Non-opioid analgesic modes of pain management are associated with reduced postoperative complications and resource utilisation: a retrospective study of obstructive sleep apnoea patients undergoing elective joint arthroplasty.

BACKGROUND: Studies on the effectiveness of multimodal analgesia, particularly in patients at higher perioperative risk from obstructive sleep apnoea (OSA), are lacking. We aimed to assess the impact of multimodal analgesia on opioid use and complications in this high-risk cohort. METHODS: We conducted a population-based retrospective cohort study of OSA patients undergoing elective lower extremity joint arthroplasty (2006-16, Premier Healthcare database). Multimodal analgesia was defined as opioid use with the addition of one, two, or more non-opioid analgesic modes including, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 inhibitors, paracetamol/acetaminophen, peripheral nerve blocks, steroids, gabapentin/pregabalin, or ketamine. Multilevel multivariable regression models measured associations between multimodal analgesia and opioid prescription (primary outcome; oral morphine equivalents). Secondary outcomes included opioid- and OSA-related complications, and resource utilisation. Odds ratios (OR) or % change and 95% confidence intervals (CI) are reported. RESULTS: Among 181 182 OSA patients included, 88.5% (n = 160 299) received multimodal analgesia with increasing utilisation trends. Multivariable models showed stepwise beneficial postoperative outcome effects with increasing additional analgesic modes compared with opioid-only analgesia. In patients who received more than two additional analgesia modes (n = 64 174), opioid dose prescription decreased by 14.9% (CI -17.0%; -12.7%), while odds were significantly decreased for gastrointestinal complications (OR 0.65, CI 0.53; 0.78), mechanical ventilation (OR 0.23, CI 0.16; 0.32), and critical care admission (OR 0.60, CI 0.48; 0.75), all P<0.0001. CONCLUSIONS: In a population at high risk for perioperative complications from OSA, multimodal analgesia was associated with a stepwise reduction in opioid use and complications, including critical respiratory failure.

Employment after a breast cancer diagnosis: a qualitative study of ethnically diverse urban women.

Employment status is related to treatment recovery and quality of life in breast cancer survivors, yet little is known about return to work in immigrant and minority survivors. We conducted an exploratory qualitative study using ethnically cohesive focus groups of urban breast cancer survivors who were African-American, African-Caribbean, Chinese, Filipina, Latina, or non-Latina white. We audio- and video-recorded, transcribed, and thematically coded the focus group discussions and we analyzed the coded transcripts within and across ethnic groups. Seven major themes emerged related to the participants' work experiences after diagnosis: normalcy, acceptance, identity, appearance, privacy, lack of flexibility at work, and employer support. Maintaining a sense of normalcy was cited as a benefit of working by survivors in each group. Acceptance of the cancer diagnosis was most common in the Chinese group and in participants who had a family history of breast cancer; those who described this attitude were likely to continue working throughout the treatment period. Appearance was important among all but the Chinese group and was related to privacy, which many thought was necessary to derive the benefit of normalcy at work. Employer support included schedule flexibility, medical confidentiality, and help maintaining a normal work environment, which was particularly important to our study sample. Overall, we found few differences between the different ethnic groups in our study. These results have important implications for the provision of support services to and clinical management of employed women with breast cancer, as well as for further large-scale research in disparities and employment outcomes.

Complications after patello-femoral versus total knee replacement in the treatment of isolated patello-femoral osteoarthritis. A meta-analysis.

PURPOSE: Both patellofemoral arthroplasty (PFA) and total knee arthroplasty (TKA) are successful in treating isolated patellofemoral osteoarthritis, but the complication rates after PFA are concerning. We performed a meta-analysis to compare the incidence of complications, re-operations, and revision following PFA and TKA for patellofemoral osteoarthritis. METHODS: We systematically identified publications with patients who underwent PFA or TKA for patellofemoral osteoarthritis with minimum 1.5 year follow-up. Demographics, implant (TKA, first [1G] or second-generation [2G] PFA), complications, and cause of re-operations were extracted. Random-effects meta-analysis was used to pool incidence data, which was compared between groups using logistic regression to adjust for length of follow-up. RESULTS: Twenty-eight observational studies and no randomized trials were included in this meta-analysis, which limits its generalizability. There was a higher likelihood of any re-operation (odds ratio 8.06) and revision (OR 8.11) in PFA compared to TKA. Re-operation (OR 4.33) and revision (OR 4.93) were more likely in 1G-PFA than 2G-PFA. When comparing 2G-PFA to TKA, there was no significant difference in re-operation, revision, pain, or mechanical complications. CONCLUSIONS: Patients who undergo PFA rather than TKA are more likely to experience complications and require re-operation or revision, but subgroup analysis suggests a relation to implant design. There is no significant difference in re-operation, revision, pain, or mechanical complications between 2G-PFA and TKA. LEVEL OF EVIDENCE: Systematic review of Level III therapeutic studies, Level III.

Molecular cloning of the retrograde transport motor cytoplasmic dynein (MAP 1C).

Overlapping cDNAs encoding the entire heavy chain of cytoplasmic dynein (MAP 1C) have been obtained. A 4644 amino acid polypeptide containing four ATP-binding consensus sequences is predicted. Homology with the sea urchin flagellar outer arm dynein beta heavy chain is observed within the C-terminal two-thirds of the protein. The N-terminal third of the two polypeptides shows no clear relationship, suggesting that this region of MAP 1C is responsible for its association with retrograde organelles and other functions. Northern blot analysis reveals a 16.5 kb band in brain and other tissues. Southern blot analysis is consistent with a single cytoplasmic dynein gene. Thus, in contrast with cilia and flagella, which contain numerous forms of dynein, our results are consistent with the existence of only a single cytoplasmic dynein heavy chain gene, which appears to produce only a single transcript.

Design and synthesis of bisubstrate inhibitors of type 1 17beta-hydroxysteroid dehydrogenase: overview and perspectives.

Type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD1) is a key steroidogenic enzyme that catalyses the reduction of steroid estrone into the most potent endogenous estrogen estradiol using the cofactor NAD(P)H. Bisubstrate inhibition is a good way to enhance the potency of inhibitors of cofactor-assisted enzymes. The design of a bisubstrate inhibitor of 17beta-HSD1, the estradiol/adenosine hybrid EM-1745, is reviewed and strategies for future designs of inhibitors are proposed.

Reproduction phase-related expression of beta-endorphin-like immunoreactivity in the nucleus lateralis tuberis of the female Indian major carp Cirrhinus mrigala: correlation with the luteinising hormone cells-ovary axis.

The present study aimed to determine whether beta-endorphin immunoreactivity (bEP-ir) in the neurones of the nucleus lateralis tuberis (NLT) is linked to the seasonal cycle and shows correlation with the number of luteinising hormone (LH) cells in the pituitary gland and ovaries in the teleost, Cirrhinus mrigala. Although LH cells were moderately immunostained during the resting phase (December to January), the morphological profile suggested increased synthetic and secretory activity during the preparatory (February to April) and prespawning (May to June) phases. However, LH immunoreactivity was greatly reduced (P < 0.001) in the spawning (July to August) phase, suggesting massive discharge of the hormone; this pool was partly replenished in the postspawning (September to November) phase. The ovaries grew rapidly in the preparatory and prespawning phases; maximal size was attained during spawning, when ovulation occurred. Thereafter, the ovaries regressed. The NLT of C. mrigala is divisible into the pars lateralis (NLTl) and medialis (NLTm). During the postspawning and resting phases, bEP-ir was readily detectable in the NLTm as well as NLTl neurones. However, a steady reduction in the immunoreactivity was observed in the NLTm neurones during the preparatory through spawning phases (P < 0.001), suggesting a negative correlation with the LH cells-ovary axis. Thus, the inhibitory influence of beta-endorphin on the gonadotrophin-releasing hormone (GnRH)-LH axis appears to be attenuated during the preparatory through spawning phases. This may be necessary for the rapid stimulation of the axis culminating in spawning. Neurones of the NLTl also showed a gradual reduction in bEP-ir during the preparatory and prespawning phases (P < 0.01) and may therefore play a similar role. However, significant augmentation of the immunoreactivity was noticed in these neurones during the spawning phase (P < 0.001), the physiological significance of which is unknown. Although the present study demonstrated a temporal correlation between the beta-endorphin in the NLT, LH cells and the ovary, we suggest that the peptide in the NLTl and NLTm may show functional duality during the spawning phase.

Clinical trials in relapsed prostate cancer: defining the target.

A re-examination of the methods of developing new treatments for patients with prostate cancer whose disease has progressed during hormone therapy is necessitated by the following: 1) the impact of prostate-specific antigen (PSA) testing on patient selection, 2) the increasing number of studies using noncytotoxic approaches, and 3) the lack of validated methods to report outcomes. PSA monitoring after primary therapy has increased the number of patients referred for therapy with a rising value in this marker or an asymptomatic change in a radionuclide bone scan as the only manifestation(s) of relapse. The development of drugs for this population of patients presents a unique challenge because the classical criterion used to assess efficacy in the phase II setting, i.e., the presence of objective changes in measurable disease sites, frequently does not apply. Since no approach has been proven to prolong survival, the highest priority must be placed on developing new therapies. Standardizing the methods for evaluating treatments is also essential so that promising strategies are pursued and inactive therapies are not developed further.

Phase II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors.

BACKGROUND: Between 20% and 30% of patients with advanced germ cell tumors (GCTs) fail to have durable complete response to conventional cisplatin-based induction chemotherapy. However, third-line therapy with high-dose carboplatin and etoposide plus autologous bone marrow transplantation (AuBMT) has induced durable complete response in 10%-20% of patients with cisplatin-resistant GCT. PURPOSE: We conducted a phase II trial of first-line therapy that included high-dose carboplatin and etoposide plus AuBMT in untreated men with advanced GCTs and unfavorable prognosis (i.e., "poor-risk" patients). METHODS: Twenty-eight patients were treated with a conventional-dose, cisplatin-containing regimen (VAB-6 [cisplatin, vinblastine, bleomycin, cyclophosphamide, dactinomycin]) with or without high-dose carboplatin (1500 mg/m2) and etoposide (1200 mg/m2) plus AuBMT. Twenty-two of these patients were selected for treatment with two cycles of high-dose carboplatin and etoposide plus AuBMT when reduced clearance of serum tumor markers (alpha-fetoprotein [AFP] or human chorionic gonadotropin [HCG]), as evidenced by prolonged half-life (> 7 days for AFP and > 3 days for HCG), was observed after two cycles of conventional treatment. RESULTS: Fifteen (56%) of 27 patients considered assessable for response achieved a complete response (12 treated with high-dose chemotherapy plus AuBMT). Sixteen (57%) are alive; 13 (46%) are free of disease at a median follow-up of 31.2 months. For 36 cycles of high-dose chemotherapy, the median duration from bone marrow infusion until a granulocyte count of 0.5/mm3 and a platelet count of 50,000/mm3 was 16 days (range, 7-41 days and 8-30 days, respectively). Analysis showed a trend toward improved survival (P = .07) in patients treated with high-dose chemotherapy in this study, compared with 68 poor-risk patients with GCT treated with conventional-dose therapy alone in two earlier studies. Toxicity was not cumulative, and recovery of blood counts after AuBMT was generally rapid. CONCLUSIONS: Inclusion of high-dose carboplatin-containing chemotherapy in treatment of poor-risk GCT patients is feasible when serum tumor marker half-life is used to predict resistance to standard cisplatin-based therapy. High-dose therapy in this setting was well tolerated. IMPLICATIONS: Early use of a dose-intensive regimen may increase survival compared with conventional-dose therapy alone. Further studies with standard induction therapy and intensive high-dose therapy using hematopoietic growth factor support are warranted, followed by a randomized trial comparing this strategy with standard therapy.

Allelic deletions in renal tumors: histopathological correlations.

Allelic loss on the short arm of chromosome 3 (3p) is considered to be one of the early detectable events in the pathogenesis of renal cell carcinoma (RCC). Conflicting reports, however, suggest that this event may be absent in some renal tumors. The present study attempts to further define subgroups of renal tumors associated with 3p deletions. In addition, we have also attempted to identify late genetic events associated with tumorigenesis and tumor progression. Eighty-two primary renal tumors (69 RCC and 13 oncocytic tumors) were analyzed by restriction fragment length polymorphism analysis directed at chromosomes 3, 11p, 17p, and 18q. Results were correlated with histopathological information. Deletions of 3p were seen in nonpapillary RCC of all cell types, but were absent in oncocytic and most papillary tumors. Among the 60 nonpapillary RCC, significant correlations were seen between deletion of 17p and tumor grade (P = 0.037), P stage (P = 0.027), and nodal metastases (P = 0.042). We therefore conclude that 3p deletions, although not specific to any cell type or histological pattern of RCC, are seen in a majority of clear cell nonpapillary RCC but are absent in oncocytic and most papillary tumors. Additional allelic losses on chromosome 17p are associated with advanced disease and, therefore, may be related to tumor progression. Further studies on larger series of patients with extended follow-up will be necessary to investigate the prognostic value of molecular genetic markers in RCC.

Phase I trial with pharmacokinetic analyses of high-dose carboplatin, etoposide, and cyclophosphamide with autologous bone marrow transplantation in patients with refractory germ cell tumors.

Thirty patients with cisplatin-refractory germ cell tumor were treated with high-dose carboplatin, etoposide, and cyclophosphamide and autologous bone marrow transplantation. The total dose of carboplatin was 1500 mg/m2, etoposide 1200 mg/m2, and cyclophosphamide was increased by increments from 60 to 150 mg/kg. Twenty-five cycles of treatment, given to 17 patients, did not include granulocyte-colony stimulating factor (G-CSF). Nineteen cycles of high-dose chemotherapy, given to 13 patients at the 2 highest dose levels of cyclophosphamide, included G-CSF. The dose of cyclophosphamide was escalated to 150 mg/kg/cycle without prohibitive toxicity. The use of G-CSF resulted in a shorter duration of neutropenia (P = 0.07); the median number of days until the recovery of an absolute granulocyte count > 0.5 was 25 without G-CSF and 14 with G-CSF. The most frequent nonhematological toxicity was hepatic, and there were 2 (7%) treatment-related deaths. Thirteen (43%) patients achieved a complete response, and 8 are alive and free of disease (27%); 7 are in continuous complete response (23%), and 1 after resection of a solitary site of disease following a relapse after high-dose chemotherapy. Five patients had pharmacology studies performed to determine the area under the curve (AUC) of free and total platinum, carboplatin, etoposide, cyclophosphamide, and phosphoramide mustard. There was a decrease in the AUC of cyclophosphamide and an increase in the AUC of phosphoramide mustard, the "active" metabolite, with successive days of treatment. The interpatient variability of the AUC of cyclophosphamide/phosphoramide mustard that was demonstrated was most likely a result of each individual's metabolic capacity. The measured AUC of carboplatin and/or free platinum closely approximated the predicted AUC of carboplatin calculated by renal function in 3 of the 5 patients. In summary, cyclophosphamide administered at a dose of 50 mg/kg x 3 days was achieved with acceptable toxicity, and no further dose escalation is planned. High-dose carboplatin, etoposide, and cyclophosphamide achieved a 23% continuous complete response proportion (27% alive, free of disease) when used as third-line therapy in germ cell tumor patients refractory to cisplatin + ifosfamide-based chemotherapy. Ongoing studies are addressing the role of high-dose carboplatin-containing chemotherapy in previously untreated patients with poor prognostic features or as a part of first-line salvage.

Non-migratory tumorigenic intrinsic cancer stem cells ensure breast cancer metastasis by generation of CXCR4(+) migrating cancer stem cells.

Although the role of metastatic cancer stem cells (mCSCs) in tumor progression has been well documented, our study reveals a hitherto unidentified role of tumorigenic intrinsic CSCs (iCSCs) in breast cancer metastasis. We show that unlike highly migratory mCSCs residing in the breast tumor disseminating/peripheral regions, iCSCs populate the inner mass of the tumor and are non-migratory. However iCSCs, via paracrine signaling, induce conversion of non-stem cancer cells to CSCs that (i) are identical to the previously reported mCSCs, and (ii) in contrast to iCSCs, express chemokine receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), which is crucial for their metastatic potential. These mCSCs also demonstrate high in vivo tumorigenicity. Physical non-participation of iCSCs in metastasis is further validated in vivo, where only mCSCs are found to exist in the metastatic sites, lymph nodes and bone marrow, whereas the primary tumor retains both iCSCs and mCSCs. However, iCSCs ensure metastasis since their presence is crucial for deliverance of highly metastatic CXCR4(+) mCSCs to the migrating fraction of cells. Cumulatively, these results unveil a novel role of iCSCs in breast cancer metastasis as parental regulators of CXCR4(+) mCSCs, and highlight the therapeutic requisite of targeting iCSCs, but not CXCR4(+) mCSCs, to restrain breast cancer metastasis from the root by inhibiting the generation of mCSCs from iCSCs. Considering the pivotal role of iCSCs in tumor metastasis, the possibility of metastasis to be a 'stem cell phenomena' is suggested.

High-dose carboplatin, etoposide, and cyclophosphamide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors.

PURPOSE: A treatment program that included high-dose carboplatin, etoposide, and cyclophosphamide (CEC) followed by autologous bone marrow transplantation (AuBMT) was investigated as first-line therapy in patients with poor-risk germ cell tumors (GCTs). PATIENTS AND METHODS: Previously untreated GCT patients with poor-risk features were treated with etoposide, ifosfamide, and cisplatin (VIP) with or without high-dose CEC plus AuBMT. Patients qualified for a change to high-dose CEC if a prolonged clearance of elevated serum tumor markers was observed after two cycles of the cisplatin-containing regimen. RESULTS: Sixteen patients were treated with VIP alone and 14 with VIP and high-dose CEC. Seventeen patients (57%) achieved a complete response. Twenty are alive (67%) and 15 (50%) are free of disease at a median follow-up time of 30 months. For 23 cycles of high-dose CEC, the median time from AuBMT to a granulocyte count > or = 0.5/microL was 11 days (range, 0 to 14) and to a platelet count 50,000/microL, 19 days (range, 14 to 34). The survival of 58 patients treated in two of our center's programs that incorporated high-dose chemotherapy (high-dose carboplatin plus etoposide [CE] and CEC) was compared with our prior experience with conventional-dose cisplatin chemotherapy alone in poor-risk GCT. Patients treated with marker-dependent, early-intervention high-dose chemotherapy experienced longer survival (P = .001). CONCLUSION: In this setting, high-dose CEC was well tolerated, cumulative toxicity was lacking, and the recovery of blood counts after AuBMT was rapid. A randomized trial has been initiated to investigate further the role of high-dose CEC in first-line therapy for patients with poor-risk GCT.

Ifosfamide- and cisplatin-containing chemotherapy as first-line salvage therapy in germ cell tumors: response and survival.

PURPOSE: To evaluate the efficacy and toxicity of ifosfamide- and cisplatin-containing chemotherapy as first-line salvage treatment for patients with germ cell tumors (GCT). PATIENTS AND METHODS: Fifty-six patients with advanced GCT resistant to one prior cisplatin-containing regimen were treated with a salvage chemotherapy regimen of ifosfamide, cisplatin, and either vinblastine or etoposide (VeIP/VIP). RESULTS: Twenty of 56 (36%) assessable patients achieved a complete response (CR). Thirteen (23%) are alive and continuously free of disease at a median follow-up time of 52 months; the median survival duration was 18 months. Among patients with a testis primary tumor site and a prior CR to first-line therapy, 65% are alive and 41% continuously disease-free, and the median survival time has not been reached. In contrast, for patients with an extragonadal primary tumor or with a testis primary tumor site and an incomplete response (IR) to first-line therapy, 31% are alive and 15% continuously free of disease, with a median survival time of 12 months (P < .03). CONCLUSION: Ifosfamide- and cisplatin-containing therapy achieves a durable CR in a minority of patients with resistant GCT as first-line therapy. Patients with a primary testis site who relapsed from a CR to first-line cisplatin therapy have a better prognosis than patients with an extragonadal primary tumor site or an IR to first-line therapy. Risk-directed clinical trials to improve response and survival in both subsets are warranted.

Prostate-specific antigen as a measure of disease outcome in metastatic hormone-refractory prostate cancer.

PURPOSE: To evaluate the prognostic significance of pretreatment parameters and posttherapy declines in prostate-specific antigen (PSA) in relation to the survival of patients with hormone-refractory prostate cancer. PATIENTS AND METHODS: One hundred ten assessable patients treated on seven sequential protocols at Memorial Sloan-Kettering Cancer Center (MSKCC) for hormone-refractory prostate cancer were evaluated for 29 different pretherapy and posttherapy parameters, including a posttherapy decline in PSA of 50% and 80% from baseline. RESULTS: In the univariate analysis, initial Karnofsky performance status (KPS) > or = 80% was associated with a favorable outcome (P = .005), while age, extent of disease on bone scan, and individual sites of metastatic disease were not significant. No difference in survival was observed between patients with measurable or assessable (bone only) disease. Initial hemoglobin (HGB; P = .0012), alkaline phosphatase (ALK; P = .0015), and lactate dehydrogenase (LDH; P = .0002) levels were significant discriminators, while the initial PSA was not. Using a landmark analysis, a significantly longer median survival rate was observed for patients with a > or = 50% decline in PSA (median not reached) versus patients with a less than 50% decline in PSA (median, 8.6 months; P = .0001). Multivariate analysis using the Cox proportional hazards model showed that a > or = 50% decline in PSA (P = .0004) and the natural log of LDH (P = .0001) were the two most significant variables predicting survival. The model was confirmed on an independent data set from the Norwegian Radium Hospital (NRH) in Oslo, Norway. CONCLUSION: The results suggest that posttherapy PSA declines can be used as a surrogate end point to evaluate new agents in hormone-refractory prostate cancer. The criteria for response need prospective validation in phase III trials.

High-dose carboplatin, etoposide, and cyclophosphamide for patients with refractory germ cell tumors: treatment results and prognostic factors for survival and toxicity.

PURPOSE: The efficacy and toxicity of high-dose carboplatin, etoposide, and cyclophosphamide with autologous bone marrow transplantation (AuBMT) was investigated in a prospective trial for patients with cisplatin-refractory germ cell tumor (GCT). Prognostic factors for survival and treatment-related toxicity were identified. PATIENTS AND METHODS: Fifty-eight patients with refractory GCT were treated with high-dose carboplatin, etoposide, and cyclophosphamide plus AuBMT. Prognostic factors for toxicity and survival were examined in multivariate analyses. RESULTS: Twenty-three patients (40%) achieved a complete response and 12 (21%) are alive and free of disease at a median follow-up time of 28 months. Myelosuppression was severe and there were seven (12%) treatment-related deaths. Independently predictive factors that resulted in faster blood count recovery were the use of granulocyte colony-stimulating factor (G-CSF) for the number of days to neutrophil count recovery (P = .013) and prior treatment with cisplatin limited to six cycles or less for the number of days to platelet count recovery (P = .0012). Both were predictive for the number of days of hospitalization (P = .04 and .03, respectively). The two independently predictive variables for survival were pretreatment level of HCG; human chorionic gonadotrophin (HCG; < or = 100 times the upper limit of normal [xnl] v > 100 xnl, P = .02) and the presence of retroperitoneal metastases (yes or no, P = .04). Patients grouped by HCG < or = 100 xnl with retroperitoneal metastases, HCG < or = 100 xnl without retroperitoneal metastases, and all patients with HCG more than 100 xnl had median survival times of 14, 11, and 3 months, respectively (P = .04). CONCLUSION: High-dose carboplatin, etoposide, and cyclophosphamide is an effective therapy for patients with refractory GCT, and results in a complete response proportion of 40% and a 2-year survival rate of 31% at a median follow-up time of 28 months. This was accomplished in a group of patients with a dismal prognosis to conventional-dose therapy.

Effect of cytokine therapy on survival for patients with advanced renal cell carcinoma.

PURPOSE: To evaluate the relationship between treatment with cytokine therapy and survival, investigate the effect of nephrectomy on survival, and identify long-term survivors among a cohort of 670 patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS: A total of 670 patients with advanced RCC treated on 24 clinical trials of systemic chemotherapy or cytokine therapy were the subjects of this retrospective analysis. Treatment was categorized as cytokine (containing interferon alfa and/or interleukin-2) in 396 patients (59%) and as chemotherapy (cytotoxic or hormonal therapy) in 274 (41%). Among the 670 patients, those with survival times of greater than 5 years were identified as long-term survivors. RESULTS: Patients treated with cytokine therapy had a longer survival time than did those treated with chemotherapy, regardless of the year of treatment or risk category based on pretreatment features. The median survival times for favorable-, intermediate-, and poor-risk patients were 27, 12, and 6 months for those treated with cytokines and 15, 7, and 3 months for those treated with chemotherapy, respectively. The magnitude of difference in median survival was greater in the favorable- and intermediate-risk groups. The median survival time was less than 6 months in the poor-risk group for both treatment programs. Median survival time was 14 months among patients with prior nephrectomy plus time from diagnosis to treatment greater than 1 year versus 8 months among those with time from diagnosis to treatment less than 1 year, regardless of pretreatment nephrectomy status. Thirty patients (4.5%) among the 670 patients were identified as long-term survivors; 12 were free of disease after nephrectomy and treatment with interferon alfa, interleukin-2, or surgical resection of metastasis. CONCLUSION: The low proportion of patients with advanced RCC who achieve long-term survival emphasizes the need for clinical investigation to identify more effective therapy.

Predicting outcome to chemotherapy in patients with germ cell tumors: the value of the rate of decline of human chorionic gonadotrophin and alpha-fetoprotein during therapy.

PURPOSE: The prognostic significance of the rate of decline of the serum tumor marker alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) during the first two cycles of chemotherapy in germ cell tumor (GCT) patients was initially reported by us, but its value has been debated. We re-examined this issue in the context of the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification system and investigated the role of including in the analysis patients whose markers normalized early. PATIENTS AND METHODS: One hundred eighty-nine GCT patients with elevated AFP/HCG marker values treated with platinum-based chemotherapy between 1986 and 1998 were included in this analysis. Patients were classified as good, intermediate, or poor risk by the IGCCCG criteria and as having satisfactory or unsatisfactory marker decline. Risk and marker decline were correlated with response, event-free survival, and overall survival. RESULTS: Satisfactory marker decline predicted improved complete response (CR) proportion and event-free and overall survival (P <.0001). The CR proportion, 2-year event-free, and 2-year overall survival rates for patients with a satisfactory and unsatisfactory marker decline were 92% versus 62%, 91% versus 69%, and 95% versus 72%, respectively. Marker decline remained a significant variable for all three end points when adjusted for risk (P <.01) with the outcome differences most pronounced in the poor-risk group. CONCLUSION: The rate of marker decline during chemotherapy has prognostic value independent of risk and may play a significant role in the management of poor-risk patients. It is appropriate to include patients whose markers normalized early.

Interferon alfa-2a in advanced renal cell carcinoma: treatment results and survival in 159 patients with long-term follow-up.

PURPOSE: Three trials were conducted to define the efficacy and toxicity of interferon alfa-2a in the treatment of metastatic renal cell cancer. Univariate and multivariate analyses were performed to identify prognostic factors for survival. PATIENTS AND METHODS: Prospectively, 159 patients were treated with interferon alfa-2a. In the first trial, 42 patients received 50 x 10(6) U/m2 intramuscularly three times per week. In the second trial, 64 patients received gradually escalating doses of interferon alfa-2a from 3 to 36 x 10(6) U subcutaneously administered daily. The third trial was randomized; 25 patients received daily interferon alfa-2a alone and 28 were treated with daily interferon alfa-2a and 0.15 mg/kg vinblastine every 3 weeks. RESULTS: The overall response proportion was 10% (two complete and 14 partial responses). The median response duration was 12.2 months. The median survival duration was 11.4 months, with 3% of patients alive at 5 or more years. A univariate statistical analysis showed that a Karnofsky performance status > or = 80, prior nephrectomy, and interval from diagnosis to treatment of longer than 365 days were significant prognostic factors for survival. In a multivariate analysis, only prior nephrectomy and Karnofsky performance status > or = 80 were shown to be independent predictors of survival. CONCLUSION: Interferon alfa-2a had minimal antitumor activity in patients with advanced renal cell carcinoma and long-term survival was achieved in a small proportion of patients. The need for continued investigation and the identification of more effective therapy for advanced renal cell carcinoma is evident from the poor overall survival rate observed in these 159 patients. The investigation of new agents and of interferon alfa-2a in combination with other agents remains a priority.

Molecular and cytogenetic studies in the diagnosis of patients with poorly differentiated carcinomas of unknown primary site.

PURPOSE: A minority of patients with poorly differentiated carcinoma achieve a complete response to cisplatin therapy. Recently, specific chromosomal abnormalities have been described for several solid tumor malignancies. Molecular and cytogenetic techniques were used to study tumors of patients with midline carcinoma of unknown primary site. MATERIALS AND METHODS: Forty patients with poorly differentiated carcinoma of unknown primary site had fresh tumor samples studied by cytogenetic analysis, Southern blot analysis for 12p copy number, and fluorescence in situ hybridization (FISH) for the identification of i(12p) and chromosome 12 aneuploidy. The response to cisplatin therapy was correlated to the diagnosis provided by the genetic studies. RESULTS: In 17 (42%) patients, a diagnosis was suggested by the genetic studies. This included a germ cell tumor in 12 (30%) patients by the finding of i(12p), increased 12p copy number, or a deletion of the long arm of chromosome 12. In five patients, a specific diagnosis other than germ cell tumor was suggested by tumor karyotype. These were neuroepithelioma, lymphoma, desmoplastic small-cell tumor, melanoma, and clear-cell sarcoma. The 75% response proportion to cisplatin therapy in patients with tumors showing chromosome structural abnormalities of germ cell tumor was greater than the 18% response proportion in patients for whom no diagnosis was provided (P = .002). CONCLUSION: Molecular and cytogenetic studies are useful in establishing specific diagnoses in patients with poorly differentiated carcinomas of unknown primary site. This group of tumors is heterogeneous and is composed of germ cell tumors, melanoma, lymphoma, neuroepithelioma, and desmoplastic small-round-cell tumor in addition to some that are not yet classifiable. Response to cisplatin therapy correlates with the finding of i(12p) in tumor by either molecular or cytogenetic studies.