Heat-evolved microalgal symbionts increase coral bleaching tolerance.

Coral reefs worldwide are suffering mass mortalities from marine heat waves. With the aim of enhancing coral bleaching tolerance, we evolved 10 clonal strains of a common coral microalgal endosymbiont at elevated temperatures (31°C) for 4 years in the laboratory. All 10 heat-evolved strains had expanded their thermal tolerance in vitro following laboratory evolution. After reintroduction into coral host larvae, 3 of the 10 heat-evolved endosymbionts also increased the holobionts' bleaching tolerance. Although lower levels of secreted reactive oxygen species (ROS) accompanied thermal tolerance of the heat-evolved algae, reduced ROS secretion alone did not predict thermal tolerance in symbiosis. The more tolerant symbiosis exhibited additional higher constitutive expression of algal carbon fixation genes and coral heat tolerance genes. These findings demonstrate that coral stock with enhanced climate resilience can be developed through ex hospite laboratory evolution of their microalgal endosymbionts.

Genomic innovations, transcriptional plasticity and gene loss underlying the evolution and divergence of two highly polyphagous and invasive Helicoverpa pest species.

BACKGROUND: Helicoverpa armigera and Helicoverpa zea are major caterpillar pests of Old and New World agriculture, respectively. Both, particularly H. armigera, are extremely polyphagous, and H. armigera has developed resistance to many insecticides. Here we use comparative genomics, transcriptomics and resequencing to elucidate the genetic basis for their properties as pests. RESULTS: We find that, prior to their divergence about 1.5 Mya, the H. armigera/H. zea lineage had accumulated up to more than 100 more members of specific detoxification and digestion gene families and more than 100 extra gustatory receptor genes, compared to other lepidopterans with narrower host ranges. The two genomes remain very similar in gene content and order, but H. armigera is more polymorphic overall, and H. zea has lost several detoxification genes, as well as about 50 gustatory receptor genes. It also lacks certain genes and alleles conferring insecticide resistance found in H. armigera. Non-synonymous sites in the expanded gene families above are rapidly diverging, both between paralogues and between orthologues in the two species. Whole genome transcriptomic analyses of H. armigera larvae show widely divergent responses to different host plants, including responses among many of the duplicated detoxification and digestion genes. CONCLUSIONS: The extreme polyphagy of the two heliothines is associated with extensive amplification and neofunctionalisation of genes involved in host finding and use, coupled with versatile transcriptional responses on different hosts. H. armigera's invasion of the Americas in recent years means that hybridisation could generate populations that are both locally adapted and insecticide resistant.

Isomer-specific comparisons of the hydrolysis of synthetic pyrethroids and their fluorogenic analogues by esterases from the cotton bollworm Helicoverpa armigera.

The low aqueous solubility and chiral complexity of synthetic pyrethroids, together with large differences between isomers in their insecticidal potency, have hindered the development of meaningful assays of their metabolism and metabolic resistance to them. To overcome these problems, Shan and Hammock (2001) [7] therefore developed fluorogenic and more water-soluble analogues of all the individual isomers of the commonly used Type 2 pyrethroids, cypermethrin and fenvalerate. The analogues have now been used in several studies of esterase-based metabolism and metabolic resistance. Here we test the validity of these analogues by quantitatively comparing their hydrolysis by a battery of 22 heterologously expressed insect esterases with the hydrolysis of the corresponding pyrethroid isomers by these esterases in an HPLC assay recently developed by Teese et al. (2013) [14]. We find a strong, albeit not complete, correlation (r = 0.7) between rates for the two sets of substrates. The three most potent isomers tested were all relatively slowly degraded in both sets of data but three esterases previously associated with pyrethroid resistance in Helicoverpa armigera did not show higher activities for these isomers than did allelic enzymes derived from susceptible H. armigera. Given their amenability to continuous assays at low substrate concentrations in microplate format, and ready detection of product, we endorse the ongoing utility of the analogues in many metabolic studies of pyrethroids.

Long-term follow-up of patients undergoing auto-SCT for advanced germ cell tumour: a multicentre cohort study.

Failure of cisplatin-based chemotherapy in advanced germ cell tumour (GCT) is associated with a poor outcome. High-dose chemotherapy and auto-SCT is one therapeutic option, although the long-term outcome after this procedure is unclear. We conducted a multicentre cohort study of consecutive patients undergoing a single auto-SCT for GCT between January 1986 and December 2004. Of 71 subjects, median follow-up is 10.1 years. OS at 5 years is 44.7% (95% confidence interval (CI) 32.9-56.5%) and EFS is 43.5% (95% CI 31.4-55.1%). There were seven (10%) treatment-related deaths within 100 days of auto-SCT. Three (4.2%) patients developed secondary malignancies. Of 33 relapses, 31 occurred within 2 years of auto-SCT. Two very late relapses were noted 13 and 11 years after auto-SCT. In multivariate analysis, favourable outcome was associated with IGCCC (International Germ Cell Consensus Classification) good prognosis disease at diagnosis, primary gonadal disease and response to salvage chemotherapy. We conclude that auto-SCT results in successful outcome for a relatively large subgroup of patients with high-risk GCT. Late relapses may occur, a finding not previously reported.

Targeted therapy for advanced renal cell carcinoma.

BACKGROUND: Advanced renal cell carcinoma has been resistant to drug therapy of different types and new types of drug therapy are needed. Targeted agents inhibit known molecular pathways involved in cellular proliferation and neoangiogenesis, the induction by the tumour of host microvascular networks. Angiogenesis is of special interest in the clear cell histologic subtype of renal cancer because of its vascularity and constitutively activated hypoxia-inducible path in the majority of tumours. OBJECTIVES: 1) To provide a systematic review of studies testing targeted agents.2) To identify the type and degree of clinical benefit, if any, of targeted agents over the prior standard of care, particularly any impact on overall survival. SEARCH STRATEGY: 1) Electronic search of CENTRAL, MEDLINE and EMBASE databases.2) Hand search of international cancer meeting abstract and other sources specified in the protocol. SELECTION CRITERIA: Randomized controlled studies of targeted agents in patients with advanced renal cell cancer reporting major remission rate or overall survival by allocation. Progression-free survival (PFS) was adopted as an additional outcome because PFS was a commonly chosen primary outcome, and because several pivotal studies allowed crossover from the control to the investigational arm after closure to accrual thereby making overall survival a problematic endpoint. DATA COLLECTION AND ANALYSIS: Nineteen fully eligible studies tested ten different targeted agents (Table 04). One additional study was excluded because no outcome data by allocation have been reported (Hutson 2007). For purposes of comparison, the studies were divided into three groups: Group 1 studies compared different doses of the same agents; Group 2 studies examined the impact of targeted agents in patients who had received prior cytokine or other systemic therapy; and Group 3 studies tested targeted agents in systemically naive patients, either against standard interferon-alfa or against another control therapy. Meta-analysis was not utilized because there were very few situations where the same agents had been tested in the same group in more than one study. MAIN RESULTS: In systemically untreated patients in studies using subcutaneous interferon-alfa as control therapy, the major findings were: 1) An improvement in overall survival has been demonstrated only with the use of weekly intravenous temsirolimus in patients with unselected renal cancer histology and adverse prognostic features (median survival 10.9 months versus 7.3 months for temsirolimus or interferon-alfa respectively, HR 0.73, P = 0.008 log rank, Hudes 2007). However, the chance of major remission was low and not improved with temsirolimus. 2) In patients with mostly good or intermediate prognostic risk with clear cell renal cancer, oral sunitinib improves the chance of major remission, the probability of symptomatic improvement, and freedom from disease progression (Motzer 2007); in a similar setting, the addition of biweekly intravenous bevacizumab to interferon-alfa also improved the chance of major remission and prolonged progression-free survival (Escudier 2007b); overall survival had not changed at the time of interim reporting of either study. In patients with clear cell renal cancers who had failed prior cytokine therapy, oral sorafenib gives a better quality of life than placebo as well as improved chance of being free of disease progression; overall survival may have improved but is hard to evaluate because of crossover of placebo-assigned patients after the study closed to accrual (Escudier 2007a). AUTHORS' CONCLUSIONS: Based on less than a decade of experience, some targeted agents with specified molecular targets have demonstrated clinically useful benefits over the previous standard of care for patients with advanced renal cancer. Much more research is required to fully establish the role of targeted agents in this condition.

Antigen clearing from porcine heart valves with preservation of structural integrity.

Bioprostheses currently used for replacement of diseased cardiovascular tissue are preserved and partially protected from immune rejection through chemical fixation. However, after implantation, chemically preserved (fixed) material has limited durability and lacks the ability to revitalize through cellular ingrowth and remodeling. As an alternative to fixation, we aimed at thoroughly removing antigens from tissue, leaving an intact scaffold, suitable for integration and revitalization in the host. Extensive washing of porcine heart valves with a mixture of two detergents (SDS and Triton X-100) yielded an intact matrix devoid of cells and depleted of soluble proteins that was minimally immunogenic in rabbits. A detailed characterization of the biomechanics and durability of the tissue is under way. If the lack of immunogenicity is confirmed in primates, our results would suggest that a detergent-washed, unfixed porcine heart valve can be an attractive non-inflammatory scaffold for heart valve regeneration in humans.

Immunotherapy for advanced renal cell cancer.

BACKGROUND: The course of advanced renal cell carcinoma is extremely variable, ranging from spontaneous remission to disease progression refractory to chemotherapy. Immunotherapy has held promise of improved outcomes based on uncontrolled studies and randomized controlled trials generally limited by small size and low power. OBJECTIVES: To evaluate immunotherapy for advanced renal cell carcinoma by comparing: (1) high dose interleukin-2 to other options and (2) interferon-alfa to other options. The primary outcome of interest was overall survival at one year, with remission as the main secondary outcome of interest. SEARCH STRATEGY: A systematic search of the CENTRAL, MEDLINE, and EMBASE databases was conducted for the period 1966 through end of December 2003. Handsearches were made of the proceedings of the periodic meetings of the American Urologic Association, the American Society of Clinical Oncology, ECCO - the European Cancer Conference, and the European Society of Medical Oncology for the period 1995 to June 2004. SELECTION CRITERIA: Randomized controlled trials that selected (or stratified) patients with advanced renal cell carcinoma, utilized an immunotherapeutic agent in at least one study arm, and reported remission or survival by allocation. Fifty-three identified studies involving 6117 patients were eligible and all but one reported remission; 32 of these studies reported the one-year survival outcome. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted each article by following a prospectively designed protocol. Dichotomous outcomes for treatment remission (partial plus complete) and for deaths at one year were used for the main comparisons. Survival hazard ratios were also used for studies of interferon-alfa versus controls, and for two randomized studies of the value of initial nephrectomy prior to interferon-alfa in fit patients with metastases detected at the time of diagnosis. MAIN RESULTS: Combined data for a variety of immunotherapies gave an overall chance of partial or complete remission of only 12.9% (99 study arms), compared to 2.5% in 10 non-immunotherapy control arms, and 4.3% in two placebo arms. Twenty-eight percent of these remissions were designated as complete (data from 45 studies). Median survival averaged 13.3 months (range by arm, 6 to 27+ months). The difference in remission rate between arms was poorly correlated with the difference in median survival so that remission rate is not a good surrogate or intermediate outcome for survival for advanced renal cancer. We were unable to identify any published randomized study of high-dose interleukin-2 versus a non-immunotherapy control, or of high-dose interleukin-2 versus interferon-alfa reporting survival. It has been established that reduced dose interleukin-2 given by intravenous bolus or by subcutaneous injection provides equivalent survival to high dose interleukin-2 with less toxicity. Results from four studies (644 patients) indicate that interferon-alfa is superior to controls (OR for death at one year = 0.56, 95% confidence interval 0.40 to 0.77). Using the method of Parmar 1998, the pooled overall hazard ratio for death was 0.74 (95% confidence interval 0.63 to 0.88). The weighted average median improvement in survival was 3.8 months. T he optimal dose and duration of interferon-alfa remains to be elucidated. The addition of a variety of enhancers, including lower dose intravenous or subcutaneous interleukin-2, has failed to improve survival compared to interferon-alfa alone. Two recent randomized studies have examined the role of initial nephrectomy prior to interferon-alfa therapy in highly selected fit patients with metastases at diagnosis and minimal symptoms: despite minimal improvement in the chance of remission, both studies of up-front nephrectomy improved median survival by 4.8 months over interferon-alfa alone. Recent studies have been examining anti-angiogenesis agents. A landmark study of bevacizumab, an anti-vascular endothelial growth factor antibody, was associated with significant prolongation of the time to progression of disease when given at high dose compared to low-dose or placebo therapy though frequency of remissions or survival were not improved. AUTHORS' CONCLUSIONS: interferon-alfa provides a modest survival benefit compared to other commonly used treatments and should be considered for the control arm of future studies of systemic agents. In fit patients with metastases at diagnosis and minimal symptoms, nephrectomy followed by interferon-alfa gives the best survival strategy for fully validated therapies. The need for more effective specific therapy for this condition is apparent.

Enzymatic bioremediation: from enzyme discovery to applications.

1. Enzymatic bioremediation is potentially a rapid method of removing environmental pesticide residues. Applications include the treatment of residues resulting from agricultural production and processing industries, such as the treatment of irrigation waters, surface-contaminated fruit and vegetables and spent dip liquors. 2. A specific application for some organophosphate-degrading enzymes involves detoxification of nerve agent stockpiles. Effective and affordable remediation requires highly specialized enzymes, so protein engineering techniques are being used to improve properties of various source enzymes to enhance catalytic rates, stability and substrate range. 3. Trials with an optimized organophosphate-degrading enzyme have shown the feasibility of such technology in various applications. 4. The enzymes developed for environmental remediation for specific pesticide classes also have applications as antidotes for high-dose pesticide poisonings and as prophylaxis for people at risk of high pesticide doses.

Immunotherapy for advanced renal cell cancer.

BACKGROUND: The course of advanced renal cell carcinoma is extremely variable, ranging from spontaneous remission to disease progression refractory to chemotherapy. Immunotherapy has held promise of improved outcomes based on uncontrolled studies and randomized controlled trials generally limited by small size and low power. OBJECTIVES: To evaluate immunotherapy for advanced renal cell carcinoma by comparing: (1) high dose interleukin-2 to other options and (2) interferon-alpha to other options. SEARCH STRATEGY: A search of MEDLINE, Cancerlit, EMBASE and Cochrane Library databases from 1966 through the end of 1999. Handsearches were made of the proceedings of the annual meetings of the American Urologic Association, ASCO, and biennial European ECCO meetings, and the references of identified studies. SELECTION CRITERIA: Randomized controlled trials that selected (or stratified) patients with advanced renal cell carcinoma, utilized an immunotherapeutic agent in at least one study arm, and reported response or survival by allocation. Forty-two studies involving 4216 patients were eligible and reported response and 26 of these reported survival outcome (3089 patients). DATA COLLECTION AND ANALYSIS: Two independent reviewers abstracted each article by following a prospectively designed protocol. Dichotomous outcomes for treatment response (partial plus complete) and for deaths at one year were used for the main comparisons. Survival hazard ratios were also used for studies of interferon-alpha versus controls. MAIN RESULTS: The average response rate was 10.2 % (range by arm, 0 - 39%) and complete response rate was 3.2% (123/3852; n = 38 studies). Median survival averaged 11.6 months (range by arm, 6 - 28 months) and two-year survival averaged 22% (16 studies, range by arm 8 - 41%). There were no placebo-controlled studies and no randomized controlled studies examined survival for high dose interleukin-2 versus controls. Results from 6 studies (n = 963) indicate that interferon-alpha is superior to controls (OR for death at one year = 0.67, 95% CI 0.50 - 0.89. The pooled hazard ratio for survival of 0.78 (0.67 - 0.90) indicates that the treatment effect persisted until 24 months from randomization. The weighted average median improvement in survival was 2.6 months. Additional comparisons failed to prove a survival benefit from the addition of other agents to either modified schedules of interleukin-2 or to interferon-alpha. Dose-response studies examining survival for either agent could not be identified. The difference in response rate between arms was correlated with the difference in survival (P<0.001) suggesting that response rate difference may be a surrogate intermediate endpoint for survival. REVIEWER'S CONCLUSIONS: Interferon-alpha provides a modest survival benefit compared to other commonly used treatments and should be considered for the control arm of future studies of systemic agents. Interleukin-2 has not been validated in controlled randomized studies.

Locoregional first recurrence after mastectomy: prospective cohort studies with and without immediate chemotherapy.

PURPOSE: To evaluate prospectively the impact of combination chemotherapy in the combined modality treatment of isolated first locoregional recurrence (LRR) following mastectomy for breast cancer. METHODS AND MATERIALS: Between 1979 and 1989, 120 chemotherapy-naive women with isolated LRR as first failure after mastectomy were prospectively identified, uniformly staged, and systematically followed. Treatment consisted of excision if feasible, radical locoregional radiotherapy, and a hormonal maneuver (unless estrogen receptor negative). The initial chemotherapy cohort also received 8 cycles of doxorubicin and cyclophosphamide. This was compared to a subsequent control cohort. RESULTS: For all patients, the 10-year actuarial relapse-free survival +/- 95% confidence interval was 42.1+/-9.2%, and overall survival was 56.8+/-9.1%. No difference was seen in locoregional control between cohorts. At 5 years, distant recurrence-free survival for chemotherapy and control cohort respectively was 75.4+/-10.8% and 60.7+/-12.5% (p = 0.33) and overall survival was 81.9%+/-9.6 and 74.3%+/-11.2 (p = 0.24). Univariate analysis showed no prognostic importance for any imbalance between cohorts. Cox modeling confirmed that complete resection was strongly associated with fewer LRR (hazard ratio [HR] 0.32, p = 0.001) and also with better overall survival (HR 1.82, p = 0.019). Chemotherapy produced a substantial reduction in risk of death (HR 0.72 CI 0.421-1.235, p = 0.23). CONCLUSIONS: In this prospective but nonrandomized study of treatment for first LRR, the risk of death in the later control cohort was 1.39 times the risk in the chemotherapy cohort but failed to reach statistical significance. The results justify further study.

An episode of accelerated amino acid change in Drosophila esterase-6 associated with a change in physiological function.

In most lineages of the subgenus Sophophora esterase-6 is a homodimeric haemolymph protein. In the melanogaster subgroup of species it has become a monomer which is mainly expressed in the male sperm ejaculatory duct. Our analyses of esterase-6 sequences from three melanogaster subgroup species and two close relatives reveal a brief period of accelerated amino acid sequence change during the transition between the ancestral and derived states. In this period of 2-6Myr the ratio of replacement to silent site substitutions (0.51) is about three times higher than the values in other lineages of the phylogeny. There are about 50 more replacements in this period than would be predicted from the ratios of replacement to silent site substitutions found elsewhere in the phylogeny. Modelling on the known structure of a related acetylcholinesterase suggests that an unusually high proportion of the replacements in the transitional branch are non-conservative changes on the protein surface. Up to half the accelerated replacement rate can be accounted for by clusters of changes to the face of the molecule containing the opening of the active site gorge. This includes changes in and around regions homologous to peripheral substrate binding sites in acetylcholinesterase. There are also three changes in glycosylation status. One region predicted to lie on the protein surface which becomes markedly more hydrophilic is proposed to be the ancestral dimerisation site that is lost in the transitional branch.

Abbreviated treatment for elderly, infirm, or noncompliant patients with limited-stage small-cell lung cancer.

PURPOSE: To evaluate the efficacy of an abbreviated treatment plan consisting of two cycles of chemotherapy plus thoracic irradiation in a population of limited-stage small-cell lung cancer (LSCLC) patients who were elderly, infirm, or noncompliant with standard-duration therapy. PATIENTS AND METHODS: Fifty-five LSCLC patients (median age, 73) were treated with one cycle of cyclophosphamide, doxorubicin, and vincristine (CAV) followed 3 weeks later by one cycle of etoposide and cisplatin (EP). Both regimens were administered at conventional full dose. Thoracic irradiation (20 to 30 Gy) was delivered concurrently with EP. RESULTS: Complete response occurred in 28 patients (51%) and partial response in 21 (38%). The median survival time was 54 weeks; the 2-year survival rate was 28% and the actual 5-year survival rate was 18%. Three patients died of toxicity. CONCLUSION: Elderly, infirm, or noncompliant LSCLC patients who are unable to receive standard-duration chemotherapy may have useful palliation and potential for long-term survival with abbreviated chemotherapy (two cycles) and thoracic irradiation.

A four base pair insertion polymorphism in the 3' untranslated region of the COL1A1 gene is highly informative for null-allele testing in patients with osteogenesis imperfecta type I.

In patients with osteogenesis imperfecta (OI) type I, a decrease in synthesis of type I collagen is usually observed as a result of a COL1A1 null allele. Testing for COL1A1 null alleles can be done using polymorphic markers in the coding region of the COL1A1 gene. Until now, only one marker for polymorphism in the 3' untranslated region (3' UTR) of the COL1A1 gene has been available. We have identified a 4 bp insertion in the 3' UTR of the COL1A1 gene localized downstream of the MnlI RFLP and used both markers in combination for the analysis of patients with OI type I. In a total of 50 patients, 28 showed heterozygosity for one of the two markers; 14 of them were shown to have a COL1A1 null allele.

Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer.

BACKGROUND: Radiotherapy after mastectomy to treat early breast cancer has been known since the 1940s to reduce rates of local relapse. However, the routine use of postoperative radiotherapy began to decline in the 1980s because it failed to improve overall survival. We prospectively tested the efficacy of combining radiotherapy with chemotherapy. METHODS: From 1978 through 1986, 318 premenopausal women with node-positive breast cancer were randomly assigned, after modified radical mastectomy, to receive chemotherapy plus radiotherapy or chemotherapy alone. Radiotherapy was given to the chest wall and locoregional lymph nodes between the fourth and fifth cycles of cyclophosphamide, methotrexate, and fluorouracil. RESULTS: After 15 years of follow-up, the women assigned to chemotherapy plus radiotherapy had a 33 percent reduction in the rate of recurrence (relative risk, 0.67; 95 percent confidence interval, 0.50 to 0.90) and a 29 percent reduction in mortality from breast cancer (relative risk, 0.71; 95 percent confidence interval, 0.51 to 0.99), as compared with the women treated with chemotherapy alone. CONCLUSIONS: Radiotherapy combined with chemotherapy after modified radical mastectomy decreases rates of locoregional and systemic relapse and reduces mortality from breast cancer.

The load dependence of kinesin's mechanical cycle.

Kinesin is a dimeric motor protein that transports organelles in a stepwise manner toward the plus-end of microtubules by converting the energy of ATP hydrolysis into mechanical work. External forces can influence the behavior of kinesin, and force-velocity curves have shown that the motor will slow down and eventually stall under opposing loads of approximately 5 pN. Using an in vitro motility assay in conjunction with a high-resolution optical trapping microscope, we have examined the behavior of individual kinesin molecules under two previously unexplored loading regimes: super-stall loads (>5 pN) and forward (plus-end directed) loads. Whereas some theories of kinesin function predict a reversal of directionality under high loads, we found that kinesin does not walk backwards under loads of up to 13 pN, probably because of an irreversible transition in the mechanical cycle. We also found that this cycle can be significantly accelerated by forward loads under a wide range of ATP concentrations. Finally, we noted an increase in kinesin's rate of dissociation from the microtubule with increasing load, which is consistent with a load dependent partitioning between two recently described kinetic pathways: a coordinated-head pathway (which leads to stepping) and an independent-head pathway (which is static).

Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: A prospective randomized trial was conducted to determine whether the addition of concurrent cisplatin to preoperative or definitive radiation therapy in patients with muscle-invasive bladder cancer improved local control or survival. PATIENTS AND METHODS: Ninety-nine eligible patients with T2 to T4b transitional cell bladder cancer participated, 64% with cT3b or cT4. Patients and their physicians selected either definitive radiotherapy or precystectomy radiotherapy; patients were then randomly allocated to receive intravenous cisplatin 100 mg/m2 at 2-week intervals for three cycles concurrent with pelvic radiation, or to receive radiation without chemotherapy. Patients were stratified by clinical tumor stage and by radiation plan. The median follow-up duration is 6.5 years. RESULTS: The occurrence of distant metastases was the same in both study arms. However, 25 of 48 control patients have had a first recurrence in the pelvis, compared with 15 of 51 cisplatin-treated patients (P = .036). The pelvic relapse rate in the two groups was significantly reduced by concurrent cisplatin (P = .038, log-rank test) and this effect was preserved in a stepwise Cox regression model of prognostic factors (hazards ratio, 0.50; 90% confidence interval [CI], 0.29 to 0.86; P = .036). The hazard reduction was similar for both radiation plans. Pretreatment leukocytosis and high clinical stage were independent adverse factors in a Cox model of overall survival, but the effect of cisplatin was not significant. CONCLUSION: Concurrent cisplatin may improve pelvic control of locally advanced bladder cancer with preoperative or definitive radiation, but has not been shown to improve overall survival. The use of concurrent cisplatin had no detectable effect on distant metastases.

Teratoma in primary testis tumor reduces complete response rates in the retroperitoneum after primary chemotherapy. The case for primary retroperitoneal lymph node dissection of stage IIb germ cell tumors with teratomatous elements.

BACKGROUND: Recent advances in the therapy of advanced testicular nonseminomatous germ cell tumors (NSGCT) have resulted in increased attention to avoiding double therapy in cases where single modality therapy will suffice. METHODS: Over an 8-year period, 104 patients with Stage II and III testicular NSGCT received primary chemotherapy. Seventy-nine patients had retroperitoneal lymph nodal metastases, 33 of whom had a radiologic complete response, 43 a radiologic incomplete response, and 3 were not re-evaluated after induction chemotherapy. Thirty-nine patients underwent retroperitoneal lymph node dissection (RPLND). The radiologic and pathologic response of the nodes to primary chemotherapy was correlated with tumor burden (lymph node metastasis size < or = 2 cm, 2.1-5 cm, 5.1-10 cm, and >10 cm), primary tumor pathology, and prechemotherapy marker levels. RESULTS: Larger initial lymph node size, metastases size, the presence of teratoma in the primary tumor, and prechemotherapy alpha-fetoprotein (alpha-FP) > 80 mg/L and beta-HCG (bHCG) 10000 IU/L were found to correlate significantly with an incomplete radiologic response. Lymph node metastases size was the only independent prognostic factor on multivariable logistic regression analysis. Prechemotherapy alpha-FP > 80 mg/L and beta-HCG > 10000 IU/L were associated with the presence of teratoma or carcinoma in the retroperitoneal nodes. The presence of teratoma in the primary tumor is associated with a higher incomplete response rate and residual teratoma in the retroperitoneal lymph nodes after primary chemotherapy. CONCLUSIONS: Predictors of need for postchemotherapy RPLND include large lymph node metastasis size and presence of teratomatous elements in the primary tumor. To reduce the need for and morbidity of double therapy, patients with low volume clinical Stage II, NSGCT and teratomatous elements in the primary tumor are arguably better served by primary RPLND.