Lee Wiederhold

Mammalian DNA base excision repair proteins: their interactions and role in repair of oxidative DNA damage

The DNA base excision repair (BER) is a ubiquitous mechanism for removing damage from the genome induced by spontaneous chemical reaction, reactive oxygen species (ROS) and also DNA damage induced by a variety of environmental genotoxicants. DNA repair is essential for maintaining genomic integrity. As we learn more about BER, a more complex mechanism emerges which supersedes the classical, simple pathway requiring only four enzymatic reactions. The key to understand the complete BER process is to elucidate how multiple proteins interact with one another in a coordinated process under specific physiological conditions.

Identification and characterization of mitochondrial abasic (AP)-endonuclease in mammalian cells

Abasic (AP)-endonuclease (APE) is responsible for repair of AP sites, and single-strand DNA breaks with 3′ blocking groups that are generated either spontaneously or during repair of damaged or abnormal bases via the DNA base excision repair (BER) pathway in both nucleus and mitochondria. Mammalian cells express only one nuclear APE, 36 kDa APE1, which is essential for survival. Mammalian mitochondrial (mt) BER enzymes other than mtAPE have been characterized. In order to identify and characterize mtAPE, we purified the APE activity from beef liver mitochondria to near homogeneity, and showed that the mtAPE which has 3-fold higher specific activity relative to APE1 is derived from the latter with deletion of 33 N-terminal residues which contain the nuclear localization signal. The mtAPE-sized product could be generated by incubating 35S-labeled APE1 with crude mitochondrial extract, but not with cytosolic or nuclear extract, suggesting that cleavage of APE1 by a specific mitochondria-associated N-terminal peptidase is a prerequisite for mitochondrial import. The low abundance of mtAPE, particularly in cultured cells might be the reason for its earlier lack of detection by western analysis.

Accelerated partial breast irradiation: Past, present, and future

Accelerated partial breast irradiation (APBI) focuses higher doses of radiation during a shorter interval to the lumpectomy cavity, in the setting of breast conserving therapy for early stage breast cancer. The utilization of APBI has increased in the past decade because of the shorter treatment schedule and a growing body of outcome data showing positive cosmetic outcomes and high local control rates in selected patients undergoing breast conserving therapy. Technological advances in various APBI modalities, including intracavitary and interstitial brachytherapy, intraoperative radiation therapy, and external beam radiation therapy, have made APBI more accessible in the community. Results of early APBI trials served as the basis for the current consensus guidelines, and multiple prospective randomized clinical trials are currently ongoing. The pending long term results of these trials will help us identify optimal candidates that can benefit from ABPI. Here we provide an overview of the clinical and cosmetic outcomes of various APBI techniques and review the current guidelines for selecting suitable breast cancer patients. We also discuss the impact of APBI on the economics of cancer care and patient reported quality of life.

Gemcitabine-induced radiation recall myositis in a patient with relapsed nasopharyngeal carcinoma

Combined modality therapy with surgery, irradiation, and chemotherapy is the standard of care for many pediatric solid tumors. Although the adverse effects of an individual modality are well known, the adverse events resulting from interaction between the modalities is not well understood. The toxicity of radiation therapy is influenced by multiple factors, including the tissue volume irradiated (daily and cumulative dose), fraction size and schedule, treatment techniques, patient age, physiologic reserve, comorbidities, and genetics. Radiation therapy toxicity may also depend on concomitant chemotherapy; a quintessential example is the phenomenon of “radiation recall” reaction secondary to subsequent systemic chemotherapy.1 D’Angio initially described a radiation recall reaction as an acute inflammatory response evident in previously irradiated fields that is induced when chemotherapy is administered after radiation therapy.1 Chemotherapeutic agents reported to cause a radiation recall reaction include dactinomycin, anthracyclines (doxorubicin), taxanes (docetaxel), and antimetabolites (gemcitabine).2‐4 It is unclear whether the association of a radiation recall reaction with

Adjuvant Management of Pathologic Node–Positive Disease After Definitive Surgery for Clinical T1-2 N0 Rectal Cancer

Introduction: Patients with cT1–2N0M0 rectal cancer are often treated with up‐front surgical resection, with adjuvant treatment reserved for patients upstaged with pathologic node‐positive (pN+) disease at surgery. This study evaluates practice patterns and clinical outcomes when comparing different forms of adjuvant treatment for this patient population. Methods: The National Cancer Data Base was queried for cT1–2N0M0 rectal cancer patients between 2004 and 2015 with postoperative pN+ disease treated without neoadjuvant treatment. Patients were divided into groups receiving observation, chemotherapy, or chemoradiotherapy (CRT). Multivariable logistic regression determined factors associated with receipt of adjuvant treatment. Kaplan‐Meier curves compared overall survival (OS), and Cox regression determined patient factors associated with OS. Results: Altogether, 1466 patients met the inclusion criteria; 536 patients (36.6%) received adjuvant chemotherapy, 413 (28.2%) received adjuvant CRT, and 517 (35.3%) were observed postoperatively. Use of adjuvant treatment was associated with superior median OS (124.1 vs. 51.1 months, P < .001), persisting after propensity score matching (124.0 vs. 61.9 months, P < .001), but not between adjuvant CRT versus chemotherapy on subset analysis. Patients with positive surgical margins receiving adjuvant CRT showed a trend toward OS improvement compared to patients managed with chemotherapy (54.9 vs. 47.4 months, P = .10). Increased age, pN2 status, positive margin status, and observation were associated with poorer OS. Conclusion: Most patients found to have pN+ disease after up‐front surgery for cT1–2N0 rectal cancer receive adjuvant treatment, which is associated with improved OS. Chemotherapy or CRT are appropriate options, although there was a trend toward higher OS for patients with positive surgical margins receiving CRT. Micro‐Abstract: Most patients with cT1–2N0M0 rectal cancer are treated surgically, followed by adjuvant treatment if pathologically positive lymph nodes are subsequently discovered. With the National Cancer Data Base, clinical outcomes for 1466 patients were compared on the basis of the type of adjuvant management received. Postoperative adjuvant treatment is associated with improved overall survival compared to observation and may be offered to patients.

Pleomorphic Lobular Carcinoma of the Breast: A Review of 35 Cases at a Single Institution

Objectives: Pleomorphic lobular carcinoma (PL) is an aggressive subtype of invasive lobular carcinoma. There are few case series reporting on this aggressive form of breast cancer. This report features a descriptive and survivorship comparison of a large case series of PL reviewed by a single breast pathologist. Methods: From 1993-2010 we retrospectively reviewed 198 cases of invasive lobular carcinomas, 35 cases (34 patients with one patient presenting with 2 independent cancers) of PL and 163 cases of non-pleomorphic invasive lobular carcinoma (NPL). The pathology was reviewed by a single breast pathologist and classified as either PL or NPL according to WHO classification. Kaplan-Meier survivals were computed and compared with a log rank test using SPSS 18. Overall survival (OS) was computed from date of diagnosis. Progression free survival (PFS) until either local or metastatic failure was computed. Results: Median follow-up was 59.5 months and 73 months, for NPL and PL respectively. Median age of diagnosis was 55 and 58.67 for PL and NPL groups. Of the NPL group, 75.5% were post-menopausal opposed to 67.6% in PL group. PL cases were ER positive 87.1% vs. 90.1% of the NPL cases. Her-2/neu status was known in nearly 50% of cases with 17 positive NPL and 5 positive PL. Clinical stage at presentation was stage IIB or less in 67.6% of the PL and 80.1% of the NPL. Six presented (17.6%) with metastatic disease in the PL group and 12 (7.7%) in the NPL group. None of the descriptive comparisons were significantly different by c2 analyses. PFS at 5 years was 30% and 21% in PL and NPL, respectively (p=0.73). OS at 5 years was 68.5% for PL and 83.9% for NPL (p=0.031). Conclusions: PL patients showed a statistically significant decreased OS, but no significant difference in PFS, at 5 years from diagnosis.