Immunization with a P53 synthetic long peptide vaccine induces P53-specific immune responses in ovarian cancer patients, a phase II trial.

The prognosis of ovarian cancer, the primary cause of death from gynecological malignancies, has only modestly improved over the last decades. Immunotherapy is one of the new treatment modalities explored for this disease. To investigate safety, tolerability, immunogenicity and obtain an impression of clinical activity of a p53 synthetic long peptide (p53-SLP) vaccine, twenty patients with recurrent elevation of CA-125 were included, eighteen of whom were immunized 4 times with 10 overlapping p53-SLP in Montanide ISA51. The first 5 patients were extensively monitored for toxicity, but showed no > or = grade 3 toxicity, thus accrual was continued. Overall, toxicity was limited to grade 1 and 2, mostly locoregional, inflammatory reactions. IFN-gamma producing p53-specific T-cell responses were induced in all patients who received all 4 immunizations as measured by IFN-gamma ELISPOT. An IFN-gamma secretion assay showed that vaccine-induced p53-specific T-cells were CD4(+), produced both Th1 and Th2 cytokines as analyzed by cytokine bead array. Notably, Th2 cytokines dominated the p53-specific response. P53-specific T-cells were present in a biopsy of the last immunization site of at least 9/17 (53%) patients, reflecting the migratory capacity of p53-specific T-cells. As best clinical response, stable disease evaluated by CA-125 levels and CT-scans, was observed in 2/20 (10%) patients, but no relationship was found with vaccine-induced immunity. This study shows that the p53-SLP vaccine is safe, well tolerated and induces p53-specific T-cell responses in ovarian cancer patients. Upcoming trials will focus on improving T helper-1 polarization and clinical efficacy.

Semen quality in men with disseminated testicular cancer: relation with human chorionic gonadotropin beta-subunit and pituitary gonadal hormones.

OBJECTIVE: To compare the semen quality and hormonal status between patients with testicular cancer and normal versus increased serum levels of beta-hCG. DESIGN: Retrospective study. SETTING: Academic research environment. PATIENT(S): All 203 patients with testicular cancer who required chemotherapy in the period 1995-2003 were included. INTERVENTION(S): In 107 patients semen samples were stored by cryopreservation; 62 patients could be analyzed because both semen was stored and hormones were determined before starting chemotherapy (median age 25 years, range 17-49 years). MAIN OUTCOME MEASURE(S): Total motile sperm count, T, E(2), LH, FSH, and PRL. RESULT(S): Total motile sperm count was decreased in patients with increased beta-hCG (median 11.9 x 10(6)) compared with patients with normal beta-hCG (median 21.5 x 10(6)). Testosterone, E(2), and PRL were significantly higher in patients with increased beta-hCG levels, whereas LH and FSH were lower. Semen quality was significantly and negatively correlated with beta-hCG, E(2), and PRL. CONCLUSION(S): Patients with increased beta-hCG had an inferior spermatogenesis compared with patients with normal beta-hCG. Increased beta-hCG appears to be associated with impaired spermatogenesis and increased levels of E(2) and PRL.

Locoregional control in patients with palpable medullary thyroid cancer: results of standardized compartment-oriented surgery.

BACKGROUND: Extent of neck dissection is controversial in patients with palpable medullary thyroid cancer (MTC). METHODS: We evaluated 64 MTC patients (19 hereditary, 45 sporadic) with palpable thyroid nodules (group 1, n = 35) or palpable lymph node metastases (group 2, n = 29). Standard surgery included total thyroidectomy, central compartment dissection, and additional neck dissection on indication. RESULTS: In group 1, 40% of the patients were cured. Thirty-one percent of all patients had central, 23% ipsilateral, 14% contralateral, and 14% mediastinal, metastases. Fifty-one percent developed locoregional recurrence. Locoregional recurrence (p = .043) and reoperations (p = .020) were noted more often after a less than standard initial procedure. In group 2, no patients were cured. All had central, 93% ipsilateral, 45% contralateral, and 52% mediastinal metastases. Thirty-eight percent developed locoregional recurrence. CONCLUSIONS: Locoregional recurrence frequently occurs in palpable MTC, and tumor control may be improved by standard central, bilateral, and upper mediastinal neck dissection.

Determinants of life expectancy in medullary thyroid cancer: age does not matter.

OBJECTIVE: In medullary thyroid cancer (MTC) age is considered an important prognostic factor but survival has never been properly adjusted for baseline mortality in the general population. We aimed to identify prognostic factors by analysing patients with MTC regarding life expectancy. DESIGN: We described a retrospective cohort study with a median follow-up of 8 years (range 1-35 years). PATIENTS: We included 120 consecutive patients of whom 66 (55%) had sporadic MTC. Male/female ratio was 1 : 1; median age was 45 years (range 3-83 years). MEASUREMENTS: Measurements were overall and disease-specific survival and life expectancy expressed as survival adjusted for baseline mortality rate in the general population. RESULTS: Overall and disease-specific 10-year survival was 65% and 73%, respectively. After 10 years, 29% of patients were biochemically and 63% clinically cured. Median overall life expectancy was 0.58 (95%CI 0.37-0.80). Detectable recurrence occurred in 60 patients after a median of 36 months (range 5-518 months). On multivariate regression analysis only stage of disease and extrathyroidal extension predicted recurrence-free life expectancy. Extrathyroidal extension was the only independent predictor of overall life expectancy. Persistent biochemical MTC did not independently affect life expectancy but calcitonin doubling time of less than one year indicated worse prognosis. Patients without detectable recurrences after initial treatment had a life expectancy similar to the general population. CONCLUSIONS: In MTC patients, extrathyroidal extension and stage at diagnosis are the only independent predictors of (recurrence-free) life expectancy. Patients diagnosed in an early stage of disease and patients without detectable recurrence have favourable life expectancy independently of biochemical cure.

Chemotherapy decreases epiphyseal strength and increases bone fracture risk.

To establish the effect of three frequently used chemotherapeutic agents in childhood cancer on the skeleton, growing male Wistar rats were studied. Treatment with doxorubicin, methotrexate, and cisplatin reduces the proximal tibial growth plate shear strength because of a decreased surface area and maximum shear stress. After treatment the bone fracture risk of the tibia and femur is increased because of decreased bending resistance. Doxorubicin and cisplatin reduce the maximum shear stress of the proximal tibial growth plate, none of the chemotherapeutic agents inhibit bone mineralization. These effects are caused by treatment-induced malnutrition and the accompanying weight reduction and a direct effect of the chemotherapeutic agents on the skeleton. The current study confirmed the importance of preventing malnutrition during chemotherapeutic treatment in view of possible skeletal complications. During followup of children treated with chemotherapy, attention should be given to signs and symptoms suggestive of such complications.