Comparison of perinatal outcomes between spontaneous vs. commissioned cycles in gestational carriers for single and same-sex male intended parents.

PURPOSE: To determine whether gestational carrier (GC) in vitro fertilization (IVF) cycles (commissioned cycles) for same-sex or single male intended parents have an increased incidence of adverse perinatal outcomes compared with spontaneous cycles in the same GCs. DESIGN: GC singleton pregnancies were identified from a database of 895 commissioned cycles from a large fertility center. Of these, 78 commissioned cycles met inclusion and exclusion criteria and were compared with 71 spontaneous cycles by the same GCs. The primary outcome was the composite score for adverse perinatal outcomes. Secondary outcomes included mode of delivery, birthweight, and gestational age. Chi-square test of association and Mann-Whitney U tests were used to compare categorical and continuous variables between the cohorts, respectively. Logistic and linear regressions controlling for GC age were constructed to determine the influence of GC cycle type on adverse perinatal outcomes. RESULTS: Commissioned cycles were significantly associated with adverse perinatal outcomes (25.6% vs. 9.9%; p = 0.02) and lower average gestational age (38.7 ± 1.5 vs. 39.4 ± 0.9; p < 0.001) compared with spontaneous cycles. Commissioned cycle increased the likelihood of adverse perinatal outcomes (OR 3.3; p = 0.03) and was a significant independent predictor of a lower average gestational age (ß = 0.897; p < 0.001). There were no significant differences in the incidence of vaginal deliveries or cesarean sections between commissioned and spontaneous cycles. CONCLUSIONS: Commissioned cycles confer a greater incidence of composite perinatal complications and were independently associated with a lower average gestational age when compared with spontaneous pregnancies carried by the same GC despite a confirmed healthy uterine environment, sperm samples, and donor oocytes.

Evaluation of the reliability of the Cutaneous Dermatomyositis Disease Area and Severity Index and the Cutaneous Assessment Tool-Binary Method in juvenile dermatomyositis among paediatric dermatologists, rheumatologists and neurologists.

BACKGROUND: The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) and Cutaneous Assessment Tool-Binary Method (CAT-BM) have been shown to be reliable and valid outcome measures to assess cutaneous disease in adult dermatomyositis (DM) and juvenile DM (JDM), respectively. OBJECTIVES: This study compared the CDASI and CAT-BM for use by paediatric dermatologists, paediatric rheumatologists and paediatric neurologists in patients with JDM. METHODS: Five paediatric dermatologists, five paediatric rheumatologists and five paediatric neurologists each evaluated 14 patients with JDM using the CDASI, CAT-BM, and skin Physician Global Assessment (PGA) scales. Inter-rater reliability, intra-rater reliability, construct validity and completion time were compared. RESULTS: Inter-rater reliability for CDASI activity and damage scores was good to moderate for paediatric dermatologists and rheumatologists, but poor for paediatric neurologists. The inter-rater reliability for CAT-BM activity scores was moderate for paediatric dermatologists and rheumatologists, but poor for paediatric neurologists and poor across all specialties for damage scores. Intra-rater reliability for the CDASI and CAT-BM activity and damage scores was moderate to excellent for paediatric dermatologists, rheumatologists and neurologists. Strong associations were found between skin PGA activity and damage scores and CDASI or CAT-BM activity and damage scores, respectively (P < 0·002). The CDASI had a mean completion time of 5·4 min compared with that for the CAT-BM of 3·1 min. CONCLUSIONS: Our data confirm the reliability of the CDASI activity and damage scores and the CAT-BM activity scores when used by paediatric dermatologists and rheumatologists in assessing JDM. Significant variation existed in the paediatric neurologists' scores.

The importance of thinking about the future in culture and cumulative cultural evolution.

Thinking about possibilities plays a critical role in the choices humans make throughout their lives. Despite this, the influence of individuals' ability to consider what is possible on culture has been largely overlooked. We propose that the ability to reason about future possibilities or prospective cognition, has consequences for cultural change, possibly facilitating the process of cumulative cultural evolution. In particular, by considering potential future costs and benefits of specific behaviours, prospective cognition may lead to a more flexible use of cultural behaviours. In species with limited planning abilities, this may lead to the development of cultures that promote behaviours with future benefits, circumventing this limitation. Here, we examine these ideas from a comparative perspective, considering the relationship between human and nonhuman assessments of future possibilities and their cultural capacity to invent new solutions and improve them over time. Given the methodological difficulties of assessing prospective cognition across species, we focus on planning, for which we have the most data in other species. Elucidating the role of prospective cognition in culture will help us understand the variability in when and how we see culture expressed, informing ongoing debates, such as that surrounding which social learning mechanisms underlie culture. This article is part of the theme issue 'Thinking about possibilities: mechanisms, ontogeny, functions and phylogeny'.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) in adulthood: A Dutch pilot study exploring clinical and patient-reported outcomes.

Background: Little is known about pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) in adulthood, as the genetic basis of the disorder has only been elucidated 15 years ago. This creates a knowledge gap for physicians, pediatric patients and their parents, which was aimed to address in this study using clinical data as well as patient-reported outcome measures (PROMs) for the patient's perspective. Methods: Dutch, genetically confirmed PDE-ALDH7A1 patients ≥18 years were eligible for inclusion. Clinical data were collected as well as PROMs (PROMIS item banks Anxiety, Depression, Anger, Physical Functioning, Cognitive Functioning, Cognitive Abilities, Ability to Participate and Satisfaction with Social Roles). Results: Ten out of 11 patients agreed to participate (91% response rate). Seizure control at last follow up (median age 25.2 years, range 17.8-29.8 years) was achieved with pyridoxine monotherapy in 70%, 20% with adjunct common-anti epileptic drugs and 10% did not obtain complete seizure control. Neurologic symptoms were present in all but one patient (90%) and included tremors, noted in 40%. Neuro-imaging abnormalities were present in 80%. Intellectual disability was present in 70%. One patient (10%) attended university, three maintained a job without assistance, five maintained a job with assistance or attended social daycare, and one patient never followed regular education. The cohort scored significantly lower on the PROMIS Cognitive Functioning compared to the general (age-related) population. Distribution of scores was wide on all PROMIS item banks. Discussion & conclusion: Outcomes of this young adult cohort are heterogeneous and individualized approaches are therefore needed. Long-term seizure control with pyridoxine was achieved for almost all patients. Neurologic symptoms were noted in the majority, including tremors, as well as neuro-imaging abnormalities and intellectual disability, additionally reflected by the PROMIS Cognitive Functioning. PDE-ALDH7A1 patients scored comparable to the general population on all other PROMs, especially regarding Ability to Participate and Satisfaction with Social Roles this may indicate a positive interpretation of their functioning. The aim is to expand this pilot study to larger populations to obtain more solid data, and to advance the use of PROMs to engage patients in research and provide the opportunity for personalized care.

Cognitive and neurological outcome of patients in the Dutch pyridoxine-dependent epilepsy (PDE-ALDH7A1) cohort, a cross-sectional study.

BACKGROUND: Pyridoxine monotherapy in PDE-ALDH7A1 often results in adequate seizure control, but neurodevelopmental outcome varies. Detailed long-term neurological outcome is unknown. Here we present the cognitive and neurological features of the Dutch PDE-ALDH7A1 cohort. METHODS: Neurological outcome was assessed in 24 patients (age 1-26 years); classified as normal, complex minor neurological dysfunction (complex MND) or abnormal. Intelligence quotient (IQ) was derived from standardized IQ tests with five severity levels of intellectual disability (ID). MRI's and treatments were assessed. RESULTS: Ten patients (42%) showed unremarkable neurological examination, 11 (46%) complex MND, and 3 (12%) cerebral palsy (CP). Minor coordination problems were identified in 17 (71%), fine motor disability in 11 (46%), posture/muscle tone deviancies in 11 (46%) and abnormal reflexes in 8 (33%). Six patients (25%) had an IQ > 85, 7 (29%) borderline, 7 (29%) mild, 3 (13%) moderate, and 1 severe ID. Cerebral ventriculomegaly on MRI was progressive in 11. Three patients showed normal neurologic exam, IQ, and MRI. Eleven patients were treated with pyridoxine only and 13 by additional lysine reduction therapy (LRT). LRT started at age <3 years demonstrated beneficial effect on IQ results in 3 patients. DISCUSSION: Complex MND and CP occurred more frequently in PDE-ALDH7A1 (46% and 12%) than in general population (7% and 0.2%, Peters et al., 2011, Schaefer et al., 2008). Twenty-five percent had a normal IQ. Although LRT shows potential to improve outcomes, data are heterogeneous in small patient numbers. More research with longer follow-up via the International PDE Registry (www.pdeonline.org) is needed.

RNA-loaded CD40-activated B cells stimulate antigen-specific T-cell responses in dogs with spontaneous lymphoma.

Cell-based vaccination strategies to induce functional tumor-specific T cells in cancer patients have focused on using autologous dendritic cells. An alternative approach is to use RNA-loaded CD40 activated B cells (CD40-B) that are highly efficient antigen-presenting cells capable of priming naive T cells, boosting memory T-cell responses and breaking tolerance to tumor antigens. The use of tumor RNA as the antigenic payload allows for gene transfer without viruses or vectors and permits major histocompatibility complex (MHC)-independent, multiple-antigen targeting. Here, we use CD40L transfected K562 cells to generate functional CD40-B cells from the peripheral blood of humans and dogs. Testing of RNA-loaded CD40-B cells in dogs allows not only for its development in veterinary medicine but also for determination of its safety and efficacy in a large animal model of spontaneous cancer prior to initiation of human clinical trials. We found that CD40-B cells from healthy humans, healthy dogs and tumor-bearing dogs express increased levels of immune molecules such as MHC and CCR7. Moreover, RNA-loaded CD40-B cells induce functional, antigen-specific T cells from healthy dogs and dogs with lymphoma. These findings pave the way for immunotherapy trials using tumor RNA-loaded CD40-B cells to stimulate antitumor immunity in a large animal model of spontaneous neoplasia.

Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis.

The antitumor effect and mechanisms activated by murine IL-12 and IL-18, cytokines that induce IFN-gamma production, were studied using engineered SCK murine mammary carcinoma cells. In syngeneic A/J mice, SCK cells expressing mIL-12 or mIL-18 were less tumorigenic and formed tumors more slowly than control cells. Neither SCK.12 nor SCK.18 cells protected significantly against tumorigenesis by distant SCK cells. However, inoculation of the two cell types together synergistically protected 70% of mice from concurrently injected distant SCK cells and 30% of mice from SCK cells established 3 d earlier. Antibody neutralization studies revealed that the antitumor effects of secreted mIL-12 and mIL-18 required IFN-gamma. Interestingly, half the survivors of SCK.12 and/or SCK.18 cells developed protective immunity suggesting that anti-SCK immunity is unlikely to be responsible for protection. Instead, angiogenesis inhibition, assayed by Matrigel implants, appeared to be a property of both SCK.12 and SCK.18 cells and the two cell types together produced significantly greater systemic inhibition of angiogenesis. This suggests that inhibition of tumor angiogenesis is an important part of the systemic antitumor effect produced by mIL-12 and mIL-18.

The effect of interleukin 12 desensitization on the antitumor efficacy of recombinant interleukin 12.

Use of the cytokine interleukin 12 (IL-12) has been shown to enhance the rejection of a variety of murine tumors, but preclinical and clinical studies have revealed that recombinant IL-12 (rlL-12) can produce severe toxicity. In an effort to improve the tolerance and therapeutic effectiveness of this cytokine, we investigated the influence of giving a single dose of recombinant murine IL-12 (rmIL-12) a week prior to daily cytokine administration (predosing) on its toxic and antitumor effects. These studies were performed in C3H/HeN mice, in which a course of rmIL-12 at standard doses without predosing induced rejection of syngeneic K1735 melanomas in 33%, and in A/J mice, in which treatment induced rejection of syngeneic B7-1+ SCK (SCK.B7-1) mammary carcinomas in 63%. Administration of a predose of rmIL-12 markedly reduced cytokine toxicity in a dose-dependent manner and allowed safe administration of up to 8-fold higher doses of daily rmIL-12 in C3H/HeN mice and 4-fold higher doses of rmIL-12 in A/J mice. Predosing followed by either standard or high daily doses of rmIL-12 did not significantly alter most end points of rmIL-12 treatment of K1735 or SCK.B7-1 tumors (survival, death from tumor, development of protective immunity, and so on), but they appeared to attenuate early control of tumorigenesis by rmIL-12. Evidence for the latter comes from a shortening of the characteristic rmIL-12-induced delay in tumor appearance and in the frequent appearance of tumors that subsequently regress. However, higher doses appear to produce better therapeutic results than standard doses of rmIL-12 after predosing. Predosing severely blunted induction of serum IFN-gamma levels by rmIL-12, which probably accounts for many of the effects of predosing on rmIL-12 toxicity and efficacy. Thus, predosing desensitizes mice to the toxic effects of rIL-12 and allows much higher doses to be given but, despite this, it does not improve and, by some criteria, it attenuates rIL-12 therapeutic outcome. Our results do not support the use of predosing as a way to enhance the effectiveness of rIL-12 in cancer clinical trials.

B7-1 and interleukin 12 synergistically induce effective antitumor immunity.

Enhanced host rejection of tumor cells is the primary goal of cancer immunotherapy and, in many murine tumor models, has been accomplished by engineering cells to express B7 costimulatory molecules or creating an environment rich in certain cytokines. We examined the effect of tumor cell B7-1 expression and administered recombinant interleukin 12 (IL-12) on the syngeneic host response to rapidly growing, poorly immunogenic SCK mammary carcinoma cells and to more slowly growing, immunogenic K1735 melanoma cells. Whereas B7-1 expression induced rejection of K1735 cells in 78% of mice, and IL-12 induced rejection in 38%, B7-1 expression induced rejection of SCK cells in only 28% of mice, and IL-12 induced rejection in none. The relative ineffectiveness of either B7-1 or IL-12 alone to induce rejection of SCK cells led us to combine the two manipulations. This resulted in rejection of SCK cells in 74% of mice and dramatically delayed tumor development in the remainder. Tumor rechallenge studies indicated that the surviving mice developed specific immunity to wild-type SCK cells. Lymphocyte subset ablation and IFN-gamma depletion studies indicated that rejection of SCK tumor cells brought about by the synergistic effects of B7-1 and IL-12 is mediated by a rapidly developing, systemic antitumor immune response that is dependent on the presence of both CD8+ and CD4+ T cells and involves IFN-gamma. Additionally, the synergistic effect of B7-1 expression and IL-12 administration is capable of inducing rejection of control SCK tumors simultaneously established in the opposite flank. The efficacy of B7-1 and IL-12 in inducing protective immunity against a poorly immunogenic, aggressive murine tumor indicates that this combination is particularly effective at producing a potent antitumor immune response that may be of therapeutic benefit.

Phase I study of topotecan plus cranial radiation for glioblastoma multiforme: results of Radiation Therapy Oncology Group Trial 9507.

PURPOSE: A phase I trial was conducted by the Radiation Therapy Oncology Group (RTOG) to determine the maximum-tolerated dose of topotecan that could be safely combined with standard cranial radiation for glioblastoma multiforme. A secondary objective was to document the acute and late toxicities of this combination of chemotherapy and radiation. PATIENTS AND METHODS: Forty-seven patients with histologically confirmed glioblastoma multiforme were entered onto this phase I trial. Three cycles of topotecan were administered at 21-day intervals commencing at day 1 of cranial radiotherapy (60 Gy/30 fractions). Each cycle consisted of daily 30-minute intravenous (IV) infusions for 5 days. The dose of topotecan was escalated in three-dose increments from 0.5 mg/m(2)/d to 1.0 mg/m(2)/d to 1.5 mg/m(2)/d in different patient groups. RESULTS: The majority of patients were over age 50. Three dose levels of topotecan were tested. Fifteen patients accrued to level 1 (topotecan dose 0.5 mg/m(2)/d). No grade 4 toxicities were seen. Sixteen patients accrued to level 2 (topotecan dose 1.0 mg/m(2)/d), five of whom had brief episodes of grade 4 neutropenia. Seventeen patients accrued to level 3 (1.5 mg/m(2)/d). Six of these patients had brief episodes of grade 4 neutropenia and four developed grade 3 thrombocytopenia. No serious nonhematologic or late toxicities were seen. Median survival for all patients was 9.7 months. There was no apparent difference in survival by topotecan dose schedule. CONCLUSION: Toxicity was acceptable at an IV topotecan dose of 1.5 mg/m(2)/d administered daily for 5 days every 21 days for three cycles. A phase II trial has been performed using this dose of topotecan.

Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85-31.

PURPOSE: Although androgen suppression results in a tumor response/remission in the majority of patients with carcinoma of the prostate, its potential value as an adjuvant has not been substantiated. MATERIALS AND METHODS: In 1987, the Radiation Therapy Oncology Group (RTOG) initiated a randomized phase III trial of adjuvant goserelin in definitively irradiated patients with carcinoma of the prostate. A total of 977 patients had been accessioned to the study. Of these, 945 remained analyzable: 477 on the adjuvant arm and 468 on the observation arm. RESULTS: Actuarial projections show that at 5 years, 84% of patients on the adjuvant goserelin arm and 71% on the observation arm remain without evidence of local recurrence (P < .0001). The corresponding figures for freedom from distant metastases and disease-free survival are 83% versus 70% (P < .001) and 60% and 44% (P < .0001). If prostate-specific antigen (PSA) level greater than 1.5 ng is included as a failure (after > or = 1 year), the 5-year disease-free survival rate on the adjuvant goserelin arm is 53% versus 20% on the observation arm (P < .0001). The 5-year survival rate (for the entire population) is 75% on the adjuvant arm versus 71% on the observation arm (P = .52). However, in patients with centrally reviewed tumors with a Gleason score of 8 to 10, the difference in actuarial 5-year survival (66% on the adjuvant goserelin arm v 55% on the observation arm) reaches statistical significance (P = .03). CONCLUSION: Application of androgen suppression as an adjuvant to definitive radiotherapy has been associated with a highly significant improvement in local control and freedom from disease progression. At this point, with a median follow-up time of 4.5 years, a significant improvement in survival has been observed only in patients with centrally reviewed tumors with a Gleason score of 8 to 10.

Myelofibrosis associated with multiple myeloma.

Two patients had both multiple myeloma and myelofibrosis. One, who had both conditions, had autopsy confirmation of diagnosis three months later. The typical picture of agnogenic myeloid metasplasia with myelofibrosis developed in the second patient almost four years after the onset of k light chain myeloma. At this time all evidence of multiple myeloma had disappeared perhaps related to cyclophosphamide therapy. We were able to find two similar cases described in the English language literature. The two conditions may be related.

Idiopathic thrombocytopenia purpura: Treatment patterns and an analysis of cost associated with intravenous immunoglobulin and anti-D therapy.

A retrospective study was conducted to determine treatment patterns for idiopathic thrombocytopenia purpura (ITP) across the US and to determine the cost of its treatment with high-dose intravenous immunoglobulin (IVIg) and anti-D therapy. Information on the incidence, treatment patterns, hospital care, and costs for ITP was derived from three data bases and supplemented by in-depth case studies from five hospital centers in the US. Data collection forms were developed to collect data on treatment patterns and costs at the five hospital centers. Treatment patterns were analyzed and used to model the comparative costs of IVIg and anti-D therapy. Cost estimations were based on a process and cost-finding analysis reflecting current practice patterns for the use of IVIg and anti-D therapy in an outpatient clinic. The incidence of ITP was estimated at 65 per 10,000 in human immunodeficiency virus (HIV)-positive individuals and 1.5 per 10,000 in HIV-negative individuals. Hospital discharge data from all 1991 and 1992 hospital discharges in Maryland revealed that both Medicare patients and patients who had other payment options spent less time in hospital compared to Medicaid patients. The limited case study data indicate that anti-D therapy increased platelet counts to greater than 25,000/microL in 82% of evaluable episodes and that IVIg-treated patients reached 25,000/microL in 48% of treated episodes. The estimated cost per treated episode of ITP was $4,269 for IVIg and $2,716 for anti-D therapy, reflecting a cost savings of $1,553 per episode. This retrospective study has shown that the use of anti-D therapy is associated with lower costs compared with IVIg treatment in patients with ITP. The shorter infusion time required for anti-D therapy may also contribute to a better quality of life for patients.

Carboplatin as a potentiator of radiation therapy.

A rationale for coordinating the administration of carboplatin with radiation to achieve enhancement of cancer therapy is developed. This approach is based upon a review of the reports of effects in a variety of systems, effects attributed to interactions between cisplatin or other platinum analogs and radiation. Two major effects include radiosensitization (RS) of hypoxic cells with platinum present during irradiation and potentiation of cell kill with platinum complexes administered after irradiation. Both these effects are expected to result in an improved therapeutic ratio. The latter effect may include inhibition of recovery from radiation-induced potentially lethal damage (PLD) and sublethal damage (SLD). Evidence for RS by carboplatin with an enhancement ratio (ER) of 1.8 is presented in Chinese hamster lung cells (V79) irradiated in culture under hypoxic conditions. Potentiation of radiation therapy in mice bearing a transplanted mouse mammary tumor (MTG-B) is reported as a supra-additive tumor growth delay when 60 mg/kg carboplatin is administered either 30 minutes before or immediately after 20 Gy of X-irradiation. Improved efficacy resulting from ongoing clinical trials coordinating cisplatin with radiation should support the role for carboplatin as a potentiator of radiation therapy since this second generation complex of platinum also interacts with radiation and larger concentrations of platinum should be attainable in tumors using the new drug.

Biologic and clinical developments of cisplatin combined with radiation: concepts, utility, projections for new trials, and the emergence of carboplatin.

Controlled experiments have shown that more than one mechanism leads to the potentiation of radiation-induced cell killing by cisplatin, and that this potentiation is not uniformly expressed among different cell types. A firm investigative base for the design of clinical trials using cisplatin and radiation has not been established. Coincident with this deficiency of experimental guidance, the independent clinical investigator has developed an array of therapeutic strategies applying different doses and sequences of cisplatin and radiation to a variety of tumor types. Results of clinical studies integrating cisplatin and radiation that can be judged for perceived survival benefit are evaluated in comparison with existing radiobiologic information. Both the clinical and radiobiologic results lead to similar conclusions at this time. Cells that are relatively sensitive to the cytotoxic action of cisplatin alone would best be considered for combined treatment with radiation. Large and infrequent, rather than small and frequent, individual administrations of cisplatin are better used with radiation for enhanced therapeutic effectiveness. Administration of cisplatin close in time to radiation is best for therapeutic response, although perceived efficacy follows from rather flexible integrations of these two modalities. It is not possible to know if clinical efficacy results from radiation potentiation as opposed to some degree of additivity of the two modalities. It is nonetheless useful to anticipate strategies that might lead to radiation potentiation by cisplatin in therapeutic designs. Two general mechanisms by which cisplatin potentiates radiation-induced cell killing are identified. One mechanism of potentiation is free radical-mediated, at least in part leads to an active radiolytic species following one-electron reduction of cisplatin, and is more readily expressed with bacterial cells than with mammalian cells in tissue culture. A second mechanism of potentiation is biochemical in nature, involves an effect of cisplatin on cellular components in ways that inhibit the recovery of radiation-induced damage, and likely applies more to the potentiation of oxic mammalian cells than bacterial cells. The latter mechanism is not universally supported in the literature. However, a unifying hypothesis, and one in need of confirmation at this time, is that the biochemical mechanism of radiation potentiation by cisplatin operates in oxic mammalian cells that are inherently sensitive to the cytotoxic action of cisplatin. This hypothesis ostensibly applies to tumor cells that are responsive to chemotherapy with cisplatin.(ABSTRACT TRUNCATED AT 400 WORDS)

Platinum based combined modality approach for locally advanced head and neck carcinoma.

Radiation therapy delivered soon after cisplatin administration is used for the treatment of advanced head and neck cancer. A radiation dose of 4800 cGy is given in standard fractions, followed by clinical evaluation and either surgical resection or an additional radiation dose of 2000 cGy. The histopathology of the surgical specimens from 21 patients undergoing resection in this protocol is compared with the corresponding clinical evaluation of tumor response. A significant number of both false negative and false positive clinical assessments are revealed by this comparison. In addition, it appears that local control of bulky head and neck cancer is approached by 4800 cGy combined soon after cisplatin. Discussion of the likely bases for this apparently favorable clinical interaction between cisplatin and radiation is presented.

Platinum drug delivery and radiation for locally advanced prostate cancer.

Combined therapies of cisplatin and radiation have resulted in clinical reports of apparent efficacious control of locoregional cancer and enhanced survival. Mechanisms of interaction between platinum and radiation that may explain these clinical observations all have in common the prediction that higher concentrations of platinum in all tumor cells close in time to irradiation should lead to greater potentiation of radiation-induced killing of those cells. Cisplatin is thus viewed as providing some radiation-equivalent, or a radiation dose-effect factor, for sterilization of tumors. One disease site that has not been well investigated for response to cisplatin plus radiation therapy, but that could benefit from it, is locally advanced prostate cancer. A body of literature now supports the view that local control of stage C (T3, N0, M0) prostate cancer is correlated with disease-free survival. This correlation makes prostate cancer a candidate for potentially achieving improved cure rates following local tumor sterilization by combining cisplatin with radiation therapy. The need and approaches to optimize delivery of cisplatin within tumor tissue is explored. Increasing cisplatin concentration to all the cells of a tumor, i.e., homogeneously delivering systemic high-dose cisplatin, should benefit the efficacious response otherwise expected for cisplatin combined with radiation. Strategies to increase the homogeneity of cisplatin delivery to a tumor are considered to be those that increase perfusion to that tumor. Vasoactive agents used in anticancer protocols are especially considered for their potential value in serving to increase tumor perfusion. These protocol-inclusive agents include certain cytokines and L-arginine antagonists, and should be better managed and accepted in practice compared to other vasoactive agents that need to be developed as specific additives to protocol designs.

Interstitial microwave hyperthermia and brachytherapy for malignancies of the vulva and vagina. I: Design and testing of a modified intracavitary obturator.

A vaginal obturator was fabricated to be used in combination with implanted catheters to provide microwave hyperthermia and brachytherapy to the vulva and vaginal wall. This site is difficult to heat or irradiate solely with interstitial techniques. The obturator was modified to provide grooves for the mounting of interstitial catheters into the outer wall and was matched with a template for circumferential implants. Power deposition tests were done using arrays of three microwave antenna designs: dipole (hA = hB = 3.9 cm), helical (3.9 cm coil, shorted), and modified dipole (1.0 cm helix on dipole tip) to test the performance of the obturator. The obturator and four non-obturator catheters were positioned in muscle-equivalent phantom. Two obturator catheters along with two free-standing catheters formed the obturator array. Four freestanding catheters formed the non-obturator array. Power deposition or specific absorption rate (SAR) measurements were made along the central axis, bisect, and diagonal transect of each array. SAR results showed that antennas in the obturator wall radiated as dipole theory predicts, although with less power density when compared to antennas in the same catheters spaced 1.8 cm from the obturator. This could be compensated for by increasing the power to the antennas in the obturator by 42%. Adjacent pairs of antennas were placed 90 degrees out of phase for 0.25 sec and rotated around the array. Phase rotation demonstrated that the central array SAR peaks could be lowered from 100% to 50% SAR, with dipole antennas thus resulting in lowered peak temperatures and the ability to heat larger volumes by improving the distribution of power. With helical antennas, there was 50% SAR at the array center when operated coherently without phase rotation. Three patients were treated with the obturator and a custom-made template using dipole antennas, and temperatures were measured in five obturator catheters. Therapeutic heating was measured in the catheters on the obturator between antennas in contact with the vaginal mucosa.

A phase I/II study to evaluate the effect of fractionated hemibody irradiation in the treatment of osseous metastases--RTOG 88-22.

PURPOSE: The present study was initiated to determine the maximum tolerated total dose that can be delivered by fractionated hemibody irradiation (HBI), as defined by the acute hematological and nonhematological toxicity. Although it was designed as a dose searching trial, the influence of higher doses on occult and overt disease were considered equally important. The study was not designed to evaluate pain relief. The results were compared to Radiation Therapy Oncology Group (RTOG) 82-06, which employed single high-dose HBI, to determine if either single or fractionated HBI is more effective in controlling occult or overt disease. METHODS AND MATERIALS: A total of 144 patients were entered from September 1989 to April 1993. Only patients with a single symptomatic bone metastases from either prostate or breast cancer primaries and a KPS > or = 60 were eligible. All patients initially received 30.0 Gy in 10 fractions to the symptomatic area followed by HBI in 2.50 Gy fractions to one of five arms: I-10.0 Gy (37 patients); II-12.5 Gy (23 patients); III-15.0 Gy (18 patients); IV-17.5 Gy (40 patients), and V-20.0 Gy (26 patients). A dose limiting toxicity was defined as an observed toxicity of > or = Grade 3 lasting more than 30 days postcompletion of HBI. If three or more dose-limiting toxicities occurred at any dose level, the previous dose was considered as the maximum tolerable dose. RESULTS: Thirty-six of 142 patients experienced > or = Grade 3 hematological toxicity at some time following HBI. The distribution of dose-limiting hematological toxicity in each arm was: I-two patients; II-one patients; III-zero patients; IV-one patient; and V-three patients. The major nonhematological toxicity was gastrointestinal and occurred in 10 patients. None were dose limiting. At 12 months from the initiation of treatment, the percent of patients with new disease were: Arms I-19%; II-9%; III-17%; IV-19%; V-13%; the percent of patients requiring additional treatment in the hemibody field were: Arms I-36%; II-30%; III-33%; IV-32%; and V-19%. When compared to single high-dose HBI the estimated reduction in the failure rate was 36% after fractionated HBI which potentially represents a modest improvement. CONCLUSIONS: The maximum tolerated dose of fractionated (2.50 Gy) HBI was found to be 17.5 Gy. The major dose limiting toxicity was hematological (thromboleukopenia). There was not a significant dose response effect on occult disease (appearance of new disease) or in the requirement for additional treatment, although certain trends were noted for the higher doses. When only patients completing assigned HBI from RTOG 82-06 and 88-22 were compared, there was no difference in the time to new disease or additional treatment in the treated field. Based on the investigative parameters of this study, single high-dose HBI was as effective as fractionated HBI. The incorporation of cytokines, to ameliorate hematological toxicity, should allow for the delivery of higher doses of fractionated HBI and sequential HBI as a means of delivering systemic irradiation.