Team Approach: Management of Pathologic Fractures.

»: Optimal care for pathologic fractures centers on the use of a multidisciplinary team; thus, whenever there is a concern for pathologic fracture and proper workup is unable to be performed, prompt referral to a center equipped to manage these injuries should occur.

»: Fixation strategies for pathologic fractures must take into account patient characteristics, cancer subtypes, and overall goals of treatment.

»: As the treatments of cancers improve, patient life expectancy with disease will improve as well.

A proliferative subtype of colorectal liver metastases exhibits hypersensitivity to cytotoxic chemotherapy.

Personalized treatment approaches for patients with limited liver metastases from colorectal cancer are critically needed. By leveraging three large, independent cohorts of patients with colorectal liver metastases (n = 336), we found that a proliferative subtype associated with elevated CIN70 scores is linked to immune exclusion, increased metastatic proclivity, and inferior overall survival in colorectal liver metastases; however, high CIN70 scores generate a therapeutic vulnerability to DNA-damaging therapies leading to improved treatment responses. We propose CIN70 as a candidate biomarker to personalize systemic treatment options for patients with metastatic colorectal cancer.

Noncanonical NF-κB factor p100/p52 regulates homologous recombination and modulates sensitivity to DNA-damaging therapy.

Homologous recombination (HR) serves multiple roles in DNA repair that are essential for maintaining genomic stability, including double-strand DNA break (DSB) repair. The central HR protein, RAD51, is frequently overexpressed in human malignancies, thereby elevating HR proficiency and promoting resistance to DNA-damaging therapies. Here, we find that the non-canonical NF-κB factors p100/52, but not RelB, control the expression of RAD51 in various human cancer subtypes.

Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination.

Homologous recombination (HR) is a primary DNA double-strand breaks (DSBs) repair mechanism. The recombinases Rad51 and Dmc1 are highly conserved in the RecA family; Rad51 is mainly responsible for DNA repair in somatic cells during mitosis while Dmc1 only works during meiosis in germ cells. This spatiotemporal difference is probably due to their distinctive mismatch tolerance during HR: Rad51 does not permit HR in the presence of mismatches, whereas Dmc1 can tolerate certain mismatches.

qRT-PCR-based DNA homologous recombination-associated 4-gene score predicts pathologic complete response to platinum-based neoadjuvant chemotherapy in triple-negative breast cancer.

Purpose: Cumulative evidence suggests that the addition of platinum agents as neoadjuvant chemotherapy (NACT) could improve the pathologic complete response (pCR) rate in triple-negative breast cancer (TNBC). We aimed to develop a DNA homologous recombination (HR)-associated gene expression score to predict tumor sensitivity to platinum-based NACT in TNBC.

Methods: A retrospective cohort of 127 patients who were diagnosed with TNBC and received platinum-based NACT in Fudan University Shanghai Cancer Center from 2012 to 2017 was included in this study.

CDKN2A loss-of-function predicts immunotherapy resistance in non-small cell lung cancer.

Immune checkpoint blockade (ICB) improves outcomes in non-small cell lung cancer (NSCLC) though most patients progress. There are limited data regarding molecular predictors of progression. In particular, there is controversy regarding the role of CDKN2A loss-of-function (LOF) in ICB resistance.

Radiation-Induced Sarcoma After Heterotopic Ossification Prophylaxis: A Case Report.

Case: Heterotopic ossification (HO) is a pathological formation of bone in nonosseous tissue and is a common complication of orthopaedic procedures. Radiotherapy is often used to prevent HO despite the small risk of secondary malignancy. Here, we report a case of a patient who developed a periprosthetic, radiation-induced sarcoma after delivery of a single fraction of 7 Gy for HO prophylaxis.

Elevated Radiation Therapy Toxicity in the Setting of Germline PTEN Mutation.

Cells that lack PTEN function are radiation sensitive in cell culture-based experimental systems; therefore, patients with Cowden Syndrome (CS) may carry an increased risk for normal tissue injury after radiotherapy. Here we present the first such case of a patient with genetically-confirmed CS who, indeed, experienced greater than expected toxicity following two separate courses of radiotherapy. While a causal relationship between CS and radiation sensitivity remains unclear, this observation suggests the need for further study in larger cohorts of CS patients.

Optimization of Drug Candidates That Inhibit the D-Loop Activity of RAD51.

RAD51 is the central protein in homologous recombination (HR) repair, where it first binds ssDNA and then catalyzes strand invasion via a D-loop intermediate. Additionally, RAD51 plays a role in faithful DNA replication by protecting stalled replication forks; this requires RAD51 to bind DNA but may not require the strand invasion activity of RAD51. We previously described a small-molecule inhibitor of RAD51 named RI(dl)-2 (RAD51 inhibitor of D-loop formation #2, hereafter called 2 h), which inhibits D-loop activity while sparing ssDNA binding.

Maternal Embryonic Leucine Zipper Kinase (MELK), a Potential Therapeutic Target for Neuroblastoma.

Maternal embryonic leucine zipper kinase (MELK) activates pathways that mediate aggressive tumor growth and therapy resistance in many types of adult cancers. Pharmacologic and genomic inhibition of MELK impairs tumor growth and increases sensitivity to radiation and chemotherapy. On the basis of these promising preclinical studies, early-phase adult clinical trials testing the MELK inhibitor OTS167 are ongoing.

Effect of Endoscopic Bronchial Ultrasound on Outcomes for Stage I Non-Small-Cell Lung Cancer Patients Receiving Hypofractionated Radiotherapy.

Background: In this study we sought to determine if staging endoscopic bronchial ultrasound (EBUS) improves outcomes in stage I non-small-cell lung cancer (NSCLC) patients who received hypofractionated radiation therapy (HFRT).

Patients And Methods: Patients with stage I NSCLC treated with HFRT from 2008 to 2015 were retrospectively identified from 3 affiliated institutions. All patients underwent positron emission tomography/computed tomography staging and a subset of patients received pretreatment EBUS.

Low Recombination Proficiency Score (RPS) Predicts Heightened Sensitivity to DNA-Damaging Chemotherapy in Breast Cancer.

Molecular-based cancer tests have been developed to augment the standard clinical and pathologic features used to tailor treatments to individual breast cancer patients. Homologous recombination (HR) repairs double-stranded DNA breaks and promotes tolerance to lesions that disrupt DNA replication. Recombination Proficiency Score (RPS) quantifies HR efficiency based on the expression of four genes involved in DNA damage repair.

Recent Developments Using Small Molecules to Target RAD51: How to Best Modulate RAD51 for Anticancer Therapy?

Homologous recombination (HR) is an evolutionarily conserved DNA repair process. Overexpression of the key HR protein RAD51 is a common feature of malignant cells. RAD51 plays two distinct genome-stabilizing roles, including HR-mediated repair of double-strand breaks (DSBs) and the promotion of replication fork stability during replication stress.

Development of Small Molecules that Specifically Inhibit the D-loop Activity of RAD51.

RAD51 is the central protein in homologous recombination (HR) DNA repair and represents a therapeutic target in oncology. Herein we report a novel class of RAD51 inhibitors that were identified by high throughput screening. In contrast to many previously reported RAD51 inhibitors, our lead compound 1 is capable of blocking RAD51-mediated D-loop formation (IC50 21.

Strategies to Overcome Late Complications from Radiotherapy for Childhood Head and Neck Cancers.

Most pediatric head and neck cancers are treated with radiotherapy, but the morbidity associated with radiotherapy has become a prominent issue. This article discusses the common long-term complications associated with head and neck radiotherapy for childhood cancers. It reviews approaches to minimize toxicity and details the toxicities that head and neck radiation inflicts on relevant functional measures.

RAD54 family translocases counter genotoxic effects of RAD51 in human tumor cells.

The RAD54 family DNA translocases have several biochemical activities. One activity, demonstrated previously for the budding yeast translocases, is ATPase-dependent disruption of RAD51-dsDNA binding. This activity is thought to promote dissociation of RAD51 from heteroduplex DNA following strand exchange during homologous recombination.

The RAD51-stimulatory compound RS-1 can exploit the RAD51 overexpression that exists in cancer cells and tumors.

RAD51 is the central protein that catalyzes DNA repair via homologous recombination, a process that ensures genomic stability. RAD51 protein is commonly expressed at high levels in cancer cells relative to their noncancerous precursors. High levels of RAD51 expression can lead to the formation of genotoxic RAD51 protein complexes on undamaged chromatin.

DNA repair pathway gene expression score correlates with repair proficiency and tumor sensitivity to chemotherapy.

Mutagenesis is a hallmark of malignancy, and many oncologic treatments function by generating additional DNA damage. Therefore, DNA damage repair is centrally important in both carcinogenesis and cancer treatment. Homologous recombination (HR) and nonhomologous end joining are alternative pathways of double-strand DNA break repair.

Real-time solution measurement of RAD51- and RecA-mediated strand assimilation without background annealing.

RAD51 is the central strand exchange recombinase in somatic homologous recombination, providing genomic stability and promoting resistance to DNA damage. An important tool for mechanistic studies of RAD51 is the D-loop or strand assimilation assay, which measures the ability of RAD51-coated single-stranded DNA (ssDNA) to search for, invade and exchange ssDNA strands with a homologous duplex DNA target. As cancer cells generally overexpress RAD51, the D-loop assay has also emerged as an important tool in oncologic drug design programs for targeting RAD51.

New paradigms and future challenges in radiation oncology: an update of biological targets and technology.

Radiation oncology exploits the biological interaction of radiation within tissue to promote tumor death while minimizing damage to surrounding normal tissue. The clinical delivery of radiation relies on principles of radiation physics that define how radiation energy is deposited in the body, as well as technology that facilitates accurate tumor targeting. This review will summarize the current landscape of recent biological and technological advances in radiation oncology, describe the challenges that exist, and offer potential avenues for improvement.

An analysis of patient characteristics and clinical outcomes in primary pulmonary sarcoma.

Introduction: Literature concerning primary pulmonary sarcomas (PPS) is limited to small case series. This study examines, in a large cohort, the clinical characteristics and therapeutic strategies of PPS and their impact on overall survival (OS).

Methods: This was a retrospective analysis from the Surveillance, Epidemiology, and End Results database (1988-2008).

An optimized RAD51 inhibitor that disrupts homologous recombination without requiring Michael acceptor reactivity.

Homologous recombination (HR) is an essential process in cells that provides repair of DNA double-strand breaks and lesions that block DNA replication. RAD51 is an evolutionarily conserved protein that is central to HR. Overexpression of RAD51 protein is common in cancer cells and represents a potential therapeutic target in oncology.

RI-1: a chemical inhibitor of RAD51 that disrupts homologous recombination in human cells.

Homologous recombination serves multiple roles in DNA repair that are essential for maintaining genomic stability. We here describe RI-1, a small molecule that inhibits the central recombination protein RAD51. RI-1 specifically reduces gene conversion in human cells while stimulating single strand annealing.