Amit K. Garg

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.

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

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.

The Nuclear Transcription Factor κB/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 κB (NF-κB)/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-κB 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-κB. Results: Sixty-one percent of the tumors were positive for bcl-2, 85% were positive for bax, and 16% were positive for NF-κB. All bcl-2-positive tumors were also bax positive (P < 0.0001) and all NF-κB-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-κB positive 0% (0 of 13) versus NF-κB 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-κB correlates with bcl-2 and bax expression and that the NF-κB/bcl-2 pathway may be associated with a poor response to neoadjuvant doxorubicin-based chemotherapy.

Phase 1/2 Trial of Single-Session Stereotactic Body Radiotherapy for Previously Unirradiated Spinal Metastases

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.

Nuclear Transcription Factor-kappaB in Hodgkin's Disease

Nuclear factor-kappaB (NF- κ B) is a transcriptional factor that was originally discovered in the nucleus of B cells that bind to the kappa light chain of the immunoglobulins. Research during 15 years, however, has revealed that NF- κ B is present in its inactive state in the cytoplasm of almost every cell type. When activated, NF- κ B translocates to the nucleus, binds the DNA and regulates the expression of over 200 different genes. The product of these genes regulate the immune system, cell proliferation, tumor metastasis, inflammation and viral replication. Several tumor cell types express constitutively activated form of NF- κ B and it is required for the proliferation of the tumor cells. Numerous studies have shown that Hodgkins disease cells exhibit constitutive active NF- κ B. The present review examines the mechanism how NF- κ B is activated and its relevance to Hodgkins disease.

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.

Expression of nuclear transcription factor kappa b in locally advanced human cervical cancer treated with definitive chemoradiation

PURPOSE Nuclear factor kappa B (NF-κB), a transcriptional factor that has been shown to be constitutively active in cervical cancer, is part of an important pathway leading to treatment resistance in many tumor types. The purpose of our study was to determine whether expression of NF-κB in pretreatment specimens and specimens taken shortly after treatment initiation correlated with outcome in cervical cancer patients treated with definitive chemoradiation. METHODS AND MATERIALS Eighteen patients with locally advanced cervical cancer were enrolled in a study in which cervical biopsy specimens were obtained before radiation therapy and 48 h after treatment initiation. Matched biopsy specimens from 16 of these patients were available and evaluated for the nuclear expression of NF-κB protein by immunohistochemical staining. RESULTS After a median follow-up of 43 months, there were 9 total treatment failures. Nuclear staining for NF-κB was positive in 3 of 16 pretreatment biopsy specimens (19%) and 5 of 16 postradiation biopsy specimens (31%). Pretreatment expression of NF-κB nuclear staining correlated with increased rates of local-regional failure (100% vs. 23%, p = 0.01), distant failure (100% vs. 38%, p = 0.055), disease-specific mortality (100% vs. 31%, p = 0.03), and overall mortality (100% vs. 38%, p = 0.055). CONCLUSIONS Our data suggest that pretreatment nuclear expression of NF-κB may be associated with a poor outcome for cervical cancer patients treated with chemoradiation. Although these data require validation in a larger group of patients, the results support the continued study of the relationship between NF-κB and outcome in patients treated for carcinoma of the cervix.

Effects of variable placement of superior tangential/supraclavicular match line on dosimetric coverage of level III axilla/axillary apex in patients treated with breast and supraclavicular radiotherapy.

PURPOSE To determine the differences in dosimetric coverage of the Level III axillary node target as a function of the superior tangential/supraclavicular match line in breast cancer patients undergoing with tangential breast and supraclavicular fossa radiotherapy. METHODS AND MATERIALS The data from 20 consecutive breast cancer patients who were treated with breast conservation surgery and Level I and II axillary dissection followed by radiotherapy to the undissected Level III axilla/supraclavicular fossa were retrospectively analyzed. The nodal volumes were delineated from the computed tomography simulation data set. Three composite treatment plans were generated for each patient according to the placement of the match line. RESULTS Coverage of the contoured Level III/axillary apex varied significantly with respect to the ipsilateral clavicular head, depending on the placement of the superior tangential/supraclavicular match line. The mean volume of the Level III/axillary apex covered by the 90% isodose line (45 Gy) was 100% for caudal placement of the match line, significantly greater than the 92% for intermediate placement (bisecting the clavicular head; p = 0.001) and the 68% for cranial placement with respect to the clavicular head (p < 0.001). CONCLUSION Placement of the superior tangential/supraclavicular match line caudal to the clavicular head results in statistically improved dosimetric coverage of the Level III axilla/axillary apex in breast cancer patients undergoing tangential/supraclavicular radiotherapy.

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.

Nocebo side-effects in cancer treatment

Published Online September 23, 2011 DOI:10.1016/S14702045(11)70268-6 Advancements in technology and targeted agents for cancer have improved patient outcomes and reduced toxicities; however, serious side-eff ects with systemic or local therapies continue to be a major concern. Nausea, fatigue, headache, dizziness, pain, gastrointestinal irritation, depression, memory changes, urinary symptoms, and skin irritation are among the most commonly reported non-specifi c toxic eff ects that can begin early in the course of protracted cancer therapy. The incidence and frequency of these non-specifi c side-eff ects are often correlated with objective factors such as type of therapy, total dose and duration, and physical characteristics, but accumulating clinical data suggest that patient expectations play a major part. Negative expectations engendered through unfi ltered information disclosure can lead to physical consequences through diverse mechanisms described by the nocebo eff ect—Latin for I shall harm. Recognition of these potentially nocebo-inducing stimuli can help to reduce non-specifi c side-eff ects in patients with cancer. A revised ethical perspective on informed consent that takes into account this important and potentially harmful occurrence is warranted. The physician–patient dynamic holds substantial therapeutic potential, supported by compelling clinical and basic science data in several diseases. Although the positive eff ects of this relation are shown by studies that describe them as an eff ect of placebo—Latin for I shall please—this term is most commonly attributed to the deceptive use of any medical intervention that has no specifi c activity for the disorder being treated. These eff ects, however, are not limited to the so-called sham administration of inert pills as used in placebo-controlled randomised trials, but are shown to encompass a more meaningful, eff ective, and deliberate eff ort to maximise treatment effi cacy. Nocebo eff ects can be evoked through negative conditioning. Over the past 10 years, neurobiological pathways triggered by negative expectations have been identifi ed and provide insight into the physiological manifestations of the nocebo eff ect. Although limited by ethical considerations, clinical data for nocebo eff ects collectively suggest that non-specifi c symptoms are highly likely to be aff ected by patient expectations. In patients with cancer, these non-specifi c symptoms can be triggered or exacerbated by nocebo-inducing stimuli, such as side-eff ect forms handed to patients as part of the consent process. In daily clinical practice, patients undergoing several weeks of radiotherapy can manifest non-specifi c symptoms during the fi rst week of treatment. Since these symptoms—which often include nausea, headache, gastrointestinal distress, and fatigue—usually improve with reassurance alone, it is tempting to hypothesise that the anticipation of such eff ects can have an important role in their manifestation, as shown in other diseases. For example, in a randomised study of aspirin in patients with unstable angina, more gastrointestinal distress and a higher likelihood of study withdrawal was noted in patients taking placebo whose consent forms contained the warning of gastrointestinal irritation as a possible side-eff ect of treatment than in those whose consent forms did not contain this advanced warning. The ethical basis for informing patients about every possible side-eff ect of treatment has been rooted in the principle of respect for patient autonomy. This model suggests that all information a clinician uses to make a specifi c treatment recommendation should be discussed explicitly with the patient if its helps them to make an informed decision. Thus patients are exposed to unfi ltered Heidi Traunecker Children’s Hospital for Wales, Department of Paediatric Oncology, Heath Park, Cardiff , CF14 4XW, UK Heidi.Traunecker@Cardiff andVale.wales.nhs.uk