Influence of neoadjuvant chemotherapy on radiotherapy for breast cancer.

Neoadjuvant chemotherapy is a standard treatment option for patients with locally advanced operable breast cancer and is increasingly used in early breast cancer. Initial randomized trials of neoadjuvant chemotherapy established equivalency to adjuvant chemotherapy in terms of survival, but they also demonstrated improved rates of breast conservation and the ability to modify the risk of locoregional recurrence after a favorable response to chemotherapy. High-quality nonrandomized data have helped to tailor radiotherapy treatment recommendations after neoadjuvant chemotherapy and breast-conserving surgery or mastectomy. Results from an ongoing phase 3 randomized trial (NSABP B-51/RTOG 1304) will help to clarify the value of locoregional radiotherapy for patients with clinical N1 disease that becomes node negative after neoadjuvant chemotherapy.

Isolated port-site metastases after minimally invasive hysterectomy for endometrial cancer: outcomes of patients treated with radiotherapy.

OBJECTIVE: The management and prognosis of isolated port-site metastases after laparoscopic surgery for endometrial cancer is poorly understood and rarely described in the literature. We report a series of cases treated with radiotherapy to better characterize outcomes in these patients. METHODS: We retrospectively reviewed medical records of patients with endometrial cancer who developed isolated port-site metastases and were treated with radiation therapy at MD Anderson Cancer Center from 1996 to 2013. Seven patients met these criteria for whom treatment and outcome data were collected. RESULTS: The median interval from initial surgery to port-site recurrence was 15 months. Recurrent tumor size varied from 0.5 to 9 cm as measured on axial imaging. Six of the 7 patients underwent surgical resection of the recurrence. All received radiotherapy to a dose of 45 to 66 Gy. At a median follow-up of 2 years from the time of the port-site recurrence, the rate of disease-free survival at 1 and 2 years after the recurrence was 100% and 44%, respectively. The rate of local control and overall survival at 2 years was 100%. CONCLUSIONS: Isolated port-site metastases in the setting of endometrial cancer are associated with high rates of local control when treated with multimodality therapy including radiotherapy. Long-term disease-free outcomes in some patients suggest the potential for cure and justify aggressive local therapy. The optimal integration of surgery, chemotherapy, and radiation is unknown.

The P-body component USP52/PAN2 is a novel regulator of HIF1A mRNA stability.

HIF1A (hypoxia-inducible factor 1α) is the master regulator of the cellular response to hypoxia and is implicated in cancer progression. Whereas the regulation of HIF1A protein in response to oxygen is well characterized, less is known about the fate of HIF1A mRNA. In the present study, we have identified the pseudo-DUB (deubiquitinating enzyme)/deadenylase USP52 (ubiquitin-specific protease 52)/PAN2 [poly(A) nuclease 2] as an important regulator of the HIF1A-mediated hypoxic response. Depletion of USP52 reduced HIF1A mRNA and protein levels and resulted in reduced expression of HIF1A-regulated hypoxic targets due to a 3'-UTR (untranslated region)-dependent poly(A)-tail-length-independent destabilization in HIF1A mRNA. MS analysis revealed an association of USP52 with several P-body (processing body) components and we confirmed further that USP52 protein and HIF1A mRNA co-localized with cytoplasmic P-bodies. Importantly, P-body dispersal by knockdown of GW182 or LSM1 resulted in a reduction of HIF1A mRNA levels. These data uncover a novel role for P-bodies in regulating HIF1A mRNA stability, and demonstrate that USP52 is a key component of P-bodies required to prevent HIF1A mRNA degradation.

Executive summary of the American Radium Society appropriate use criteria for brain metastases in epidermal growth factor receptor mutated-mutated and ALK-fusion non-small cell lung cancer.

The American Radium Society (ARS) Central Nervous System (CNS) committee reviewed literature on epidermal growth factor receptor mutated (EGFRm) and ALK-fusion (ALK+) tyrosine kinase inhibitors (TKIs) for the treatment of brain metastases (BrMs) from non-small cell lung cancers (NSCLC) to generate appropriate use guidelines addressing use of TKIs in conjunction with or in lieu of radiotherapy (RT). The panel developed three key questions to guide systematic review: can radiotherapy be deferred in patients receiving EGFR or ALK TKIs at (1) diagnosis or (2) recurrence? Should TKI be administered concurrently with RT (3)? Two literature searches were performed (May 2019 and December 2023). The panel developed 8 model cases and voted on treatment options using a 9-point scale, with 1-3, 4-6 and 7-9 corresponding to usually not appropriate, may be appropriate, and usually appropriate (respectively), per the UCLA/RAND Appropriateness Method. Consensus was achieved in only 4 treatment scenarios, all consistent with existing ARS-AUC guidelines for multiple BrM. The panel did not reach consensus that RT can be appropriately deferred in patients with BrM receiving CNS penetrant ALK or EGFR TKIs, though median scores indicated deferral may be appropriate under most circumstances. Whole brain RT with concurrent TKI generated broad disagreement except in cases with 2-4 BrM, where it was considered usually not appropriate. We identified no definitive studies dictating optimal sequencing of TKIs and RT for EGFRm and ALK+ BrM. Until such studies are completed, the committee hopes these cases guide decision- making in this complex clinical space.

Implementation and Efficacy of a Large-Scale Radiation Oncology Case-Based Peer-Review Quality Program across a Multinational Cancer Network.

PURPOSE: With expansion of academic cancer center networks across geographically-dispersed sites, ensuring high-quality delivery of care across all network affiliates is essential. We report on the characteristics and efficacy of a radiation oncology peer-review quality assurance (QA) system implemented across a large-scale multinational cancer network. METHODS AND MATERIALS: Since 2014, weekly case-based peer-review QA meetings have been standard for network radiation oncologists with radiation oncology faculty at a major academic center. This radiotherapy (RT) QA program involves pre-treatment peer-review of cases by disease site, with disease-site subspecialized main campus faculty members. This virtual QA platform involves direct review of the proposed RT plan as well as supporting data, including relevant pathology and imaging studies for each patient. Network RT plans were scored as being concordant or nonconcordant based on national guidelines, institutional recommendations, and/or expert judgment when considering individual patient-specific factors for a given case. Data from January 1, 2014, through December 31, 2019, were aggregated for analysis. RESULTS: Between 2014 and 2019, across 8 network centers, a total of 16,601 RT plans underwent peer-review. The network-based peer-review case volume increased over the study period, from 958 cases in 2014 to 4,487 in 2019. A combined global nonconcordance rate of 4.5% was noted, with the highest nonconcordance rates among head-and-neck cases (11.0%). For centers that joined the network during the study period, we observed a significant decrease in the nonconcordance rate over time (3.1% average annual decrease in nonconcordance, P = 0.01); among centers that joined the network prior to the study period, nonconcordance rates remained stable over time. CONCLUSIONS: Through a standardized QA platform, network-based multinational peer-review of RT plans can be achieved. Improved concordance rates among newly added network affiliates over time are noted, suggesting a positive impact of network membership on the quality of delivered cancer care.

Purification and identification of endogenous polySUMO conjugates.

The small ubiquitin-like modifier (SUMO) can undergo self-modification to form polymeric chains that have been implicated in cellular processes such as meiosis, genome maintenance and stress response. Investigations into the biological role of polymeric chains have been hampered by the absence of a protocol for the purification of proteins linked to SUMO chains. In this paper, we describe a rapid affinity purification procedure for the isolation of endogenous polySUMO-modified species that generates highly purified material suitable for individual protein studies and proteomic analysis. We use this approach to identify more than 300 putative polySUMO conjugates from cultured eukaryotic cells.

A phase II clinical trial of frameless, fractionated stereotactic radiation therapy for brain metastases.

Stereotactic radiation therapy yields high rates of local control for brain metastases, but patients in rural or suburban areas face geographic and socioeconomic barriers to its access. We conducted a phase II clinical trial of frameless, fractionated stereotactic radiation therapy for brain metastases in an integrated academic satellite network for patients 18 years of age or older with 4 or fewer brain metastases. Dose was based on gross tumor volume: less than 3.0 cm, 27 Gy in 3 fractions and 3.0 to 3.9 cm, 30 Gy in 5 fractions. Median follow-up was 10 months for 73 evaluable patients, with a median age of 68 years. Median intracranial progression-free survival was 7.1 months (95% confidence interval = 5.3 to not reached), and median survival was 7.2 months (95% confidence interval = 5.4 to not reached); there were no serious adverse events. Outcomes of this trial compare favorably with contemporary trials, and this treatment strategy provides opportunities to expand stereotactic radiation therapy access to underserved populations.

Phase 1/2 trial of single-session stereotactic body radiotherapy for previously unirradiated spinal metastases.

BACKGROUND: In this phase 1/2 study, the authors tested the hypothesis that single-fraction stereotactic body radiotherapy (SBRT) for previously unirradiated spinal metastases is a safe, feasible, and efficacious treatment approach. METHODS: All patients were evaluated by a multidisciplinary team. Spinal magnetic resonance imaging studies were obtained before treatment and at regular intervals to define both target volume and response to treatment. SBRT was delivered to a peripheral dose of 16 to 24 grays in a single fraction while limiting the dose to the spinal cord. Higher doses were used for renal cell histology. The National Cancer Institute Common Toxicity Criteria 2.0 and McCormick neurologic function score were used as toxicity assessment tools. RESULTS: In total, 61 patients who had 63 tumors of the noncervical spine were enrolled and received SBRT between 2005 and 2010 on a prospective, phase 1/2 trial at The University of Texas M. D. Anderson Cancer Center. The mean follow-up was 20 months. The actuarial 18-month imaging local control rate for all patients was 88%, the actuarial 18-month overall survival rate for all patients was 64%, and the median survival for all patients was 30 months. No significant differences in outcomes were noted with respect to tumor histology or SBRT dose. Two patients experienced radiation adverse events (grade 3 or higher). The actuarial rate of 18-month freedom from neurologic deterioration from any cause was 82%. CONCLUSIONS: Data from this phase 1/2 trial supported an expanded indication for SBRT as first-line treatment of spinal metastases in selected patients. The authors concluded that additional studies that can prospectively identify predictive factors for spinal cord toxicity after SBRT are warranted to minimize the incidence of this serious yet rare complication.

Executive summary of American Radium Society's appropriate use criteria for the postoperative management of lower grade gliomas.

Postoperative management of lower grade gliomas (grade 2 and 3) is heterogeneous. The American Radium Society's brain malignancies panel systematically reviewed and evaluated the literature to develop consensus guidelines addressing timing of postoperative therapy, monotherapy versus combined modality therapy, type of chemotherapy used with radiotherapy, and radiotherapy dose. Thirty-six studies were included. Using consensus methodology (modified Delphi), the panel voted upon representative case variants using a 9-point appropriateness scale to address key questions. Voting results were collated to develop summarized recommendations. Following gross-total surgical resection, close surveillance is appropriate for well-selected grade 2, IDH-mutant oligodendrogliomas or astrocytomas with low-risk features. For grade 2 gliomas with high-risk features or any grade 3 glioma, immediate adjuvant therapy is recommended. When postoperative therapy is administered, radiation and planned chemotherapy is strongly recommended over monotherapy. For grade 2 and 3 IDH-mutant oligodendrogliomas and astrocytomas, either adjunctive PCV (procarbazine, lomustine, vincristine) or temozolomide is appropriate. For grade 3 IDH-mutant astrocytomas, radiotherapy followed by temozolomide is strongly recommended. The recommended radiotherapy dose for grade 2 gliomas is 45-54 Gy/1.8-2.0 Gy, and for grade 3 gliomas is 59.4-60 Gy/1.8-2.0 Gy. While multiple appropriate treatment options exist, these consensus recommendations provide an evidence-based framework to approach postoperative management of lower grade gliomas.

Prospective evaluation of spinal reirradiation by using stereotactic body radiation therapy: The University of Texas MD Anderson Cancer Center experience.

BACKGROUND: Stereotactic body radiotherapy for previously irradiated, progressive spinal metastases may be a viable option in selected patients. The authors review a prospective series of spinal metastasis patients reirradiated with stereotactic body radiotherapy. METHODS: A total of 59 patients with 63 tumors of the spine were reirradiated with stereotactic body radiotherapy between 2003 and 2009. Spinal magnetic resonance imaging was performed both before treatment initiation and at regular follow-up intervals. Stereotactic body radiotherapy was delivered to a peripheral dose of 30 grays (Gy) in 5 fractions (6 Gy per fraction), or 27 Gy in 3 fractions (9 Gy per fraction). The National Cancer Institute Common Toxicity Criteria 2.0 and McCormick neurological function system were used to evaluate toxicity and neurologic status, respectively. RESULTS: Mean follow-up was 17.6 months. Actuarial 1-year radiographic local control and overall survival for all patients were both 76%. Of the tumors that progressed after stereotactic body radiotherapy, 13 (81%) of 16 patients had tumors that were within 5 mm of the spinal cord, and 6 of them eventually developed spinal cord compression. Toxicity was most commonly grade 1 or 2 fatigue. Two patients experienced mild to moderate radiation injury (lumbar plexopathy) while remaining independently ambulatory and pain free. Freedom from neurologic deterioration from any cause was 92% at 1 year. CONCLUSIONS: Reirradiation for progressive spinal metastases with stereotactic body radiotherapy results in good local control and limited toxicity. Initial surgery should be considered for tumors within 5 mm of the spinal cord. Radiation dose should be tailored for tumors near or invading the psoas muscle secondary to observed risk of lumbar plexopathy.

The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma.

We performed a small interfering RNA screen to identify targets for cutaneous squamous cell carcinoma (cSCC) therapy in the ubiquitin/ubiquitin-like system. We provide evidence for selective anti-cSCC activity of knockdown of the E3 ubiquitin ligase MARCH4, the ATPase p97/VCP, the deubiquitinating enzyme USP8, the cullin-RING ligase (CRL) 4 substrate receptor CDT2/DTL, and components of the anaphase-promoting complex/cyclosome (APC/C). Specifically attenuating CRL4CDT2 by CDT2 knockdown can be more potent in killing cSCC cells than targeting CRLs or CRL4s in general by RBX1 or DDB1 depletion. Suppression of the APC/C or forced APC/C activation by targeting its repressor EMI1 are both potential therapeutic approaches. We observed that cSCC cells can be selectively killed by small-molecule inhibitors of USP8 (DUBs-IN-3/compound 22c) and the NEDD8 E1 activating enzyme/CRLs (MLN4924/pevonedistat). A substantial proportion of cSCC cell lines are very highly MLN4924-sensitive. Pathways that respond to defects in proteostasis are involved in the anti-cSCC activity of p97 suppression. Targeting USP8 can reduce the expression of growth factor receptors that participate in cSCC development. EMI1 and CDT2 depletion can selectively cause DNA re-replication and DNA damage in cSCC cells.

Executive summary from American Radium Society's appropriate use criteria on neurocognition after stereotactic radiosurgery for multiple brain metastases.

BACKGROUND: The American Radium Society (ARS) Appropriate Use Criteria brain malignancies panel systematically reviewed (PRISMA [Preferred Reporting Items for Systematic Reviews and Meta-Analyses]) published literature on neurocognitive outcomes after stereotactic radiosurgery (SRS) for patients with multiple brain metastases (BM) to generate consensus guidelines. METHODS: The panel developed 4 key questions (KQs) to guide systematic review. From 11 614 original articles, 12 were selected. The panel developed model cases addressing KQs and potentially controversial scenarios not addressed in the systematic review (which might inform future ARS projects). Based upon quality of evidence, the panel confidentially voted on treatment options using a 9-point scale of appropriateness. RESULTS: The panel agreed that SRS alone is usually appropriate for those with good performance status and 2-10 asymptomatic BM, and usually not appropriate for >20 BM. For 11-15 and 16-20 BM there was (between 2 case variants) agreement that SRS alone may be appropriate or disagreement on the appropriateness of SRS alone. There was no scenario (among 6 case variants) in which conventional whole-brain radiotherapy (WBRT) was considered usually appropriate by most panelists. There were several areas of disagreement, including: hippocampal sparing WBRT for 2-4 asymptomatic BM; WBRT for resected BM amenable to SRS; fractionated versus single-fraction SRS for resected BM, larger targets, and/or brainstem metastases; optimal treatment (WBRT, hippocampal sparing WBRT, SRS alone to all or select lesions) for patients with progressive extracranial disease, poor performance status, and no systemic options. CONCLUSIONS: For patients with 2-10 BM, SRS alone is an appropriate treatment option for well-selected patients with good performance status. Future study is needed for those scenarios in which there was disagreement among panelists.

A framework for evaluation of deformable image registration spatial accuracy using large landmark point sets.

Expert landmark correspondences are widely reported for evaluating deformable image registration (DIR) spatial accuracy. In this report, we present a framework for objective evaluation of DIR spatial accuracy using large sets of expert-determined landmark point pairs. Large samples (>1100) of pulmonary landmark point pairs were manually generated for five cases. Estimates of inter- and intra-observer variation were determined from repeated registration. Comparative evaluation of DIR spatial accuracy was performed for two algorithms, a gradient-based optical flow algorithm and a landmark-based moving least-squares algorithm. The uncertainty of spatial error estimates was found to be inversely proportional to the square root of the number of landmark point pairs and directly proportional to the standard deviation of the spatial errors. Using the statistical properties of this data, we performed sample size calculations to estimate the average spatial accuracy of each algorithm with 95% confidence intervals within a 0.5 mm range. For the optical flow and moving least-squares algorithms, the required sample sizes were 1050 and 36, respectively. Comparative evaluation based on fewer than the required validation landmarks results in misrepresentation of the relative spatial accuracy. This study demonstrates that landmark pairs can be used to assess DIR spatial accuracy within a narrow uncertainty range.

Effect of postmastectomy radiotherapy in patients <35 years old with stage II-III breast cancer treated with doxorubicin-based neoadjuvant chemotherapy and mastectomy.

PURPOSE: Postmastectomy radiotherapy (PMRT) improves locoregional control (LRC) in patients with high-risk features after mastectomy. Young age continues to evolve as a potentially important risk factor. The objective of this study was to assess the benefits of PMRT in patients <35 years old treated with doxorubicin-based neoadjuvant chemotherapy for Stage II-III breast cancer. PATIENTS AND METHODS: We retrospectively analyzed 107 consecutive breast cancer patients <35 years old with Stage IIA-IIIC disease treated at our institution with doxorubicin-based neoadjuvant chemotherapy and mastectomy, with or without PMRT. The treatment groups were compared in terms of LRC and overall survival. RESULTS: Despite more advanced disease stages, the patients who received PMRT (n = 80) had greater rates of LRC (5-year rate, 88% vs. 63%, p = 0.001) and better overall survival (5-year rate, 67% vs. 48%, p = 0.03) than patients who did not receive PMRT (n = 27). CONCLUSION: Among breast cancer patients <35 years old at diagnosis, the use of PMRT after doxorubicin-based neoadjuvant chemotherapy and mastectomy led to a statistically greater rate of LRC and overall survival compared with patients without PMRT. The benefit seen for PMRT in young patients provides valuable data to better tailor adjuvant, age-specific treatment decisions after mastectomy.

Radiation proctopathy in the treatment of prostate cancer.

PURPOSE: To compile and review data on radiation proctopathy in the treatment of prostate cancer with respect to epidemiology, clinical manifestations, pathogenesis, risk factors, and treatment. METHODS: Medical literature databases including PubMed and Medline were screened for pertinent reports, and critically analyzed for relevance in the scope of our purpose. RESULTS: Rectal toxicity as a complication of radiotherapy has received attention over the past decade, especially with the advent of dose-escalation in prostate cancer treatment. A number of clinical criteria help to define acute and chronic radiation proctopathy, but lack of a unified grading scale makes comparing studies difficult. A variety of risk factors, related to either radiation delivery or patient, are the subject of intense study. Also, a variety of treatment options, including medical therapy, endoscopic treatments, and surgery have shown varied results, but a lack of large randomized trials evaluating their efficacy prevents forming concrete recommendations. CONCLUSION: Radiation proctopathy should be an important consideration for the clinician in the treatment of prostate cancer especially with dose escalation. With further study of possible risk factors, the advent of a standardized grading scale, and more randomized trials to evaluate treatments, patients and physicians will be better armed to make appropriate management decisions.

The nuclear transcription factor kappaB/bcl-2 pathway correlates with pathologic complete response to doxorubicin-based neoadjuvant chemotherapy in human breast cancer.

PURPOSE: Molecular factors involved in apoptosis may affect breast cancer response to chemotherapy. Herein, we studied the nuclear factor kappaB (NF-kappaB)/bcl-2 pathway to determine whether or not activation of this antiapoptotic pathway was associated with a poor response of human breast cancer to anthracycline-based neoadjuvant chemotherapy. EXPERIMENTAL DESIGN: We studied 82 human breast cancer samples from patients treated with neoadjuvant doxorubicin-based chemotherapy and studied whether or not nuclear location of the transcription factor NF-kappaB was associated with expression of bcl-2 and bax and whether or not expression of these proteins correlated with chemotherapy response. Protein expression was measured with immunohistochemical staining. A dedicated breast cancer pathologist who was unaware of the clinical outcome data dichotomized the slides as positive or negative based on the presence or absence of cytoplasmic staining for bcl-2 and bax or nuclear staining for NF-kappaB. RESULTS: Sixty-one percent of the tumors were positive for bcl-2, 85% were positive for bax, and 16% were positive for NF-kappaB. All bcl-2-positive tumors were also bax positive (P < 0.0001) and all NF-kappaB-positive tumors were both bcl-2 positive (P = 0.001) and bax positive (P = 0.113). Eleven of the 82 patients (13%) had a pathologic complete response (pCR) to chemotherapy. Patients with positive staining tumors for any of the markers less commonly achieved a pCR to chemotherapy than those with negative tumor staining. The pCR rates were NF-kappaB positive 0% (0 of 13) versus NF-kappaB negative 13% (11 of 69; P = 0.130); bcl-2 positive 4% (2 of 49) versus bcl-2 negative 27% (9 of 33; P = 0.004); and bax positive 6% (4 of 69) versus bax negative 58% (7 of 12; P < 0.001). CONCLUSION: We conclude that nuclear localization of NF-kappaB correlates with bcl-2 and bax expression and that the NF-kappaB/bcl-2 pathway may be associated with a poor response to neoadjuvant doxorubicin-based chemotherapy.

Chemosensitization and radiosensitization of tumors by plant polyphenols.

The treatment of cancer with chemotherapeutic agents and radiation has two major problems: time-dependent development of tumor resistance to therapy (chemoresistance and radioresistance) and nonspecific toxicity toward normal cells. Many plant-derived polyphenols have been studied intently for their potential chemopreventive properties and are pharmacologically safe. These compounds include genistein, curcumin, resveratrol, silymarin, caffeic acid phenethyl ester, flavopiridol, emodin, green tea polyphenols, piperine, oleandrin, ursolic acid, and betulinic acid. Recent research has suggested that these plant polyphenols might be used to sensitize tumor cells to chemotherapeutic agents and radiation therapy by inhibiting pathways that lead to treatment resistance. These agents have also been found to be protective from therapy-associated toxicities. How these polyphenols protect normal cells and sensitize tumor cells to treatment is discussed in this review.

Feasibility of using intensity-modulated radiotherapy to improve lung sparing in treatment planning for distal esophageal cancer.

BACKGROUND AND PURPOSE: To evaluate the feasibility whether intensity-modulated radiotherapy (IMRT) can be used to reduce doses to normal lung than three-dimensional conformal radiotherapy (3 DCRT) in treating distal esophageal malignancies. PATIENTS AND METHODS: Ten patient cases with cancer of the distal esophagus were selected for a retrospective treatment-planning study. IMRT plans using four, seven, and nine beams (4B, 7B, and 9B) were developed for each patient and compared with the 3 DCRT plan used clinically. IMRT and 3 DCRT plans were evaluated with respect to PTV coverage and dose-volumes to irradiated normal structures, with statistical comparison made between the two types of plans using the Wilcoxon matched-pair signed-rank test. RESULTS: IMRT plans (4B, 7B, 9B) reduced total lung volume treated above 10 Gy (V(10)), 20 Gy (V(20)), mean lung dose (MLD), biological effective volume (V(eff)), and lung integral dose (P<0.05). The median absolute improvement with IMRT over 3DCRT was approximately 10% for V(10), 5% for V(20), and 2.5 Gy for MLD. IMRT improved the PTV heterogeneity (P<0.05), yet conformity was better with 7B-9B IMRT plans. No clinically meaningful differences were observed with respect to the irradiated volumes of spinal cord, heart, liver, or total body integral doses. CONCLUSIONS: Dose-volume of exposed normal lung can be reduced with IMRT, though clinical investigations are warranted to assess IMRT treatment outcome of esophagus cancers.

Reactive oxygen intermediates in TNF signaling.

Tumor necrosis factor (TNF) is arguably the most potent inducer of several intracellular signals, including apoptosis, cell differentiation, and gene transcription. It does so through the activation of caspases, specific kinases including mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), transcription factors Activated protein 1 (AP-1), and nuclear factor kappa-B (NF-kappaB). By activating these signals, TNF mediates pro-apoptotic and pro-survival mechanisms in the cell. It has also been suggested that TNF mediates its intracellular signaling by adjusting the redox potential of the cell, specifically through reactive oxygen intermediates (also known as reactive oxygen species). Here we review the evidence linking ROI to TNF-induced signaling and propose that ROI mediate both pro-apoptotic and pro-survival signals. How these antagonistic signals are balanced to maintain homeostasis is still not clear.