Health-related quality of life in patients with advanced melanoma treated with ipilimumab: prognostic implications and changes during treatment.

BACKGROUND: We have previously reported that the safety and efficacy of ipilimumab in real-world patients with metastatic melanoma were comparable to clinical trials. Few studies have explored health-related quality of life (HRQL) in real-world populations receiving checkpoint inhibitors. This study reports HRQL in real-world patients receiving ipilimumab and assesses the prognostic value of patient-reported outcome measures. PATIENTS AND METHODS: Ipi4 (NCT02068196) was a prospective, multicentre, interventional phase IV trial. Real-world patients (N = 151) with metastatic melanoma were treated with ipilimumab 3 mg/kg intravenously as labelled. HRQL was assessed by the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire at baseline and after 10-12 weeks. RESULTS: The European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire was completed by 93% (141/151 patients) at baseline, and by 82% at 10-12 weeks. Poor performance status and elevated C-reactive protein (CRP) were associated with worse baseline HRQL. Clinically relevant and statistically significant deteriorations in HRQL from baseline to weeks 10-12 were reported (P <0.05). Baseline physical functioning [hazard ratio (HR) 1.96, P = 0.016], role functioning (HR 2.15, P <0.001), fatigue (HR 1.60, P = 0.030), and appetite loss (HR 1.76, P = 0.012) were associated with poorer overall survival independent of performance status, lactate dehydrogenase (LDH), and CRP. We further developed a prognostic model, combining HRQL outcomes with performance status, LDH, and CRP. This model identified three groups with large and statistically significant differences in survival. CONCLUSIONS: Systemic inflammation is associated with impaired HRQL. During treatment with ipilimumab, HRQL deteriorated significantly. Combining HRQL outcomes with objective risk factors provided additional prognostic information that may aid clinical decision making.

Prognostic biomarkers for immunotherapy with ipilimumab in metastatic melanoma.

New therapies, including the anti-cytotoxic T lymphocyte antigen (CTLA)-4 antibody, ipilimumab, is approved for metastatic melanoma. Prognostic biomarkers need to be identified, because the treatment has serious side effects. Serum samples were obtained before and during treatment from 56 patients with metastatic or unresectable malignant melanoma, receiving treatment with ipilimumab in a national Phase IV study (NCT0268196). Expression of a panel of 17 inflammatory-related markers reflecting different pathways including extracellular matrix remodeling and fibrosis, vascular inflammation and monocyte/macrophage activation were measured at baseline and the second and/or third course of treatment with ipilimumab. Six candidate proteins [endostatin, osteoprotegerin (OPG), C-reactive protein (CRP), pulmonary and activation-regulated chemokine (PARC), growth differentiation factor 15 (GDF15) and galectin-3 binding-protein (Gal3BP)] were persistently higher in non-survivors. In particular, high Gal3BP and endostatin levels were also independently associated with poor 2-year survival after adjusting for lactate dehydrogenase, M-stage and number of organs affected. A 1 standard deviation increase in endostatin gave 1·74 times [95% confidence interval (CI) = 1·10-2·78, P = 0·019] and for Gal3BP 1·52 times (95% CI = 1·01-2·29, P = 0·047) higher risk of death in the adjusted model. Endostatin and Gal3BP may represent prognostic biomarkers for patients on ipilimumab treatment in metastatic melanoma and should be further evaluated. Owing to the non-placebo design, we could only relate our findings to prognosis during ipilimumab treatment.

Spermatogenesis after unilateral orchiectomy for testicular cancer in patients following surveillance policy.

PURPOSE: Only limited information is available on the natural course of spermatogenesis in patients with testicular cancer who underwent unilateral orchiectomy and surveillance. We analyze long-term exocrine function of the remaining testicle in patients following surveillance policy. MATERIALS AND METHODS: Sperm counts and serum follicle-stimulating hormone (FSH) levels were available in 60 nonrelapsing cases approximately 3 weeks (baseline), 1 year and 2 years or greater after orchiectomy. Contralateral testicular cancer subsequently developed in 2 men. RESULTS: At baseline 36 patients were normospermic (10 or greater x 106/ml.), 7 were azoospermic and 17 were oligospermic. After 1 year 45 patients were normospermic. Mean sperm concentrations increased significantly from 26 to 39 x 106/ml. during year 1 after orchiectomy. Elevated serum FSH at baseline was associated with incomplete recovery of spermatogenesis, although sperm counts improved in 3 of 7 patients. Furthermore, in the 2 initially oligospermic patients with subsequent contralateral testicle cancer transient normospermia was observed after 1 year. After orchiectomy fatherhood was recorded in 28 men and was assisted by fertilization using fresh semen in 2. CONCLUSIONS: In nonrelapsing testicular cancer cases on surveillance, initially reduced spermatogenesis recovers during year 1 after orchiectomy especially if baseline serum FSH is normal. Transient recovery also occurs in patients in whom contralateral testicular cancer subsequently develops. In high risk patients and in initially oligospermic patients with plans for future fatherhood, the period of improved spermatogenesis may be used for multiple semen cryopreservations enabling subsequent assisted fertilization.

Fatherhood in testicular cancer patients with carcinoma in situ in the contralateral testicle.

We report paternity by assisted fertilization in 3 highly oligospermic patients with stage-I unilateral testicular germ cell tumor and contralateral carcinoma in situ. If such patients plan future paternity, surveillance is the optimal treatment allowing maximal recovery of spermatogenesis after orchiectomy. Multiple semen cryopreservations should be done during the first post-orchiectomy year.

Ejaculation in testicular cancer patients after post-chemotherapy retroperitoneal lymph node dissection.

The purpose of this study was to evaluate fertility after different types of post-chemotherapy retroperitoneal lymph node dissection (RPLND). During 1980-1994, 192 patients with metastatic testicular cancer underwent post-chemotherapy RPLND with a gradual shift from modified bilateral template RPLND to nerve-sparing RPLND. Modified bilateral template RPLND was done in 92% of the patients operated during 1980-1984 as compared to 16% during 1989-1994. Pre- and post-treatment fertility was assessed by microscopic sperm analysis, determination of serum FSH and information on ejaculation and paternity. There was no significant difference of the survival rates between the three treatment periods. Antegrade ejaculation was preserved in 11% of the patients after modified bilateral template RPLND as compared to 89% after the nerve-sparing operation technique. The median ejaculatory volume decreased post-operatively, serum FSH increased and sperm density remained unchanged. Fifty-six patients attempted fatherhood after their treatment, and 27 fathered at least one child after an observation-time of 55 months, nine of them by assisted fertilization. Patients with initially advanced testicular cancer but limited residual retroperitoneal masses after induction chemotherapy can safely undergo limited post-chemotherapy RPLND as a part of multimodality treatment. After nerve-sparing RPLND antegrade ejaculation is preserved in 89% of the patients though the ejaculatory volume decreases after RPLND. Post-treatment fatherhood can be achieved in at least 50% of the patients attempting paternity.

External beam abdominal radiotherapy in patients with seminoma stage I: field type, testicular dose, and spermatogenesis.

PURPOSE: To establish a predictive model for the estimation of the gonadal dose during adjuvant para-aortic (PA) or dog leg (DL: PA plus ipsilateral iliac) field radiotherapy in patients with testicular seminoma. METHODS AND MATERIALS: The surface gonadal dose was measured in patients with seminoma Stage I receiving PA or DL radiotherapy. Sperm cell analysis was performed before and 1 year after irradiation. PA and DL radiotherapy were simulated in the Alderson phantom while we measured the dose to the surface and middle of an artificial testicle, varying its position within realistic anatomical constraints. The symphysis-to-testicle distance (STD), field length, and thickness of the patient were experimental variables. The developed mathematical model was validated in subsequent patients. RESULTS: The mean gonadal dose in patients was 0.09 and 0.32 Gy after PA and DL irradiation, respectively (p < 0.001). DL radiotherapy, but not PA irradiation led to significant reduction of the sperm count 1 year after irradiation. The gonadal dose-reducing effect of PA irradiation was confirmed in the Alderson phantom. A significant correlation was found between the STD and the gonadal dose during DL irradiation. A mathematical model was established for calculation of the gonadal dose and confirmed by measurements in patients. CONCLUSIONS: During radiotherapy of seminoma, the gonadal dose decreases with increasing STD. It is possible to predict the individual gonadal dose based on delivered midplane dose and STD.

A comparison of different modes for the detection of p53 protein accumulation. A study of bladder cancer.

The aim of the present study was to evaluate different techniques for the analysis of p53 protein accumulation in human bladder cancer. The accumulation was evaluated in 23 carcinomas by immunoblotting (IB), immunohistochemistry (IHC) and flow cytometry (FCM). The results revealed that six (26%), eight (35%) and ten (43%) of the tumours were p53 protein positive by IB, IHC and FCM, respectively. Mutation analysis of the TP53 gene confirmed mutations in 8 of 9 tumours which showed increased levels of p53 protein by FCM. Our results indicate that IHC could be applied for studies of p53 protein accumulation in archival formalin fixed, paraffin-embedded bladder tumours. However, FCM is a more sensitive and objective method for the detection of p53 protein than IHC and this should be taken into account when routinely evaluating the p53 protein accumulation by IHC.

Kinetics of expression of inducible beta-galactosidase in murine fibroblasts: high initial rate compared to steady-state expression.

We have constructed a murine fibroblast cell line in which synthesis of beta-galactosidase can be induced by incubation with isopropyl-beta-D-thiogalactopyranoside (IPTG). This was obtained by transfection by both a plasmid expressing lacI and a second plasmid expressing lacZ from a modified simian virus 40 (SV40) promoter containing a lac operator. We have measured the induction kinetics as well as the basal and induced differential rate of synthesis of beta-galactosidase. The steady-state rate of synthesis is tenfold higher in the presence than in the absence of inducer; we calculate an average of 1200 lacZ polypeptides are synthesized per minute per cell in the induced cultures. However, immediately after induction, the rate of accumulation of beta-galactosidase is up to 50-fold higher than the basal level. Based on our measurements of stability of beta-galactosidase, we suggest that induction may result in a subsequent down-modulation of the transcriptional activity from the induced gene. We hypothesize this inhibition may result from structural changes in DNA components, such as nucleosomes.

Metastases from renal cell carcinoma to the humerus or the shoulder girdle.

OBJECTIVE: To discuss the clinical presentation of metastases in the scapula and/or humerus resulting from renal cell carcinoma and the courses of treatment available. PATIENTS: A series of 35 patients with humeral or scapular metastases from renal cell carcinoma, treated at The Norwegian Radium Hospital (NRH) during an 11-year period, is reviewed. Two case reports are examined in detail. RESULTS: The median survival was 12 months (range 1-88) from the time of diagnosis of metastasis. Three patients lived for more than 50 months. CONCLUSION: Owing to the relatively long survival time, especially in patients with limited tumour burden elsewhere and who are in a good general state of health, long-lasting palliative treatment of the humeral or scapular metastases is aimed for. Renal cell carcinoma tends to be resistant to radiotherapy, and early treatment, combining orthopaedic surgery and high-dose radiotherapy, is advocated.

Independent clinical significance of HIV antigen determination and CD4 counts in anti-HIV positive patients.

HIV antigenemia was found in 52/243 HIV antibody positive individuals attending 2 AIDS-screening clinics, giving a prevalence of 13, 25 and 76% in CDC groups II, III and IV, respectively. No correlation was found to decreased CD4 lymphocyte values in the individual groups. HIV antigen therefore identified a separate subpopulation. For 138 asymptomatic patients followed prospectively both laboratory parameters predicted HIV-related events, the relative risk factor being 4 for low CD4 value and 6 for presence of HIV antigen. Individuals presenting with HIV antigen and decreased CD4 count all developed disease within 18 months, the relative risk factor being 24. Thus the 2 markers, when measured together, effectively separated asymptomatic HIV-infected patients into 1 of 3 risk categories.

Effect of thapsigargin on cytoplasmic Ca2+ and proliferation of human lymphocytes in relation to AIDS.

The tumor-promoting sesquiterpene lactone, thapsigargin, induced a dose-dependent increase of the cytoplasmic Ca2+ concentration ([ Ca2+]i) in human lymphocytes from a resting level between 100 and 150 nM up to about 1 microM. Half-maximum response was found at about 1 nM of thapsigargin, full response at 100 nM. The effect of thapsigargin on [Ca2+]i exceeded that of phytohaemagglutinin (PHA) which raised [Ca2+]i to maximum 300 nM. In combination with phorbol 12-myristate 13-acetate (PMA), thapsigargin stimulated the proliferation of normal lymphocytes to the same extent as did PHA, whereas the thapsigargin/PMA treatment could not restore the defective proliferation of AIDS lymphocytes in spite of the increased [Ca2+]i. Thapsigargin or PMA added separately had no stimulatory effects on cell proliferation. The thapsigargin/PMA treatment caused an increase in the interleukin-2 (IL-2) production of the lymphocytes, which was much higher than that caused by the PHA treatment, even in AIDS lymphocytes. Moreover, the thapsigargin/PMA treatment stimulated the expression of the IL-2 receptors on both normal and AIDS lymphocytes, similar to the effect of PHA. It is concluded that thapsigargin exerts its effects on lymphocyte proliferation by increasing [Ca2+]i, and that the general defect of AIDS lymphocytes, rather than being ascribed to the initiating signal systems, is associated with later events related to DNA synthesis and proliferation.