatin based standard therapy.

[The clinical value of mdm-2 (proto-oncogene) expression in testicular cancer, Correlation with tumor progression]. / Az madm-2 (protoonkogén) expresszió klinikai jelentösége hererákokban. Osszefüggés a tumorprogresszióval.

To determine whether mdm-2 protein level is aberrant in germ cell testicular tumors (GCTT) and if so, what is the relationship between mdm-2 overexpression and other disease parameter including histologic subtypes, p53 status, metastatic potential, and clinical stage, 81 testicular germ-cell tumors were screened for their mdm-2 expression at the protein levels using immunohistochemistry (IHC) and Western blot (WB) analysis. Overall, in this study 45 (55.6%) tumors showed positive mdm-2 nuclear immunoreactivity. The incidence of mdm-2 immunostaining was significantly higher (p = 0.0007) in non-seminomas (NSGCT) than in seminomas (S). The frequency of positive tumor was higher in tumors from metastatic patients than in tumors of patients free from metastasis (p = 0.011). Mdm-2 expression was detected significantly more frequently in tumors of advanced stages, i.e. II/B, II/C, and III versus tumors of early stages (I and II/A) (p = 0.0098). A significant difference could be established between the three stages of disease and the expression of mdm-2 (chi 2 = 0.0386), namely the incidence of mdm-2 expression increased with an advanced stage. Using Western blotting 22 (68.8%) out of 32 tumors overexpressed the mdm-2 oncoprotein of 90 kd (p90). Mdm-2 expression as detected by immunostaining may provide a reliable prognostic tool to subgroup of patients with more aggressive GCTT.

[Bcl-2 expression in testicular cancer in relation to tumor progression]. / Bcl-2 expresszió vizsgálata hererákokban, összefüggésben a tumorprogresszióval.

Bcl-2 expression has been studied extensively in a variety of human tumors. However, there are lack of clinical data in regard to its expression in germ cell testicular tumors (GCTTs). In this study we screened bcl-2 expression in 70 patient with GCTTs using the immunohistochemistry (IHC) and streptavidin biotin alkaline phosphatase method. Furthermore, we correlated this expression with metastatic behaviour and clinical stage. Overall, 41 (58%) carcinomas stained with anti-bcl-2 (DAKO-124) monoclonal antibody, By histologic type, these lesions included 11 (42.3%) of 26 seminomas (S) and 30 (68.18%) of 44 non seminomatous germ cell testicular tumors (NSGCT). The incidence of bcl-2 immunostaining was higher (P = 0.05, two-tailed, Fisher's test) in NSGCT than in seminomas. Bcl-2 expression was higher in tumors from metastatic patients than in tumors from metastatic-free patient (p = 0). There was a significant difference between the three stages of disease as to the expression of bcl-2 (chi 2 = 0). High level of bcl-2 was clearly dominant in tumors of advanced stages. The present finding revealed that bcl-2 expression occurs in GCTTs. Further, they suggested that bcl-2 is associated with a more progressed malignant phenotype in these tumors.

[Bilateral germ cell testicular tumors] / Kétoldali csírasejt-típusú heredaganatok.

PURPOSE: To study the clinical characteristics of bilateral testicular tumors in the cisplatin era. PATIENTS AND METHODS: Between November 1988 and November 1998 2386 testicular cancer patients were treated in our Department and 72 bilateral germ cell testicular cancer patients were retrospectively explored (3%). The incidence, the clinical and histological characteristics and, in the case of asynchronous tumor, the interval between the two tumors were analyzed. RESULTS: During the 10 years 19 synchronous (26.4%) and 53 asynchronous bilateral germ cell testicular cancers (73.6%) were treated. The incidence of bilateral synchronous seminoma was 68.4%. Among the asynchronous tumors 9 concordant seminomas and 9 concordant nonseminomas were detected. In the first, second and third 5-year follow-up period 39.6, 30.2, and 28.2% of asynchronous tumors were diagnosed. The incidence of seminoma after the first castration in the 5, 10 and 15 years was 19, 37.5, and 60%, respectively. The overall survival rates of synchronous and asynchronous testicular cancer were 84 and 93%. In cases of asynchronous tumor the prevalence of stage I cancer was significantly greater in a regularly controlled population (p=0.014) than in the not regularly followed population, but the survival rate was good in both groups. Nonseminoma showed up earlier as first and second tumor than seminoma (p=0.05, p=0.045). The interval between the two asynchronous tumors was shorter in the case of nonseminoma than in the case of seminoma (p=0.002). CONCLUSION: The prognosis of bilateral germ cell testicular cancer is good because of the high incidence rate of seminoma and the effective treatment. With regular follow-up the early diagnosis of second testicular tumors is probable. The interval between the tumors depends on the patients' age and the histology of the second tumor, in the case of seminoma it is longer. The effect of the previous treatment on the incidence of seminoma and the interval between the two asynchronous tumors requires further investigations.

Characteristics and risk factors of cisplatin-induced ototoxicity in testicular cancer patients detected by distortion product otoacoustic emission.

OBJECTIVE: The characteristics and risk factors of the long-term ototoxic effect of cisplatin in testicular cancer patients was studied by measuring distortion product otoacoustic emissions (DPOAEs), which is a highly sensitive, new method for detecting high-frequency hearing loss. METHODS: 223 patients with a median follow-up time of 4.27 years (range 0.5-20 years) and a median age of 37 years (range 18-55 years) were assessed by DPOAE. 100 mg/m2 cisplatin were administered per cycle, in EP, BEP, VeIP, VIP or VPB regimens. The control group consisted of 40 testicular cancer patients without chemotherapy (median age 35 years, range 16-54 years). A detailed medical history evaluated audiological risk factors and hearing complaints. DPOAE was measured in eight frequencies from 750 to 8,000 Hz. Paired t test and Mann-Whitney test were used for statistical evaluation. RESULTS: Symptomatic ototoxicity was observed in 20% of the patients. In patients receiving or=400 mg/m2, our method could detect significant hearing impairment at lower frequencies that are important for speech perception. At 400 mg/m2, significant amplitude change was detected at 3,000 Hz (p = 0.01); at 500-600 mg/m2, significant amplitude change was detected at 1,500, 2,000 and 3,000 Hz (p = 0.004, 0.0001 and 0.0002, respectively), and at 700 mg/m2 significant amplitude change was detected at 3,000 Hz (p = 0.01). We detected the lowest amplitudes in those 44 patients who had symptomatic ototoxicity. The only statistically significant risk factor was the cumulative dose of cisplatin; neither smoking nor noise exposure were independent risk factors. CONCLUSION: DPOAE is a fast, noninvasive and reliable method in detecting late ototoxicity in testicular cancer patients. Contrary to the literature, not only high frequencies are affected. In patients receiving at least 400 mg/m2, using DPOAE we were able to detect significant hearing impairment at lower frequencies that are important for speech perception.

Expression of bcl-2 in testicular carcinoma: correlation with tumor progression and MDR1/Pgp.

BACKGROUND: The expression of bcl-2 has been studied extensively in a variety of human tumors. However, there is a lack of clinical data regarding its expression in germ cell testicular tumors (GCTTs). METHODS: In this study, the authors screened 70 patients with GCTTs for bcl-2 expression using immunohistochemistry (IHC) and the streptavidin-biotin-alkaline phosphatase method. This expression was also correlated with the metastatic behavior, clinical stages, and multidrug resistance gene product protein (MDR1/Pgp) immunostaining of GCTTs. RESULTS: Overall, 41 carcinomas (58%) stained positively with anti-bcl-2 monoclonal antibody. According to histologic type, these lesions with positive staining included 11 of 26 seminomas (42.3%) and 30 of 44 nonseminomatous germ cell testicular tumors (NSGCTs) (68%). The incidence of bcl-2 immunostaining was higher (P = 0.05, two-tailed Fisher's exact test) among NSGCTs than among seminomas. The expression of bcl-2 was more prevalent among tumors from patients with metastases than among tumors from metastasis free patients (P = 0.000). There was a significant difference between the three stages of disease in the expression of bcl-2 (chi2 = 0.000), i.e., bcl-2 expression was clearly dominant among tumors at advanced stages. A significant association between bcl-2 and Pgp immunostaining was established (P = 0.004). CONCLUSIONS: These findings revealed that bcl-2 expression occurs in GCTTs. Furthermore, they suggest that bcl-2 is associated with a more advanced malignant phenotype of this tumor.

Three-year results of the first educational and early detection program for testicular cancer in Hungary.

OBJECTIVE: To determine whether a testicular self-examination-based early-detection program may help in the early diagnosis of testicular cancer. METHODS: Advertisements were placed in the media describing the early signs of testicular cancer, the risk factors, the correct method of self-examination and the importance of early detection. Between April 1995 and April 1998, 5,056 men underwent physical and ultrasound examination of the testicles, and in case of suspicious findings tumor markers were checked. RESULTS: Testicular tumors were found in 1.28% of the men with symptoms. No tumors were found in men without symptoms or in men with pain, sensitivity to palpation, or complaints unrelated to the testicle. Of those with a palpable lump or swollen testicle, 4.5 and 3.9% were found to have a tumor. In total, 28 testicular cancers (15 seminomas and 13 nonseminomas) in 26 volunteers and 4 benign tumors were detected. The occurrence of cancer was most frequent in the age group of 15--40 years (1.6%). CONCLUSION: The rate of cancer detection and the detected seminoma rate in the program are not sufficient to justify a widespread early detection program for testicular cancer (examination of men who reveal testicular abnormalities by self-examination) despite the increased tumor incidence. Early diagnosis should be based on an educational program for the population at risk, the training of staff engaged in the health care of the young, and the use of early ultrasound examination in men with palpable lumps and swollen testicles, especially in young men.

Cisplatin containing combination chemotherapy of advanced germ cell line testicular tumours.

One hundred ninety patients with germ cell line testicular tumours were treated according to the modified Einhorn scheme. The response rate was 67.9%. The most favourable results were found in the embryonal histologic type (RR = 76.9%) in the biological markers (beta-HCG and AFP) negative (RR = 97.4%) and in the minimal pulmonary extent group (RR = 94.1%). The authors treated 112 patients with including these VPB-resistant germ cell testicular tumour and those with recurrence after this treatment. The patients' mean age was 28.8 (limits 19 to 44) years. Patients were given Vepeside (100 mg/m in infusion for days 1-5), Adriablastin (40 mg/m in infusion on day 1) and Cisplatin (20 mg/m in infusion) for day 1-5. The treatment resulted in CR with 18 patients (16.1%) and PR with 42 (37.5%) (RR = 53.6%). The best results were obtained with the seminoma patients who were marker-negative and had small-volume metastasis. CR developed in 4 of 7 seminoma patients (57%) and in 7 of 25 marker-negative individuals (28%), and PR developed in 11 patients (44%) (RR = 72%). Out of 12 patients with small volume metastatis four (33%) showed CR and five revealed PR (41.7%), their RR turned out to be 74.6%. The average remission period was 37 (range 4-70) months in CR but merely 6.1 (range 2-38) months in PR. It can be stated that fairly good results can be achieved with second-line VpAP treatment in case of resistance developed to primary VPB therapy or subsequent relapse. The efficacy of combined chemotherapy of Vepesed+Holoxan +/- Adriablastin as third-choice was studied in advanced testicular cancer patients refractory to, or recurrent after, first- and second-line cytostatic therapy. Between September 1981 and January 1988 49 evaluable patients were treated with Vepesid (VP-16213--100 mg/m2 days 1-5), Holoxan (40 ml/kg days 1-5), hydration, urine-alkylation + Uromitexan +/- Adriablastin (40 mg/m day 1). The single dose of Uromitexan was 20% of the daily dose of Holoxan, and the patients received it i.v. just prior to Holoxan administration (h 0), the 4 and 8 h later. Two patients got into CR and 10 to PR. The rate of remission was 24.5%. The most severe side effect was leukopenia. The elevation of BUN and se. creatinine was transient and mild. In those cases where Holoxan was not included in the first- or second-line regimens, when combined with Vepesid and Adriablastin as third-choice therapy one could achieve further improvement. In case of CR the prolongation of life is also noteworthy. The first-, second- and third-line therapy plus salvage RLA and/or pulmonary metastasectomy achieved long-term survival only in one quarter of the patients.

Somatic mutations of KIT in familial testicular germ cell tumours.

Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence (except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino-acid substitutions in exon 17 and one was a 12 bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with three out of 116 unilateral cases (P=0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes.