An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer.

Individualization of cancer management requires prognostic markers and therapy-predictive markers. Prognostic markers assess risk of disease progression independent of therapy, whereas therapy-predictive markers identify patients whose disease is sensitive or resistant to treatment. We show that an experimentally derived IFN-related DNA damage resistance signature (IRDS) is associated with resistance to chemotherapy and/or radiation across different cancer cell lines. The IRDS genes STAT1, ISG15, and IFIT1 all mediate experimental resistance. Clinical analyses reveal that IRDS(+) and IRDS(-) states exist among common human cancers. In breast cancer, a seven-gene-pair classifier predicts for efficacy of adjuvant chemotherapy and for local-regional control after radiation. By providing information on treatment sensitivity or resistance, the IRDS improves outcome prediction when combined with standard markers, risk groups, or other genomic classifiers.

Targeting pathways mediating resistance to anti-EGFR therapy in squamous cell carcinoma of the head and neck.

INTRODUCTION: As epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of squamous cell carcinomas of the head and neck (SCCHN), several therapeutic agents that target EGFR have been evaluated for the treatment of SCCHN. Although patients with SCCHN derive clinical benefit from anti-EGFR agents, most notably the EGFR monoclonal antibody cetuximab, these patients eventually become resistant to EGFR-based therapies; preclinical studies have shown activation of secondary signaling pathways that lead to resistance to EGFR inhibition and, as such, serve as potential therapeutic targets to overcome resistance to EGFR inhibitors. AREAS COVERED: This review summarizes the results of recently completed trials of anti-EGFR agents in SCCHN, highlights the various mechanisms that drive resistance to EGFR inhibitors in SCCHN, and focuses on several novel targeted agents that could potentially help overcome resistance to EGFR-based therapies in SCCHN. Expert commentary: Due to the development of resistance to EGFR-targeted therapies, novel treatment approaches to overcome resistance are a key unmet need for SCCHN.

DNA base-excision repair enzyme apurinic/apyrimidinic endonuclease/redox factor-1 is increased and competent in the brain and spinal cord of individuals with amyotrophic lateral sclerosis.

Motor neurons degenerate in amyotrophic lateral sclerosis (ALS). The mechanisms for this neuronal cell death are not known, although apoptosis has been implicated. Oxidative damage to DNA and activation of p53 has been identified directly in motor neurons in cases of ALS. We evaluated whether motor neuron degeneration in ALS is associated with changes in the levels and function of the multifunctional protein apurinic/apyrimidinic endonuclease (APE/Ref-1). APE/Ref-1 functions as an enzyme in the DNA base-excision repair pathway and as a redox-regulation protein for transcription factors. The protein level and localization of APE/Ref-1 are changed in ALS. Immunoblotting showed that APE/Ref-1 protein levels are increased in selectively vulnerable central nervous system (CNS) regions in individuals with ALS compared to age-matched controls. Plasmid DNA repair assay demonstrated that APE from individuals with ALS is competent in repairing apurinic (AP) sites. DNA repair function in nuclear fractions is increased significantly in ALS motor cortex and spinal cord. Immunocytochemistry and single-cell densitometry revealed that APE/Ref-1 is expressed at lower levels in control motor neurons than in ALS motor neurons, which are decreased in number by 42% in motor cortex. APE/Ref-1 is increased in the nucleus of remaining upper motor neurons in ALS, which show a 38% loss of nuclear area. APE-Ref-1 is also upregulated in astrocytes in spinal cord white matter pathways in familial ALS. We conclude that mechanisms for DNA repair are activated in ALS, supporting the possibility that DNA damage is an upstream mechanism for motor neuron degeneration in this disease.

Accelerated partial breast irradiation using once-daily fractionation: analysis of 312 cases with four years median follow-up.

BACKGROUND: There are limited data on accelerated partial breast irradiation (APBI) using external beam techniques. Moreover, there are recent reports of increased fibrosis and unacceptable cosmesis with APBI using external beam with BID fractionation. We adopted a once daily regimen of APBI with fractionation similar to that shown to be effective in a Canadian randomized trial of whole breast irradiation. It is unclear whether patients with DCIS or invasive lobular carcinoma (ILC) are suitable for APBI. METHODS: The retrospective cohort included 310 patients with 312 tumors of T1-T2N0-N1micM0 invasive ductal carcinoma (IDC), ILC, or Tis (DCIS) treated with APBI via external beam. Most patients were treated using IMRT with 16 daily fractions of 270 cGy to a dose of 4320 cGy. The target volume included the lumpectomy cavity plus 1.0 cm to account for microscopic disease and an additional 0.5 to 1.0 cm for setup uncertainty and breathing motion. Ipsilateral breast failure (IBF) was pathologically confirmed as a local failure (LF) or an elsewhere failure (EF). RESULTS: Median follow-up was 49 months. Among the 312 cases, 213 were IDC, 31 ILC, and 68 DCIS. Median tumor size was 1.0 cm. There were 9 IBFs (2.9%) including 5 LFs and 4 EFs. The IBF rates among patients with IDC, ILC, and DCIS were 2.4%, 3.2%, and 4.4%, respectively, with no significant difference between histologies. When patients were analyzed by the ASTRO APBI consensus statement risk groups, 32% of treated cases were considered suitable, 50% cautionary, and 18% unsuitable. The IBF rates among suitable, cautionary, and unsuitable patients were 4.0%, 2.6%, and 1.8%, respectively, with no significant difference between risk groups. Acute skin reactions were rare and long-term cosmetic outcome was very good to excellent. CONCLUSIONS: External beam APBI with once daily fractionation has a low rate of IBF consistent with other published APBI studies. The ASTRO risk stratification did not differentiate a subset of patients with a higher rate of IBF. APBI may be an appropriate treatment for women with DCIS and ILC.

Chemotherapy and high dose radiotherapy followed by resection for locally advanced nonsmall cell lung cancers.

OBJECTIVES: For locally advanced but technically operable nonsmall cell lung cancer (NSCLC), neoadjuvant chemoradiotherapy is frequently used. Ideal radiotherapy dose in this context is unclear. MATERIALS AND METHODS: Twenty-six NSCLC patients with N2 disease were retrospectively reviewed. All received preoperative concurrent platinum-based chemoradiotherapy. Gross tumor volumes received a median of 58 Gy (range, 50-60 Gy). RESULTS: Two patients experienced major complications and died, resulting in a postoperative mortality rate of 7.7%. Three patients (11.5%) had minor complications. Pathologic specimens revealed downstaging in 76.9% of patients. The pathologic complete response (CR) rate was 34.6%. Downstaging of nodes was observed in 20 of 26 patients. With a median follow-up of 18.3 months, the 1- and 3-year actuarial survival rates were 80.2% and 45.7%, respectively. The 1- and 3-year actuarial disease-free survival (DFS) rates were 76.9% and 37.3%, respectively. Patients experiencing mediastinal downstaging had better DFS rates, relative to patients that did not (18-month DFS = 79.2% vs. 0%; P = 0.0001). Differences in RT dose (50-60 Gy) and types of chemotherapeutic regimens did not significantly impact pathologic downstaging rates, CR rates, DFS, or survival. DISCUSSION: Neoadjuvant chemotherapy with high-dose concurrent RT is well tolerated and results in favorable outcomes.

Diverticulitis presenting as a strangulated inguinal hernia.

BACKGROUND/AIM: Inguinal hernia is a common diagnosis for patients presenting with a painful groin mass; other potentially dangerous diagnoses may mimic a groin hernia. We present 3 unusual cases of diverticulitis with perforation. The resulting abscess presented clinically as an atypical strangulated inguinal hernia. METHODS/RESULTS: From July 1, 1999, to June 30, 2000, 344 patients were admitted to the Johns Hopkins Bayview Medical Center with the diagnosis of diverticulitis. Of these patients, 44 (12.8%) required surgical intervention. We report here 3 cases in that academic year of diverticulitis complicated by perforation and abscess formation that presented as atypical strangulated inguinal hernias. In addition to being rare and difficult to diagnose, such cases illustrate that a tender inguinal mass may not represent a hernia. CONCLUSIONS: The diagnosis of strangulated inguinal hernias remains primarily one of clinical suspicion. Radiologic and laboratory studies should augment, not replace, one's clinical diagnosis. In addition, the differential diagnosis of inguinal masses is discussed.