A world-wide survey on kidney transplantation practices in breast cancer survivors: The need for new management guidelines

Kidney transplantation reduces mortality in patients with end stage renal disease (ESRD). Decisions about performing kidney transplantation in the setting of a prior cancer are challenging, as cancer recurrence in the setting of immunosuppression can result in poor outcomes. For cancer of the breast, rapid advances in molecular characterization have allowed improved prognostication, which is not reflected in current guidelines. We developed a 19-question survey to determine transplant surgeons’ knowledge, practice, and attitudes regarding guidelines for kidney transplantation in women with breast cancer. Of the 129 respondents from 32 states and 14 countries, 74.8% felt that current guidelines are inadequate. Surgeons outside the United States (US) were more likely to consider transplantation in a breast cancer patient without a waiting period (p = .017). Within the US, 29.2% of surgeons in the Western region would consider transplantation without a waiting period, versus 3.6% of surgeons in the East (p = .004). Encouragingly, 90.4% of providers surveyed would consider eliminating wait-times for women with a low risk of cancer recurrence based on the accurate prediction of molecular assays. These findings support the need for new guidelines incorporating individualized recurrence risk to improve care of ESRD patients with breast cancer.     

Decreased perforin and granzyme B expression in senescent HIV-1-specific cytotoxic T lymphocytes

Cytotoxic T lymphocyte (CTL) senescence may be an important mechanism of immune failure in HIV-1 infection. We find that senescence of HIV-1-specific CTL clones causes loss of killing activity, preventable by transduction with telomerase. Furthermore, senescence is associated with reduced expression of the effector molecules granzyme and perforin, suggesting CTL "exhaustion" can result in hypofunction. These results agree with other studies showing that HIV-1-specific CTL exhibit abnormal phenotypes in vivo, and suggest the possibility that chronic turnover is an important mechanism of antiviral failure in HIV-1 infection.     

Phase I clinical and pharmacokinetic trial of dextran conjugated doxorubicin (AD-70, DOX-OXD)

Coupling of anthracyclines to high-molecular-weight carriers may alter drug disposition and improve antitumor effects. We have performed a clinical phase I trial of doxorubicin coupled to dextran (70000 m.w.). The drug was administered as single dose i.v. every 21–28 days. Thirteen patients have received a total of 24 courses (median 2; range 1–3). At the starting dose of 40 mg/m² doxorubicin equivalent (DOXeq), WHO grade IV thrombocytopenia was noted in 2/2 patients. WHO grade IV hepatotoxicity and WHO grade III cardiotoxicity were noted in a patient with preexisting heart disease. Five patients were treated with 12.5 mg/m² DOXeq. Maximal toxicity at this dose level was WHO grade III thrombocytopenia and local phlebitis (WHO grade II) in 1/5 patients, elevation of alkaline phosphatase (WHO grade III) and WHO grade III vomiting in another patient. Subsequently, five patients received 20 mg/m² DOXeq. Hepatotoxicity was noted in 5/5 patients (1 × WHO grade IV, 1 × WHO grade III). Thrombocytopenia was noted in 3/5 patients (1 × WHO grade IV, 2 × WHO grade III). At 12.5 mg/m² DOXeq, a patient diagnosed with a malignant fibrous histiocytoma had stable disease for 4 months. Pharmacokinetic analyses of total and free doxorubicin were performed in plasma and urine. The maximum peak plasma concentration (ppc) for total DOX was 12.3 g/ml at 40 mg/m² DOXeq. The area under the plasma concentration time curve (AUC) ranged from 28.83–80.21 g/ml^*h with dose-dependent elimination half lives (t_1/2: 0.02–0.87 h;_1/2: 2.69–11.58 h;_1/2: 41.44–136.58 h). We conclude that the maximal tolerated dose (MTD) of AD-70 using this schedule is 40 mg/m² DOXeq. The recommended dose for clinical phase II studies is 12.5 mg/m² DOXeq.Abbreviations ALT Alanine Aminotransferase - AST Aspartate Aminotransferase - DOX Doxorubicin - DOXeq Doxorubicin Equivalent - ECG Electrocardiogram - HPLC High Pressure Liquid Chromatography - LD₁₀ Lethal Dose for 10% of individuals - MTD Maximal Tolerated Dose - ppc Peak Plasma Concentration - WHO World Health Organisation     

Immunohistochemical detection of p140trkA and p75LNGFR neurotrophin receptors in neuroblastoma

In neuroblastoma, high levels of mRNA for p14h ^trkA and p75 ^LNGFR neurotrophin receptors are predictive of favorable outcome. Their evaluation by Northern blot, however, requires substantial amounts of tissue and this prevents their routine evaluation as well as the possibility for multicenter studies to be easily carried out. In an attempt to overcome these limitations, the feasibility and reliability of determining both neurotrophin receptors on cryostat sections by immunohistochemistry were assessed, and these findings were compared to those obtained from Northern blot analysis. Primary tumor samples from 28 untreated patients at all stages were evaluated by using H10 anti-p140 ^trkA and ME20.4 anti-p75 ^LNGFR mAbs. Although weak, positiveimmunostaining was found in 9 of 28 tumors for p140 ^trkA and in 5 of 28 tumors for p75 ^LNGFR . As compared to Northern blot, the concordance rate was 79% (22 of 28 cases) for p140 ^trkA (p < 0.05) and 71% (20 of 28 cases) for p75 ^LNGFR (p < 0.05). No case negative for Northern blot was found to be positive with immunohistochemistry. Since only high mRNA levels for both receptors have been shown to be clinically relevant, their immunohistochemical detection, although less sensitive than Northern blot, can be just as sufficient and reliable as a prognostic tool, and possibly with a better cost-benefit ratio.     

Transdermal Delivery of Metoprolol by Electroporation

Electroporation, i.e., the creation of transient pores in lipid membranes leading to increased permeability, could be used to promote transdermal drug delivery. We have evaluated metoprolol permeation through full thickness hairless rat skin in vitro following electroporation with an exponentially decaying pulse. Application of electric pulses increased metoprolol permeation as compared to diffusion through untreated skin. Raising the number of twin pulses (300 V, 3 ms; followed after 1 s by 100 V, 620 ms) from 1 to 20 increased drug transport. Single pulse (100 V, 620 ms) was as effective as twin pulse application (2200 V, 1100 V or 300 V, 3 ms; followed after 1 s by 100 V, 620 ms). In order to investigate the effect of pulse voltage on metoprolol permeation, 5 single pulses (each separated by 1 min) were applied at varying voltages from 24 to 450 V (pulse time 620 ms). A linear correlation between pulse voltage and cumulative metoprolol transported after 4 h suggested that voltage controls the quantity of drug delivered. Then, the effect of pulse time on metoprolol permeation was studied by varying pulse duration of 5 single 100 V pulses from 80 to 710 ms (each pulse also separated by 1 min). Cumulative metoprolol transported after 4 h increased linearly with the pulse time. Therefore, pulse time was also a control factor of the quantity of drug delivered but to a lesser extent than the voltage at least at 100 V. The mechanisms behind improved transdermal drug delivery by electroporation involved reversible increased skin permeability, electrophoretic movement of drug into the skin during pulse application, and drug release from the skin reservoir formed by electroporation. Thus, electroporation did occur as shown by the increased transdermal permeation, on indicator of structural skin changes and their reversibility. Electroporation has potential for enhancing transdermal drug delivery.     

Cytogenetic analysis of human oocytes parthenogenetically activated by puromycin

Purpose

Treatment of aged human oocytes by puromycin allows a high rate of parthenogenetic activation and development until the first cleavage division. This technique was used for the study of the chromosome complement of oocytes which remained unfertilized after in vitro fertilization. Three hundred four unfertilized oocytes were treated with 10 Μg/ml puromycin for 6–8 hr and further cultured for 12–15 hr.

Results

Activation occurred in 90.5% of the oocytes. Heterozygous diploids with two pronuclei predominated (61%), which is in contrast to the mouse, where the majority of oocytes activated by puromycin are uniform haploids (89%).

Conclusions

Therefore we conclude that puromycin treatment induces retention of the second polar body in human oocytes, unlike in mouse oocytes treated in the same way. Chromosome analysis performed on 182 oocytes suggested a nondisjunction (ND) rate for the second meiotic division of 12.7%. This is a low figure considering the fact that puromycin itself has been reported to induce nondisjunction. For the first meiotic division a ND rate of only 5.6% was found. This rate is lower than the one found in metaphase II arrested oocytes and we believe that this difference is due to the technical differences between the study of meiotic and that of mitotic chromosomes.     

Decision Aids for Preventive Treatment Alternatives for BRCA1/2 Mutation Carriers: a Systematic Review

Introduction Women with a pathogenic BRCA1/2 mutation have a markedly increased lifetime risk of developing breast and/or ovarian cancer. The current preventive treatment alternatives that are offered are an intensified breast cancer screening programme and risk-reducing operations. Before deciding on one option, medical and personal factors such as life situation and individual preferences must be weighed carefully. Decision aids are used internationally to support BRCA1/2 mutation carriers during their decision-making process. In this study these are analysed structurally for the first time and their applicability to the German context is examined. Material and Methods A systematic literature search in five electronic databases and a manual search were performed. The identified decision aids were evaluated with regard to formal criteria, medical content and quality. The qualitative assessment used the criteria of the International Patient Decision Aid Standards Collaboration (IPDASi v4.0), which examined various dimensions (e.g., information, probabilities, values). Results Twenty decision aids, which were published between 2003 and 2019 in Australia (n = 4), the United Kingdom (n = 3), Canada (n = 2), the Netherlands (n = 2) and the USA (n = 9), were included. Nine focus on BRCA1/2 mutation carriers and eleven include other risk groups. Eighteen include risk-reducing operations as decision options, 14 list screening methods for breast and/or ovarian cancer, and 13 describe the possibility of pharmacological prevention by means of selective oestrogen receptor modulators or aromatase inhibitors. Nine of the 20 decision aids meet fundamental quality criteria (IPDASi v4.0 qualification criteria). Conclusion International decision aids can serve formally as a basis for a German decision aid for BRCA1/2 mutation carriers. Some of them differ markedly in content from the recommendations of German guidelines. Only a few achieve a high quality. Key words: BRCA1, BRCA2, decision aid, familial breast cancer, familial ovarian cancer     

Adoptive Immunotherapy With Tumor-Infiltrating Lymphocytes and Subcutaneous Recombinant Interleukin-2 Plus Interferon Alfa-2a for Melanoma Patients With Nonresectable Distant Disease: A Phase I/II Pilot Trial

Background: On the basis of our previous experience, we designed this study to determine the activity and toxicity of outpatient treatment with autologous tumor-infiltrating lymphocytes (TIL) together with intermediate-dose recombinant interleukin-2 (rIL-2) and low-dose recombinant interferon alfa-2a (rIFN-2a), for patients with metastatic melanoma.Methods: Between April 1992 and October 1994, we processed 38 melanoma samples derived from 36 patients with metastases. Proliferative cultures of expanded lymphocytes (TIL) were infused only once into patients with metastatic melanoma. rIL-2 was administered subcutaneously for 1 month, starting on the day of TIL infusion, at an escalating dose of 6–18 × 10⁶ IU/m²/day for the first week and at the maximum-tolerated dose for the subsequent 3 weeks and then, after a 15-day interval, for 1 week/month for 3 months. rIFN-2a was administered subcutaneously at 3 × 10⁶ IU three times each week until progression.Results: Of 38 melanoma samples, 19 (50%) resulted in proliferative cultures and were infused. The median number of expanded lymphocytes was 18 × 10⁹ (range, 1–43 × 10⁹), and the median period of culture was 52 days (range, 45–60). rIL-2 was administered at doses ranging between 6 and 18 × 10⁶ IU/m²/day. Toxicity was mild or moderate, and no life-threatening side effects were encountered. Two of 19 treated patients experienced complete responses of their metastatic sites (soft tissue), 10 had stable disease, and 7 showed progressive disease. The response rate was 11% (95% confidence interval, 2–35%).Conclusions: Outpatient treatment with TIL plus rIL-2 and rIFN-2a is feasible, although, within the context of the small sample size, the activity of the combination was no different from the reported activity of any of the components used alone.