Glioma stem cells (GSCs) have been implicated in radio- and chemotherapeutic resistance of glioblastoma (GBM). Therapeutic targeting of GSCs has shown promise in immunocompromised rodent models but have not been translated into effective therapies for human patients. The limited success of translating therapies from rodent models to GBM patients may be attributed, in part, to the lack of co-evolution between tumors and the tumor microenvironment in immunocompromised rodent models. Thus, spontaneous canine high-grade gliomas (HGGs) may provide a complementary translational model for human therapeutic development. While described in canine HGGs, little is known about canine glioma stem cell biology. In this study, we evaluatedcellular metabolism, DNA methylation, gene expression, and functional tests of malignancy to interrogate differences between canine glioma stem-cell like (GSLC) lines and a traditional serum grown glioma cell line following exposure to hypoxia. Hypoxia increased oxygen consumption rates in GSLCs, which correlated with hypoxia-induced hypomethylation and increased mRNA levels of genes important in cellular metabolism and stemness (e.g., KCNN3, KDM4B, TCF7L2), as well as augmented features of malignancy in GSLCs. Importantly, we were able to demonstrate a positive correlation between up-regulated genes in human GBM GSCs and hypomethylation of orthologous canine genes following hypoxia. Together, these data highlight similarities between canine and human GBM GSC cellular metabolism and their epigenetic regulation.

BACKGROUND: Although immune checkpoint inhibitor-based therapy has improved the outcomes of many patients with metastatic renal cell carcinoma (mRCC), most eventually develop disease progression. Newer agents that modulate immune response can possibly potentiate checkpoint inhibitor therapy. The ITK/ETK/BTK inhibitor ibrutinib has been reported to inhibit myeloid derived suppressor cells in preclinical models and to potentiate immunotherapy. We conducted an investigator-initiated trial of ibrutinib plus the PD1 inhibitor nivolumab in mRCC patients, particularly in those previously exposed to immune checkpoint inhibitors. METHODS: Eligible patients had mRCC of any histologic subtype, completed at least one line of prior systemic therapy which could have included prior immunotherapy, and had acceptable end-organ function with ECOG performance status of 0–2. Treatment consisted of nivolumab 240 mg intravenously every 2 weeks plus ibrutinib 560 mg (dose level 0) or 420 mg (dose level -1) orally once daily. Cycle length was 28 days. Dose limiting toxicity (DLT) was defined as any Grade 3 or higher adverse event (AE) attributable to therapy. After identification of the recommended phase 2 dose (RP2D), up to 19 patients were enrolled to an expansion cohort to further evaluate toxicities and any early evidence of efficacy. The primary endpoints of the trial were establishment of RP2D and progression-free survival (PFS). RESULTS: A total of 31 patients were enrolled, 6 to dose level 0, 7 (of which one was not evaluable for DLT) in dose level -1, and 18 in the expansion cohort. Median age was 60 years (range, 36–90), most had clear cell histology (n = 27; 87%), and most had prior immune checkpoint inhibitor therapy (n = 28; 90%). Three patients experienced one DLT each, all in dose level 0 (all Grade 3), namely elevated lipase, hypoalbuminemia, and nausea. No DLTs were seen in dose level –1 which was declared the RP2D. The most common Grade 3 or higher AEs include anemia (n = 5), lymphocyte count decrease (4), nausea (2), and hypotension (2). Of 28 patients evaluable for response, one patient (3.6%) had a complete response, 2 (7.1%) had a partial response, and 11 (39.2%) had stable disease, for an objective response rate of 10.7%(95%CI: 3.7%–27.2%) and a disease control rate of 50%(95%CI: 32.6%–67.4%). All responders had received prior immune checkpoint inhibitor therapy. Median PFS was 2.5 months (95%CI, 1.9 –4.8) while median OS was 9.1 months (95%CI, 6.6 –19.0). CONCLUSIONS: Ibrutinib at a dose of 420 mg orally once daily in combination with nivolumab 240 mg IV every 2 weeks is feasible and tolerable in mRCC patients. No unique immune-related AEs were observed. Anti-tumor activity was seen in patients previously exposed to PD-1 targeted therapy.

Objectives: Chronic pain is a leading cause of morbidity and disability across the world. Cultural engagement may be a valuable tool in addressing the social disconnection that often accompanies chronic pain. This study sought to develop a framework for arts in health programs targeting individuals with chronic pain. Study design: Sequential explanatory mixed-methods study. Methods: Web-based, cross-sectional survey sent to arts and cultural professionals to assess their experience with arts in health programming. Semi-structured interviews conducted with a sample of survey respondents to explore their perspectives on targeted arts in health programming for individuals with chronic pain. Results: Between October 2019 and January 2020, 208 surveys were completed by arts and cultural professionals. One hundred and twenty (58%) of the respondents indicated that they currently run an arts in health or museums in health program. Among these 120 respondents, 52 (43%) targeted older adults, 50 (42%) targeted individuals with mental health concerns, and 18 (15%) targeted individuals living with pain. Improving well-being (101 [84%]) and reducing social isolation (90 [75%]) were the most common intended program outcomes, while improving pain was the least common outcome (26 [22%]). Fifteen survey respondents were interviewed. Interviewees identified four interdependent themes regarding best practices for arts in health programs pertaining to (1) program content and structure, (2) program facilitation, (3) partnerships, and (4) programs for individuals with chronic pain. Conclusions: The cultural sector can support chronic pain prevention and treatment efforts through the development of specialized programs. This study provides a framework for developing arts in health programs that support individuals living with chronic pain. (C) 2021 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

Heart failure (HF) is a major health care burden increasing in prevalence over time. Effective, evidence-based interventions for HF prevention and management are needed to improve patient longevity, symptom control, and quality of life. Dietary Approaches to Stop Hypertension (DASH) diet interventions can have a positive impact for HF patients. However, the absence of a consensus for comprehensive dietary guidelines and for pragmatic evidence limits the ability of health care providers to implement clinical recommendations. The refinement of medical nutrition therapy through precision nutrition approaches has the potential to reduce the burden of HF, improve clinical care, and meet the needs of diverse patients. The aim of this review is to summarize current evidence related to HF dietary recommendations including DASH diet nutritional interventions and to develop initial recommendations for DASH diet implementation in outpatient HF management. Articles involving human studies were obtained using the following search terms: Dietary Approaches to Stop Hypertension (DASH diet), diet pattern, diet, metabolism, and heart failure. Only full-text articles written in English were included in this review. As DASH nutritional interventions have been proposed, limitations of these studies are the small sample size and non-randomization of interventions, leading to less reliable evidence. Randomized controlled interventions are needed to offer definitive evidence related to the use of the DASH diet in HF management.

Several reports have shown that doctoral and postdoctoral trainees in biomedical research pursue diverse careers that advance science meaningful to society. Several groups have proposed 3-tier career taxonomy to showcase these outcomes. This 3-tier taxonomy will be a valuable resource for institutions committed to greater transparency in reporting outcomes, to not only be transparent in reporting their own institutional data but also to lend greater power to a central repository.

Genitourinary tract diseases in the palliative care setting most commonly involve urinary tract obstruction, intractable bleeding, fistulae, and bladder-associated pain. Sources of obstruction in the lower urinary tract include benign prostatic hyperplasia, invasive prostate or bladder cancer, urethral stricture, or bladder neck contracture. Upper tract obstruction includes intraluminal or extraluminal blockage of the renal collecting system and ureters, such as transitional cell carcinoma, fibroepithelial polyps, stricture, stones, pelvic or retroperitoneal malignancy, fibrosis, or prior radiation. Untreated, obstructive uropathy leads to elevated bladder, ureter, and kidney pressures, bladder dysfunction, urolithiasis, renal failure, pyelonephritis, or urosepsis. Intractable haematuria can cause problematic anaemia, frequent transfusions, clot retention, haemorrhagic shock, and death. In addition, urinary tract fistulae such as vesicovaginal and vesicoenteric fistulae are common in patients who have had prior pelvic surgery or radiation especially in the setting of immunocompromise, poor nutrition, and infection. Untreated, these symptoms lead to rash, skin breakdown, ulcers, chronic infection, and sepsis. Lastly, pelvic and bladder pain, depending on aetiology can be treated with oral medications, intravesical therapies, or surgical therapies such as palliative resection or urinary diversion. Selection of tests and treatment modalities in the palliative care setting should be based on using the least invasive means to achieve the most relief in suffering. Some genitourinary conditions are potentially fatal, and in the acute or subacute setting, require re-evaluation of the end-of-life goals and wishes of the patient and family.

Over the past decade, various graduate medical education (GME) reform proposals1, 2 have been published, but few of their recommendations have been implemented. In this issue, the Society of General Internal Medicine (SGIM) has released another sensible roadmap for GME reform, recommending increased funding for workforce assessment studies, all-payer GME financing, and increased accountability of GME institutions for producing physicians to better meet the needs of society.3 At a time when so many consensus statements have languished, how do we avoid a similar fate for this proposal? We propose that the answer lies in making our academic health centers (AHCs) more accountable—by turning them into learning health care systems (LHCS), which are integrated and aligned with GME. The LHCS model, originally proposed by the Institute of Medicine, embraces patient/family-centered care and utilizes systems engineering, decision support and payment incentives to promote continuous quality improvement (QI), reduction of waste and harm, and strong community linkages that improve population health.4 The culture and incentives of AHCs have a tremendous influence on GME, and so must be considered if any reform effort is to be successful. As SGIM emphasizes, we must rapidly and reliably shore up the leaky primary care (PC) pipeline. Despite widespread agreement about the importance of a robust PC workforce to improve health outcomes, the current output of GME programs is inadequate to meet demand. To address the shortage, 40-50 % of US medical graduates (USMGs) must join the PC workforce, but currently fewer than 20 % do. Some of the most prestigious AHCs graduate the lowest percentages of PC physicians.5 Over 90 % of students choosing family medicine enter PC practice; yet some AHCs do not even have family medicine residency programs. Simply training more PC physicians will not be enough. USMGs do not reflect the increasing racial, ethnic, and socio-economic diversity of our communities. In California, 4 % of current physicians are Latino, compared with 40 % of the population.6 California’s Central Valley, the nation’s agricultural hub, suffers from extreme shortages of both PC and specialty physicians.6 Underrepresented minority graduates are more likely to work in underserved communities than their nonminority counterparts.7 To cultivate the next generation of PC physicians, we must tackle the issue of ambulatory practice redesign. In hospital-based clinics, trainees typically confront a lack of necessary resources and infrastructure to deliver high-quality, coordinated care. Yet in-patient rotations provide them the opportunity to work in multidisciplinary teams, spend time with patients, and experience a controllable lifestyle. It’s no wonder students and residents shun PC careers. AHCs must redesign their practices or deploy trainees away from the hospital to community partners who can adequately prepare PC physicians. However, many AHCs resist reforms aimed at expanding PC and ambulatory redesign. After all, they derive significant financial benefit from the inpatient-focused GME system, in which residents provide substantial amounts of service to patients, and thus enhance hospital revenues.8 The book Switch uses a metaphor of an elephant and a rider to illustrate how difficult systemic change can be.9 Whenever the rational rider and the six-ton elephant disagree, the rider loses to the whims of the giant below. So knowing the right course is not sufficient to cause change. The elephant must be compelled to embark on a new path. Rather than informing the rider (GME leaders) we need to motivate the elephant (AHCs) to change direction. Otherwise, SGIM’s recommendations will go unheeded. AHCs face extinction within the emerging high-value health system, in which they must compete by providing the highest quality care at a reasonable cost. The LHCS model provides them a lifeline. In this model, residents—who provide the majority of the care in AHCs—are actively engaged in QI, learning to become responsible stewards of our increasingly precious health care resources.10 If AHCs fail to change, trainees will dismiss high value care as a purely academic exercise within an environment that incentivizes wasteful diagnostic testing and imaging. This high-utilization fee-for-service paradigm has been the financial backbone of many AHCs. In a LHCS, the focus of GME would build on the evaluation of educational competencies and provide meaningful experiences in high-value care delivery and population health improvement. So how do we get there? We would begin by actively engaging the leadership of AHCs in efforts to bolster the PC pipeline and improve the health of their local communities. Medical school deans must elevate the stature of PC within their institutions, including investing in improving the ambulatory experience for trainees. Medical schools must accurately track and report numbers of graduates entering PC practice and develop programs that reduce the cost of medical school (e.g., loan forgiveness, scholarships) for students who choose PC careers. AHCs should respond to society’s need for high access, high quality, and high value health care. GME and AHCs must make a greater commitment to academic-community partnerships such as Teaching Health Centers and Federally Qualified Health Centers to improve care in underserved areas. These sites present an opportunity for new models that improve access, embrace inter-professional care, and integrate novel strategies for areas such as concomitant mental health and physical health care. Learners are integral to a new team that improves chronic disease management using community resources such as food banks, legal aid and housing agencies, and transportation programs for the most vulnerable. Patients, families, and community organizations become partners in a transparent, expanded LHCS. AHC leadership must make an explicit institutional commitment to promoting a high-value, cost-conscious care curriculum for all learners.11 The institutional QI infrastructure should be held responsible for resident QI activities, and should be applied to the ambulatory setting with equal rigor as is done within the hospital, so that trainees learn high quality ambulatory care delivery and population health management. Intermountain Health has done this successfully with practicing physicians by designing data systems and reorganizing management structures to increase accountability and drive QI, while producing substantial cost savings.12 The best way to reduce cost is to improve quality. Every year as Congress ponders the $9.5 B GME price tag for the Medicare program, the possibility of a dramatic reduction in the number of funded residency positions looms—at a time when the country needs more and better-prepared physicians. If such cuts occur, we might face the day when newly minted USMGs cannot secure residency positions. We conclude by making a bold proposition to AHC leaders. Rather than continuing to develop product lines to maximize profit and utilizing trainees to provide mostly inpatient specialty care, let’s invest GME dollars in enabling the next generation of clinicians to learn and deliver better quality across the continuum of care including our local communities. This paradigm shift would attract support for GME from a broad coalition including patients, the public, and payers.

Many patients with invasive urothelial cell cancer are poor candidates for cisplatin‐based chemotherapy, and many are high risk for cystectomy. Southwest Oncology Group Trial 8733 was designed to address treatment for such patients.

BACKGROUND:Many patients with invasive urothelial cell cancer are poor candidates for cisplatin-based chemotherapy, and many are high risk for cystectomy. Southwest Oncology Group Trial 8733 was designed to address treatment for such patients.METHODS:Eligible patients had primary or recurrent muscle-invasive disease with transitional cell or squamous cell histology, a performance status from 0 to 2, no extrapelvic disease, a life expectancy >3 months, and adequate hematologic function. The treating clinician assigned patients to operable or inoperable groups. All patients received 2 cycles of 5-fluorouracil (5-FU) at a dose of 1000 mg/m(2) per day x 4 starting concurrently with radiation at a dose of 200 centigrays per day x 10 each cycle. After 2 cycles, operable patients with positive biopsies underwent cystectomy, and patients with negative biopsies received a third cycle of chemoradiotherapy. Patients in the inoperable group received 3 cycles without interim biopsy.RESULTS:Eighteen of 24 eligible patients in the operable group were evaluable for response. Five patients had a complete response (CR), 9 patients had stable disease, 1 patient had progressive disease, and 3 patients were not assessable. The median progression-free survival was 10 months (95% confidence interval [95% CI], 4-14 months), and the median overall survival was 18 months (95% CI, 7-28 months). In the inoperable group, 35 of 37 eligible patients were evaluable for response with 17 CRs (49%; 95% CI, 31%-66%). The median progression-free survival was 13 months (95% CI, 10-17 months), and the median overall survival was 20 months (95% CI, 11-53 months). There were no episodes of grade 4 toxicity.CONCLUSIONS:In the current study, the combination of 5-FU and radiation was found to be tolerated well by patients with numerous comorbidities who could not tolerate cisplatin-based therapy or cystectomy.

PURPOSEMinority patients with cancer experience worse control of their pain than do their white counterparts. This disparity may, in part, reflect more miscommunication between minority patients and their physicians. Therefore, we examined whether patient coaching could reduce disparities in pain control in a secondary analysis of a randomized controlled trial.METHODSSixty-seven English-speaking adult cancer outpatients, including 15 minorities, with moderate pain over the prior 2 weeks were randomly assigned to the experimental (N = 34) or control group (N = 33). Experimental patients received a 20-minute individualized education and coaching session to increase knowledge of pain self-management, to redress personal misconceptions about pain treatment, and to rehearse an individually scripted patient-physician dialog about pain control. The control group received standardized information on controlling pain. Data on average pain (0-10 scale) were collected at enrollment and 2-week follow-up.RESULTSAt enrollment, minority patients had significantly more pain than their white counterparts (6.0 vs 5.0, P = 0.05). At follow-up, minorities in the control group continued to have more pain (6.4 vs 4.7, P = 0.01), whereas in the experimental group, disparities were eliminated (4.0 vs 4.3, P = 0.71). The effect of the intervention on reducing disparities was significant (P = 0.04).CONCLUSIONSPatient coaching offers promise as a means of reducing racial/ethnic disparities in pain control. Larger studies are needed to validate these findings and to explore possible mechanisms.

Troubling deficits exist in palliative care (PC) of older adults under the prevailing “terminal care”-oriented model. We previously described a PC model—TLC—that provides a blueprint for remedying these shortfalls. In this model, PC is envisioned as Timely and Team-oriented, Longitudinal, and Collaborative and Comprehensive. We present results of the Palliative Care in Assisted Living pilot, comparing two TLC model-based, facility delivered interventions for improving the PC of elderly assisted living residents in Sacramento, California, a growing and under-researched population. The less intensive intervention involved one assessment followed by a PC improvement recommendation letter to the resident, family member, primary provider, and facility staff, while the more intensive intervention involved assessments and letters every three months. Primary outcomes were SF-36 Physical (PCS) and Mental (MCS) Component scores and recommendation adherence. Eighty-one subjects enrolled (mean age 85), 58 in the more and 23 in the less intensive group. A loved one attended 56% of baseline assessments. Most subjects expressed a preference for maintaining current quality of life over prolonging life at reduced quality. None were eligible for hospice care. A total of 418 recommendations (mean 5.1 per subject) were generated concerning symptoms, mood, functional impairments, and advance directives. We found no significant differences in recommendation adherence between more (42%) and less (44%) intensive groups, and no significant changes in PCS and MCS scores within or between groups. However, a loved one's attendance of the baseline assessment was associated with improved PCS scores (p=0.04). Our pilot study had methodological limitations that could account for the lack of significant outcome effects. In this context, and given the myriad unmet PC needs we detected, interventions based on the TLC model might allow delivery of timely PC to assisted living residents not eligible for hospice care. Further studies exploring the TLC model appear warranted.

Patients with endobronchial renal cell carcinoma (RCC) are at high risk for significant hemoptysis. We evaluated the palliative efficacy and risks of Nd:YAG laser phototherapy in treating such patients, and observed their survival. The medical records of all patients (n = 13) with endobronchial RCC who underwent Nd:YAG laser phototherapy from 1990 to 2003 at our institution were reviewed. Twenty-three laser procedures were performed, resulting in a 98% mean reduction in endobronchial obstruction by proximal lesions, and a 43% mean reduction in obstruction by distal lesions. All patients on mechanical ventilation (n = 2) were successfully weaned within 24 hours after laser therapy. The overall complication rate was 0.87 per procedure. Hemorrhage accounted for 60% of total complications (mean estimated blood loss, 107 ± 135.9 mL). Mean survival from date of first laser intervention was 8.8 ± 9.3 months. Patients with RCC who demonstrate respiratory symptoms ought to be promptly evaluated for an endobronchial RCC component. Nd:YAG laser phototherapy can be highly effective as a palliative procedure in patients with endobronchial RCC, despite the significant hemorrhage risk. Because potentially life-threatening hemorrhage remains the single most serious complication during bronchoscopy, these procedures ought to be performed in a tertiary referral center by bronchoscopy teams with adequate experience and expertise.

Overexpression of the HER‐2/neu oncoprotein has been reported to occur in ≤ 60% of patients with prostate carcinoma and to correlate with shortened survival. Trastuzumab is a humanized monoclonal antibody to the HER‐2 receptor and has activity against HER‐2–positive breast carcinoma, more so when combined with a taxane. The authors screened for HER‐2 overexpression in patients developing hormone‐refractory prostate carcinoma (HRPC) and conducted a Phase II trial of trastuzumab plus docetaxel in HER‐2–positive patients.

Substantial shortfalls in the quality of palliative care of the elderly can be attributed to 5 fundamental flaws in the way end-of-life care is currently delivered. First, palliative care is viewed as a terminal event rather than a longitudinal process, resulting in a reactive approach and unnecessary preterminal distress in elderly patients suffering from chronic, slowly progressive illnesses. Second, palliative care is defined in terms of a false dichotomy between symptomatic and disease-focused treatment, which distracts attention from the proper focus of healing. illness. Third, the decision about whether the focus of care should be palliative is not negotiated among patients, family members, and providers. Fourth, patient autonomy in making treatment choices is accorded undue prominence relative to more salient patient choices, such as coming to terms with their place in the trajectory of chronic illness. Fifth, palliative care is a parallel system rather than an integrated primary care process. A new theoretical framework-the TLC model-addresses these flaws in the provision of palliative care for elderly persons. In this model, optimal palliative care is envisioned as timely and team oriented, longitudinal, collaborative and comprehensive. The model is informed by the chronic illness care, shared decision making, and comprehensive geriatric assessment research literature, as well as previous palliative care research. Preliminary results of an intervention for elderly assisted living residents based on the TLC model support its promise as a framework for optimizing palliative care of elders.

Article Tools ART OF ONCOLOGY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2003.01.104 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12663735 Simultaneous Care: Disease Treatment and Palliative Care Throughout Illness Frederick J. MeyersxFrederick J. MeyersSearch for articles by this author , John LinderxJohn LinderSearch for articles by this author Show More From the Department of Internal Medicine, University of California, Sacremento, CA. https://doi.org/10.1200/JCO.2003.01.104 First Page Full Text PDF Figures and Tables © 2003 by American Society of Clinical Oncology

A novel schema of intrapatient dose escalation was applied to determine a population-based maximum tolerated dose (pMTD) for irinotecan (CPT-11, Camptosar) and carboplatin (Paraplatin) in a phase I trial. A total of 74 patients with advanced solid tumors were enrolled with the following characteristics: men/women, 46/28; median age, 61 years; 51 patients with and 23 patients without prior chemotherapy; performance status of 0-1 (93%) and 2 (7%). Patients were started at dose level 1 with irinotecan at 200 mg/m2, and carboplatin at an area under the concentration-time curve (AUC) of 5 mg/mL x min, administered every 21 days. Depending on degree of toxicity observed, the dose for each patient in each subsequent cycle was determined according to a predetermined schema of dose levels. Individual maximum tolerated dose (iMTD) was determined for each patient. The pMTD was defined as the highest dose level for which the incidence of dose-limiting toxicity occurred in less than 33% of the patient population. The most common dose-limiting toxicity included neutropenia (58%), thrombocytopenia (15%), diarrhea (8%), and nausea/emesis (7%). The iMTD ranged from dose level-3 (irinotecan at 100 mg/m2 and carboplatin at an AUC of 4) to dose level 5 (irinotecan at 350 mg/m2 and carboplatin at AUC 6). The pMTD was determined to be dose level-1 and 1 for previously chemotherapy-treated and--untreated patients, respectively. Fifty-nine patients were assessable for response. Of note, a response rate of 40% was observed in 15 patients with relapsed small-cell lung cancer previously treated with platinum-based therapy. We recommend dose level 1 of irinotecan (200 mg/m2) and carboplatin (AUC 5) for chemotherapynaive patients, and dose level-1 of irinotecan (150 mg/m2) and carboplatin (AUC 5) for chemotherapy-treated patients in phase II trials.

Objectives. To evaluate the feasibility and activity of paclitaxel, carboplatin, and methotrexate in advanced transitional cell carcinoma (TCC) of the urothelium and to relate the activity of this combination to the mutational status of p53.Methods. In the Phase I portion, paclitaxel 200 mg/m(2) (3-hour infusion), carboplatin dosed to an area under the curve (AUC) of 6 mg/mL . min, and methotrexate 10 mg/m2, increasing in 10-mg/m(2) increments, were administered on day 1 and every 21 days thereafter with granulocyte colony-stimulating factor (C-CSF) and leucovorin support. Subsequently, a Phase II study was initiated in which the carboplatin dose was lowered to an AUC of 5 to allow treatment without G-CSF. p53 expression was evaluated using immunohistochemistry.Results. Thirty-three patients were accrued. Median age was 66 years. No dose-limiting toxicities were seen in the Phase 1 portion despite escalation of the methotrexate to 60 mg/m(2). Principal toxicities were myelosuppression and neuropathy. The overall response rate (Phase I and II) was 56% (95% confidence interval 38% to 74%). Median survival was 15.5 months; 88% of patients overexpressed p53 at the primary site.Conclusions. Paclitaxel, carboplatin, and methotrexate were well tolerated and active in advanced TCC. The high response rate to this regimen despite frequent p53 mutation is consistent with the p53-independent mechanism of paclitaxel. Whether this regimen is superior to methotrexate/vinblastine/doxorubicin/cisplatin, other paclitaxel-based regimens, or to paclitaxel alone will require comparative trials. UROLOGY 55: 521-525, 2000. (C) 2000, Elsevier Science Inc.