Olaparib not cost-effective as maintenance therapy for platinum-sensitive, BRCA1/2 germline-mutated metastatic pancreatic cancer.

OBJECTIVE: To assess the cost-effectiveness and budget impact of olaparib as a maintenance therapy in platinum-responsive, metastatic pancreatic cancer patients harboring a germline BRCA1/2 mutation, using the Swiss context as a model. METHODS: Based on data from the POLO trial, published literature and local cost data, we developed a partitioned survival model of olaparib maintenance including full costs for BRCA1/2 germline testing compared to FOLFIRI maintenance chemotherapy and watch-and-wait. We calculated the incremental cost-effectiveness ratio (ICER) for the base case and several scenario analyses and estimated 5-year budget impact. RESULTS: Comparing olaparib with watch-and wait and maintenance chemotherapy resulted in incremental cost-effectiveness ratios of CHF 2,711,716 and CHF 2,217,083 per QALY gained, respectively. The 5-year costs for the olaparib strategy in Switzerland would be CHF 22.4 million, of which CHF 11.4 million would be accounted for by germline BRCA1/2 screening of the potentially eligible population. This would amount to a budget impact of CHF 15.4 million (USD 16.9 million) versus watch-and-wait. CONCLUSIONS: Olaparib is not a cost-effective maintenance treatment option. Companion diagnostics are an equally important cost driver as the drug itself.

Experts vs. machine - comparison of machine learning to expert-informed prediction of outcome after major liver surgery.

BACKGROUND: Machine learning (ML) has been successfully implemented for classification tasks (e.g., cancer diagnosis). ML performance for more challenging predictions is largely unexplored. This study's objective was to compare machine learning vs. expert-informed predictions for surgical outcome in patients undergoing major liver surgery. METHODS: Single tertiary center data on preoperative parameters and postoperative complications for elective hepatic surgery patients were included (2008-2021). Expert-informed prediction models were established on 14 parameters identified by two expert liver surgeons to impact on postoperative outcome. ML models used all available preoperative patient variables (n = 62). Model performance was compared for predicting 3-month postoperative overall morbidity. Temporal validation and additional analysis in major liver resection patients were conducted. RESULTS: 889 patients included. Expert-informed models showed low average bias (2-5 CCI points) with high over/underprediction. ML models performed similarly: average prediction 5-10 points higher than observed CCI values with high variability (95% CI -30 to 50). No performance improvement for major liver surgery patients. CONCLUSION: No clinical relevance in the application of ML for predicting postoperative overall morbidity was found. Despite being a novel hype, ML has the potential for application in clinical practice. However, at this stage it does not replace established approaches of prediction modelling.

[Polymedication and oral antitumour therapies - which drug interactions should be considered?]

INTRODUCTION: Oral anticancer therapies offer various advantages but also entail risks due to their toxicity and narrow therapeutic ranges. Since these drugs are increasingly prescribed in patients with existing polypharmacy, identifying and assessing potential drug interactions is of great importance for safe and effective therapy. This article provides an overview of the most common pharmacokinetic and pharmacodynamic drug-drug interactions of targeted anticancer therapies, with focus on protein kinase inhibitors.

Pre-treatment comorbidities, C-reactive protein and eosinophil count, and immune-related adverse events as predictors of survival with checkpoint inhibition for multiple tumour entities.

BACKGROUND: The development of immune-related adverse events (irAEs) may be associated with clinical efficacy of checkpoint inhibitors (CPIs) in patients with cancer. We therefore investigated the effect of irAEs and pre-treatment parameters on outcome in a large, real-life patient cohort. METHODS: We performed a single-centre, retrospective, observational study including patients who received CPIs from 2011 to 2018 and followed until 2021. The primary outcome was overall survival, and the secondary outcome was the development of irAEs. RESULTS: In total, 229 patients with different tumour entities (41% non-small cell lung cancer [NSCLC], 29% melanoma) received a total of 282 CPI treatment courses (ipilimumab, nivolumab, pembrolizumab or atezolizumab). Thirty-four percent of patients developed irAEs (of these 17% had CTCAE Grade ≥3). Factors independently associated with mortality were pre-treatment CRP ≥10 mg/L (hazard ratio [HR] 2.064, p = 0.0003), comorbidity measured by Charlson comorbidity index (HR 1.149, p = 0.014) and irAEs (HR 0.644, p = 0.036) (age-adjusted, n = 216). Baseline eosinophil count ≤0.2 × 109 /L was a further independent predictor of mortality (age-, CRP-, CCI- and irAE-adjusted HR = 2.252, p = 0.002, n = 166). Anti-CTLA-4 use (p < 0.001), and pre-treatment CRP <10 mg/L were independently associated with irAE occurrence (p = 0.037). CONCLUSIONS: We found an independent association between irAE occurrence and improved overall survival in a real-life cohort spanning multiple tumour entities and treatment regimens. Pre-treatment comorbidities, CRP and eosinophil count represent potential markers for predicting treatment response.

ASA score and procedure type predict complications and costs in maxillofacial reconstructive surgery: a retrospective study using a hospital administrative database.

BACKGROUND: Reconstruction of osseous and soft tissue defects after surgical resection of oral cavity cancers can be achieved by a single-stage procedure with a microvascular bone flap or by a two-step approach with a soft tissue flap and subsequent bone augmentation. The therapeutic approach should be selected based on the patient’s needs. Economic pressure requires preoperative risk assessment and estimation of the postoperative course. Flat-rate reimbursement systems via diagnosis-related groups with insufficient morbidity adjustments and financial sanction of medical complications might additionally cause false incentives in the choice of treatment. OBJECTIVE: This study aimed to assess the influence of the type of flap chosen for maxillofacial reconstructive surgery on the total costs. Complication rates of different types of flap surgery and their prediction by a preoperative risk assessment tool (American Society of Anesthesiologists [ASA] score) were determined. Overall, the fairness of the current reimbursement system was rated. METHODS: Patient characteristics, clinical data, and data on total costs and reimbursement of patients aged 18 years and older having undergone maxillofacial reconstructive flap surgery at the University Hospital of Zurich (Switzerland) between 2012 and 2014 were analysed. The preoperative risk was classified by the ASA score. Complications were graded according to the Clavien-Dindo classification system and the comprehensive complication index (CCI). Statistical analysis included Spearman and Pearson rank correlation, Kruskal-Wallis and Mann-Whitney nonparametric tests, and linear regression analysis. RESULTS: 129 patients were included in this study. Soft tissue flaps were performed in 82 patients, of which 56 were radial forearm flaps (43.4%), bone flaps in 41 patients, of which 32 were fibula flaps (24.8%), and combined flaps in 6 patients (4.7%). Patients with fibula flaps showed a significantly higher CCI and higher total costs. Higher preoperative ASA scores were significantly associated with increased length of stay, total costs and complications. Both the ASA score and reconstruction with a radial forearm flap were significant predictors of complications and total costs. Total median costs for radial forearm flaps were CHF 50,560 (reimbursement: CHF 60,851; difference: CHF 10,291) and for fibula flaps CHF 66,982 (reimbursement: CHF 58,218; difference: CHF −8,764). CONCLUSION: The ASA score allows a reliable preoperative assessment of patient outcomes and financial burden in maxillofacial reconstructive flap surgery. The type of flap reconstruction significantly influences complications and ultimately total costs. The current reimbursement system via diagnosis-related groups (DRGs) does not take sufficient account of this fact. Adaptations are therefore needed to prevent misplaced incentives to the detriment of patients.

Impact of graft and tunnel orientation on patient-reported outcome in anterior cruciate ligament reconstruction using bone-patellar tendon-bone autografts.

BACKGROUND: The optimal positioning of anterior cruciate ligament graft is still controversially discussed. We therefore wanted to determine the tunnel-to-joint (TJA), tunnel-to-shaft (TSA), and graft-tunnel divergence angles which would provide the best outcome, determined by the KOOS (Knee Injury and Osteoarthritis Outcome Score). This study evaluated the clinical influence of graft orientation as measured with the KOOS questionnaire in patients with anterior cruciate ligament reconstruction with bone-patellar tendon-bone autografts. METHODS: We designed a prospective cohort study, with a 1 » year recruitment phase from March 2011 to July 2012 and a minimal follow-up period of 1 year. Inclusion criteria were patients ≥ 18 years of age receiving an ACL reconstruction with bone-patellar tendon-bone autografts at our institution after having suffered an acute ACL rupture. The primary outcome was the KOOS. Independent variables were patient age, gender, laterality of rupture, mechanism of trauma, and type of femoral and tibial fixation, as well as sagittal graft-tunnel divergence, TJA, and TSA, the latter two being assessed on coronal slices of magnetic resonance imaging. Equations modeling the relationship between TJA, TSA, and graft-tunnel divergence with the KOOS overall score were fitted, and the optimum angles were mathematically determined. RESULTS: In total, 31 patients were included in our study. Our cohort with a median age of 28 years was predominantly male. The mathematically determined optimal placement of the implant in the coronal plane was a TJA of 74.8°, a TSA of 80.1°, and a graft-tunnel divergence angle of 8.5°. CONCLUSION: With regard to patient-reported outcome, the optimal graft orientation is provided by a coronal tunnel-to-shaft angle of 80° and tunnel-to-joint angle of 75°, respectively. Interestingly, in our series, patients reported best clinical outcomes with a sagittal graft-tunnel divergence. These results should be validated in larger studies.

The Comprehensive Complication Index (CCI®): Added Value and Clinical Perspectives 3 Years "Down the Line".

OBJECTIVE: To explore the added value of the comprehensive complication index (CCI) to standard assessment of postoperative morbidity, and to clarify potential controversies for its application. BACKGROUND: The CCI was introduced about 3 years ago as a novel metric of postoperative morbidity, integrating in a single formula all complications by severity, ranging from 0 (uneventful course) to 100 (death). It remains unclear, how often the CCI adds to standard reporting of complications and how to apply it in complex postoperative courses. METHODS: CCI data were prospectively collected over a 1-year period at our institution. The proportion of patients with more than 1 complication and the severity of those complications were assessed to determine the additional value of the CCI compared to the Clavien-Dindo classification. Complex and controversial cases were presented to 90 surgeons worldwide to achieve consensus in weighing each postoperative event. Descriptive statistics were used to evaluate agreement among surgeons and to suggest solutions for consistent use of the CCI. RESULTS: Complications were identified in 24% (290/1212) of the general surgical population. Of those, 44% (127/290) developed more than 1 complication by the time of discharge, and thereby CCI added information to the standard grading system of complications. Information gained by the CCI increased with the complexity of surgery and observation time. CONCLUSIONS: The CCI adds information on postoperative morbidity in almost half of the patients developing complications, with particular value following extensive surgery and longer postoperative observation up to 3 months. Each single complication, independently of their inter-connection, should be included in the CCI calculation to best mirror the patients' postoperative morbidity.

Complications After Cosmetic Surgery Tourism.

Background: Cosmetic surgery tourism characterizes a phenomenon of people traveling abroad for aesthetic surgery treatment. Problems arise when patients return with complications or need of follow-up care. Objectives: To investigate the complications of cosmetic surgery tourism treated at our hospital as well as to analyze arising costs for the health system. Methods: Between 2010 and 2014, we retrospectively included all patients presenting with complications arising from cosmetic surgery abroad. We reviewed medical records for patients' characteristics including performed operations, complications, and treatment. Associated cost expenditure and Diagnose Related Groups (DRG)-related reimbursement were analyzed. Results: In total 109 patients were identified. All patients were female with a mean age of 38.5 ± 11.3 years. Most procedures were performed in South America (43%) and Southeast (29.4%) or central Europe (24.8%), respectively. Favored procedures were breast augmentation (39.4%), abdominoplasty (11%), and breast reduction (7.3%). Median time between the initial procedure abroad and presentation was 15 days (interquartile range [IQR], 9) for early, 81.5 days (IQR, 69.5) for midterm, and 4.9 years (IQR, 9.4) for late complications. Main complications were infections (25.7%), wound breakdown (19.3%), and pain/discomfort (14.7%). The majority of patients (63.3%) were treated conservatively; 34.8% became inpatients with a mean hospital stay of 5.2 ± 3.8 days. Overall DRG-related reimbursement premiums approximately covered the total costs. Conclusions: Despite warnings regarding associated risks, cosmetic surgery tourism has become increasingly popular. Efficient patients' referral to secondary/tertiary care centers with standardized evaluation and treatment can limit arising costs without imposing a too large burden on the social healthcare system. Level of Evidence: 4.

Impact of structural and economic factors on hospitalization costs, inpatient mortality, and treatment type of traumatic hip fractures in Switzerland.

The assessment of structural and potentially economic factors determining cost, treatment type, and inpatient mortality of traumatic hip fractures are important health policy issues. We showed that insurance status and treatment in university hospitals were significantly associated with treatment type (i.e., primary hip replacement), cost, and lower inpatient mortality respectively. INTRODUCTION: The purpose of this study was to determine the influence of the structural level of hospital care and patient insurance type on treatment, hospitalization cost, and inpatient mortality in cases with traumatic hip fractures in Switzerland. METHODS: The Swiss national medical statistic 2011-2012 was screened for adults with hip fracture as primary diagnosis. Gender, age, insurance type, year of discharge, hospital infrastructure level, length-of-stay, case weight, reason for discharge, and all coded diagnoses and procedures were extracted. Descriptive statistics and multivariate logistic regression with treatment by primary hip replacement as well as inpatient mortality as dependent variables were performed. RESULTS: We obtained 24,678 inpatient case records from the medical statistic. Hospitalization costs were calculated from a second dataset, the Swiss national cost statistic (7528 cases with hip fractures, discharged in 2012). Average inpatient costs per case were the highest for discharges from university hospitals (US$21,471, SD US$17,015) and the lowest in basic coverage hospitals (US$18,291, SD US$12,635). Controlling for other variables, higher costs for hip fracture treatment at university hospitals were significant in multivariate regression (p < 0.001). University hospitals had a lower inpatient mortality rate than full and basic care providers (2.8% vs. both 4.0%); results confirmed in our multivariate logistic regression analysis (odds ratio (OR) 1.434, 95% CI 1.127-1.824 and OR 1.459, 95% confidence interval (CI) 1.139-1.870 for full and basic coverage hospitals vs. university hospitals respectively). The proportion of privately insured varied between 16.0% in university hospitals and 38.9% in specialized hospitals. Private insurance had an OR of 1.419 (95% CI 1.306-1.542) in predicting treatment of a hip fracture with primary hip replacement. CONCLUSION: The seeming importance of insurance type on hip fracture treatment and the large inequity in the distribution of privately insured between provider types would be worth a closer look by the regulatory authorities. Better outcomes, i.e., lower mortality rates for hip fracture treatment in hospitals with a higher structural care level advocate centralization of care.

Interleukin-1 receptor antagonist (anakinra) for Schnitzler syndrome.

Schnitzler syndrome is a rare autoinflammatory disease, which is defined by the presence of two major criteria: chronic urticaria and monoclonal immunoglobulin M (IgM) or immunoglobulin G gammopathy, in combination with at least two additional minor criteria: recurrent fever, leukocytosis and/or elevated C-reactive protein (CRP), objective signs of abnormal bone remodelling and a neutrophilic infiltrate in skin biopsy. We report on a 68-year-old female patient with a 10-year medical history of chronic urticaria, recurrent fever, severe arthralgia and increased CRP. Over the years, multiple diagnostic investigations were performed without conclusive findings, and therapeutic attempts with anti-histamines and several immunosuppressive agents had failed. The decision to initiate monotherapy with interleukin-1 (IL-1) receptor antagonist was based on immunohistochemical detection of the abundance of IL-1ß positive cells in the patient's skin biopsy. After starting treatment with anakinra, disappearance of symptoms could be observed within 24 h. Discontinuation of the treatment resulted in a rapid relapse of the symptoms. Finally, already after the initiation of therapy with anakinra, the suspected diagnosis of Schnitzler syndrome could be confirmed by detection of IgM-gammopathy that was initially absent.

Expression of CD164 on Malignant T cells in Sézary Syndrome.

Sézary syndrome is a primary cutaneous T-cell lymphoma characterized by pruritic erythroderma, peripheral lymphadenopathy and the presence of malignant T cells in the blood. Unequivocal detection of malignant cells in patients with Sézary syndrome is of important diagnostic, prognostic and therapeutic value. However, no single Sézary syndrome specific cell surface marker has been identified. In a cohort of patients with Sézary syndrome, CD164 expression on total CD4+ lymphocytes was significantly upregulated compared with healthy controls. CD164 expression was in most cases limited to CD4+CD26- malignant T lymphocytes, unequivocally identified using flow-cytometry by the expression of a specific Vß clone for each patient. Increased expression of CD164 may be a promising diagnostic parameter and a potential target for a CD164-linked therapeutic approach in Sézary syndrome.

Metastatic patterns and metastatic sites in mucosal melanoma: a retrospective study.

OBJECTIVES: Melanomas arising from mucosa are rare and associated with a poor prognosis. This study aims to provide an analysis of metastatic pathways, time intervals, factors influencing metastatic spread and organs for distant metastases. METHODS: A total of 116 patients with mucosal melanomas of different sites were included. The mean follow-up interval was 47 ± 52 months. Patients were assigned to two different metastatic pathways, either presenting loco-regional lymph node metastases as first spread or direct distant metastases. The distribution of distant metastases was assessed. RESULTS: Twenty-six patients presented with a pre-existing metastatic spread and were not assigned to pathways. Of the included patients, 44 developed metastases after treatment of the primary tumour; 25 patients directly developed distant metastases; 16 patients developed regional lymph node metastases prior to distant metastases. Location of the primary tumour in the upper airway or GI tract and advanced T stage were significant risk factors of direct distant metastases. Distant metastases are mainly located in the lung, the liver and non-regional lymph nodes. CONCLUSIONS: Mucosal melanomas show a high rate of direct distant metastases rather than regional lymph node metastases. Thus the follow-up should always include a whole-body cross-sectional imaging in high-risk tumours. KEY POINTS: • Mucosal melanomas show a high rate of direct distant metastases. • T stage and primary location are predictors for direct distant metastases. • Distant metastases were mainly found in lung, liver and lymph nodes. • Follow-up of a high-risk mucosal melanoma should include whole-body imaging.

Diagnostic relevance of direct immunofluorescence in ocular mucous membrane pemphigoid.

BACKGROUND AND OBJECTIVES: The objective was to determine the diagnostic value of direct immunofluorescence (DIF) in ocular mucous membrane pemphigoid (ocular MMP), taking into account immunofluorescence patterns and biopsy sites. PATIENTS AND METHODS: DIF results and medical records of 54 patients with a suspected diagnosis of ocular MMP were reviewed. RESULTS: There was an overall prevalence of ocular MMP in 70.4 % of cases. Linear deposition of IgA, IgG, or C3 showed a high positive predictive value (84-100 %). Sensitivity and negative predictive value of IgG, IgM, IgG, and C3 in DIF were higher in cutaneous samples than in conjunctival biopsies, thus yielding a higher diagnostic accuracy. The sensitivity of DIF in ocular MMP seems to be lower than in bullous pemphigoid. CONCLUSIONS: The diagnostic value of DIF in the workup of ocular MMP was confirmed. However, biopsies taken from non-conjunctival, cutaneous tissue appear to yield more accurate results.

The Phytotherapeutic Fenugreek as Trigger of Toxic Epidermal Necrolysis.

We describe the case of a 32-year-old woman who presented to the hospital with generalized painful exanthema, blisters and erosions 1 month after giving birth to a healthy girl. The patient's medical history was inconspicuous for comorbidities; however, it included the incidental intake of pain killers and a herbal preparation (fenugreek), which she took regularly over the last 4 weeks to improve lactation. Based on the clinical characteristics, we suspected toxic epidermal necrolysis (TEN), a severe cutaneous adverse drug reaction, which was confirmed by skin biopsy. The patient was treated with high-dose intravenous human immunoglobulins and was discharged 2 weeks after hospital admission in good condition. The allergological workup identified fenugreek as the most likely causative agent. Given the increased self-medication of freely available phytotherapeutics by patients in industrialized countries, herbal mixtures should be taken into consideration in the diagnostic workup of TEN.

Ophthalmic Rosacea: Case Report in a Child and Treatment Recommendations.

We report a rare case of rosacea with ocular involvement in a child that remitted with prolonged anti-inflammatory oral tetracycline therapy and provide general expert recommendations. A 14-year-old girl presented with discrete papules and pustules on both cheeks with blepharitis and conjunctivitis. Ophthalmologic examination confirmed bilateral severe blepharitis, as well as a corneal infiltrate in the right eye with additional neovascularization. The diagnosis of rosacea with ocular involvement was made. In addition to the existing antibiotic and anti-inflammatory topical eye therapy, systemic treatment with minocycline 50 mg twice a day was started. After marked improvement, the dose was reduced to 50 mg once a day. After further amelioration, treatment was switched to maintenance therapy with 40 mg of prolonged-release doxycycline. Three years after a 12-month course of anti-inflammatory therapy, the patient remained recurrence free.

Brentuximab as a treatment for CD30+ mycosis fungoides and Sézary syndrome.

IMPORTANCE: The prognosis of advanced cutaneous T-cell lymphoma (CTCL), including Sézary syndrome and mycosis fungoides (MF), is poor. So far, no curative option apart from allogeneic stem cell transplantation is available. Large cell transformation often hallmarks cases with a more aggressive clinical course, and large tumor cells may express CD30. Recently, brentuximab vedotin, a conjugate of an anti-CD30 antibody and monomethylauristatin E, which inhibits the polymerization of microtubuli, has produced promising results in phase 2 trials in CD30+ Hodgkin lymphoma and anaplastic large cell lymphoma. OBSERVATIONS: We describe 4 patients with advanced CTCL, 3 with MF and 1 with Sézary syndrome, who were treated with brentuximab. All patients had received multiple previous systemic therapies. In 2 cases of MF, a remission enabling subsequent allogeneic stem cell transplantation was achieved. CONCLUSIONS AND RELEVANCE: Brentuximab is a well-tolerated, promising new treatment option for advanced CTCL that can be integrated in an allogeneic stem cell transplantation plan by selectively depleting malignant CD30+ cutaneous lymphoma cells.

Primary localization and tumor thickness as prognostic factors of survival in patients with mucosal melanoma.

BACKGROUND: Data on survival with mucosal melanoma and on prognostic factors of are scarce. It is still unclear if the disease course allows for mucosal melanoma to be treated as primary cutaneous melanoma or if differences in overall survival patterns require adapted therapeutic approaches. Furthermore, this investigation is the first to present 10-year survival rates for mucosal melanomas of different anatomical localizations. METHODOLOGY: 116 cases from Sep 10 1984 until Feb 15 2011 retrieved from the Comprehensive Cancer Center and of the Central Register of the German Dermatologic Society databases in Tübingen were included in our analysis. We recorded anatomical location and tumor thickness, and estimated overall survival at 2, 5 and 10 years and the mean overall survival time. Survival times were analyzed with the Kaplan-Meier method. The log-rank test was used to compare survival times by localizations and by T-stages. PRINCIPAL FINDINGS: We found a median overall survival time of 80.9 months, with an overall 2-year survival of 71.7%, 5-year survival of 55.8% and 10-year survival of 38.3%. The 10-year survival rates for patients with T1, T2, T3 or T4 stage tumors were 100.0%, 77.9%, 66.3% and 10.6% respectively. 10-year survival of patients with melanomas of the vulva was 64.5% in comparison to 22.3% of patients with non-vulva mucosal melanomas. CONCLUSION: Survival times differed significantly between patients with melanomas of the vulva compared to the rest (p = 0.0006). It also depends on T-stage at the time of diagnosis (p < 0.0001).

T-helper-1-cell cytokines drive cancer into senescence.

Cancer control by adaptive immunity involves a number of defined death and clearance mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-γ (IFN-γ) requires additional undefined mechanisms that arrest cancer cell proliferation. Here we show that the combined action of the T-helper-1-cell cytokines IFN-γ and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from oncogene-induced senescence, we used a mouse model in which the Simian virus 40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumours by attenuating p53- and Rb-mediated cell cycle control. When combined, IFN-γ and TNF drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16INK4a (also known as CDKN2A), and downstream Rb hypophosphorylation at serine 795. This cytokine-induced senescence strictly requires STAT1 and TNFR1 (also known as TNFRSF1A) signalling in addition to p16INK4a. In vivo, Tag-specific T-helper 1 cells permanently arrest Tag-expressing cancers by inducing IFN-γ- and TNFR1-dependent senescence. Conversely, Tnfr1(-/-)Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in TNFR1-expressing hosts. Finally, as IFN-γ and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.