Adjuvant enzalutamide for the treatment of early-stage androgen-receptor positive, triple-negative breast cancer: a feasibility study.

PURPOSE: Chemotherapy with or without immunotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC). A subset of TNBCs express the androgen receptor (AR), representing a potential new therapeutic target. This study assessed the feasibility of adjuvant enzalutamide, an AR antagonist, in early-stage, AR-positive (AR +) TNBC. METHODS: This study was a single-arm, open-label, multicenter trial in which patients with stage I-III, AR ≥ 1% TNBC who had completed standard-of-care therapy were treated with enzalutamide 160 mg/day orally for 1 year. The primary objective of this study was to evaluate the feasibility of 1 year of adjuvant enzalutamide, defined as the treatment discontinuation rate of enzalutamide due to toxicity, withdrawal of consent, or other events related to tolerability. Secondary endpoints included disease-free survival (DFS), overall survival (OS), safety, and genomic features of recurrent tumors. RESULTS: Fifty patients were enrolled in this study. Thirty-five patients completed 1 year of therapy, thereby meeting the prespecified trial endpoint for feasibility. Thirty-two patients elected to continue with an optional second year of treatment. Grade ≥ 3 treatment-related adverse events were uncommon. The 1-year, 2-year, and 3-year DFS were 94%, 92% , and 80%, respectively. Median OS has not been reached. CONCLUSION: This clinical trial demonstrates that adjuvant enzalutamide is a feasible and well-tolerated regimen in patients with an early-stage AR + TNBC. Randomized trials in the metastatic setting may inform patient selection through biomarker development; longer follow-up is needed to determine the effect of anti-androgens on DFS and OS in this patient population.

Constitutional chromosome rearrangements that mimic the 2017 world health organization "acute myeloid leukemia with recurrent genetic abnormalities": A study of three cases and review of the literature.

OBJECTIVES: To identify and characterize constitutional chromosomal rearrangements that mimic recurrent genetic abnormalities in acute myeloid leukemia (AML). METHODS: Bone marrow and blood chromosome studies were reviewed to identify constitutional rearrangements that resemble those designated by the 2017 revised World Health Organization (WHO) "AML with recurrent genetic abnormalities". Mate-pair sequencing (MPseq) was performed on cases with constitutional chromosome mimics of recurrent AML abnormalities to further define the rearrangement breakpoints. RESULTS: Three cases with constitutional rearrangements were identified, including t(6;9)(p23;q34), inv(16)(p13.1q22), and t(9;22)(q34.1;q12.2). Two cases were bone marrow specimens being evaluated for hematologic neoplasms, while one case was a blood specimen being evaluated for primary ovarian insufficiency. MPseq provided high-resolution and precise rearrangement breakpoints, and resolved the atypical FISH results generated with each rearrangement. CONCLUSIONS: Our findings illustrate that constitutional rearrangements can mimic recurrent genetic abnormalities observed in AML, and we emphasize the importance of correlating genetic data with clinical and hematopathologic information.

The C-Terminal Intact Forms of Periostin (iPTN) Are Surrogate Markers for Osteolytic Lesions in Experimental Breast Cancer Bone Metastasis.

Periostin is an extracellular matrix protein that actively contributes to tumor progression and metastasis. Here, we hypothesized that it could be a marker of bone metastasis formation. To address this question, we used two polyclonal antibodies directed against the whole molecule or its C-terminal domain to explore the expression of intact and truncated forms of periostin in the serum and tissues (lung, heart, bone) of wild-type and periostin-deficient mice. In normal bones, periostin was expressed in the periosteum and specific periostin proteolytic fragments were found in bones, but not in soft tissues. In animals bearing osteolytic lesions caused by 4T1 cells, C-terminal intact periostin (iPTN) expression disappeared at the invasive front of skeletal tumors where bone-resorbing osteoclasts were present. In vitro, we found that periostin was a substrate for osteoclast-derived cathepsin K, generating proteolytic fragments that were not recognized by anti-periostin antibodies directed against iPTN. In vivo, using an in-house sandwich immunoassay aimed at detecting iPTN only, we observed a noticeable reduction of serum periostin levels (- 26%; P < 0.002) in animals bearing osteolytic lesions caused by 4T1 cells. On the contrary, this decrease was not observed in women with breast cancer and bone metastases when periostin was measured with a human assay detecting total periostin. Collectively, these data showed that mouse periostin was degraded at the bone metastatic sites, potentially by cathepsin K, and that the specific measurement of iPTN in serum should assist in detecting bone metastasis formation in breast cancer.

Rituximab-Induced Splenic Rupture and Cytokine Release.

BACKGROUND: Rituximab is a therapeutic monoclonal antibody that is used for many different lymphomas. Post-marketing surveillance has revealed that the risk of fatal reaction with rituximab use is extremely low. Splenic rupture and cytokine release syndrome are rare fatal adverse events related to the use of therapeutic monoclonal antibodies, especially in aggressive malignancies with high tumor burden. CASE REPORT: A 55-year-old woman presented with abdominal pain and type B symptoms and was diagnosed with mantle cell lymphoma. Initial peripheral blood flow cytometry showed findings that mimicked features of chronic lymphocytic leukemia. Further treatment with rituximab led to catastrophic treatment complications that proved to be fatal for the patient. CONCLUSIONS: Severe cytokine release syndrome associated with biologics carries a very high morbidity and case fatality rate. With this case report we aim to present the diagnostic challenge with small B-cell neoplasms, especially mantle cell lymphoma and chronic lymphocytic lymphomas, and underscore the importance of thorough risk assessment for reactions prior to treatment initiation.

A multiplexed marker-based algorithm for diagnosis of carcinoma of unknown primary using circulating tumor cells.

Real-time, single-cell multiplex immunophenotyping of circulating tumor cells (CTCs) is hypothesized to inform diagnosis of tissue of origin in patients with carcinoma of unknown primary (CUP). In 20 to 50% of CUP patients, the primary site remains unidentified, presenting a challenge for clinicians in diagnosis and treatment. We developed a post-CellSearch CTC assay using multiplexed Q-dot or DyLight conjugated antibodies with the goal of detecting multiple markers in single cells within a CTC population. We adapted our approach to size-based CTC enrichment protocols for capturing CTCs and subsequent immunofluorescence (IF) using a minimal set of markers to predict the primary sites for common metastatic tumors. The carcinomas are characterized with cytokeratin 7 (CK7), cytokeratin 20 (CK20), thyroid transcription factor 1 (TTF-1), estrogen receptor (ER) or prostate-specific antigen (PSA. IF has been optimized in cultured tumor cells with individual antibodies, then with conjugated antibodies to form a multiplex antibody set. With IF, we evaluated antibodies specific to these 5 markers in lung, breast, colorectal, and prostate cancer cell lines and blood from metastatic prostate and breast cancer patients. This advanced technology provides a noninvasive, diagnostic blood test as an adjunct to routine tissue biopsy. Its further implementation requires prospective clinical testing.

Fatal malignant metastastic epithelioid angiomyolipoma presenting in a young woman: case report and review of the literature.

Epithelioid angiomyolipomas (EAMLs) are rare mesenchymal tumors whose malignant variant is extremely uncommon and highly aggressive. Treatment strategies include chemo radiation, transcatheter arterial embolization and surgical resection, which has remained the mainstay treatment. Targeted therapies including mammalian target of rapamycin (mTOR) inhibitors such as Temsirolimus may offer some hope for progressive malignant EAMLs that are not amenable to other treatment modalities. We report a fatal case in a young female who presented with rapidly progressive metastatic EAML that did not respond to mTOR therapy. The literature has shown reduction in tumor burden with the use of mTOR inhibitors, but unfortunately due to the rarity of malignant EAML, a meaningful approach to treatment remains challenging.

Contradictory KRAS mutation test results in a patient with metastatic colon cancer: a clinical dilemma in the era of personalized medicine.

The KRAS oncogene is mutated in 40‒50% of colorectal cancers and confers resistance to EGFR-targeted therapy. In the clinic, agents such as cetuximab or panitumumab target the EGFR receptor for therapeutic benefit. Cetuximab was approved by the FDA in 2012 as first-line therapy for KRAS mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer, in combination with FOLFIRI (5-fluorouracil, irinotecan, leucovorin). Herein we report a case of metastatic colon cancer with conflicting testing results for the KRAS oncogene from two different reference laboratories. The discordant reports complicated the decision-making process regarding the administration of targeted anti-EGFR personalized therapy. As the second test result was wild-type from the same original pathological specimen, the patient was treated with cetuximab-containing combination chemotherapy and appeared to have a response after prior disease progression. It is unclear whether the observed response was fully due to regression of wild-type KRAS-containing tumor or any component of antibody-dependent cellular cytotoxicity to a heterogeneous tumor in this patient.

Predicting therapy response in live tumor cells isolated with the flexible micro spring array device.

Cells disseminated from primary epithelial tumors into peripheral blood, called circulating tumor cells (CTCs), can be monitored to assess metastases and to provide a surrogate marker of treatment response. Here, we demonstrate how the flexible micro spring array (FMSA) device-a novel microfluidic device that enriches CTCs by two physical parameters: size and deformability-could be used in the rational development of treatment intervention and as a method to study the fundamental biology of CTCs. Cancer cells of different origins were spiked into healthy samples of donor blood to mimic blood samples of metastatic cancer patients. This spiked human blood was filtered using the FMSA device, and the recovered cells were successfully expanded in vitro and in a novel in vivo system. A series of experiments were performed to characterize these cells and to investigate the effect of chemotherapy on the resulting cultures. As few as 20 colon cancer cells in 7.5 mL blood could be isolated with the FMSA device, expanded both in vitro and in vivo and used at 25 cells per well to obtain significant and reliable chemosensitivity data. We also show that isolating a low number of viable patient CTCs and maintaining them in culture for a few weeks is possible. The isolation of viable cancer cells from human blood using the FMSA device provides a novel and realistic means for studying the biology of viable CTCs and for testing drug efficacy on these rare cells-a hypothesis that can be tested in future clinical trials.

Impact of genetic markers on treatment of non-small cell lung cancer.

Non-small cell lung cancer represents a group of heterogeneous diseases. The last decade witnessed significant progress in improving our understanding of the biology of non-small cell lung cancer, which led to the identification of several genetic targets. Those genetic targets were utilized to explain clinical phenomena, such as the occurrence of non-small cell lung cancer in never-smokers, to predict response to conventional chemotherapy and biological agents, and to explain and predict resistance to therapy. The progress in the treatment of non-small cell lung cancer in the last few years was based on a new generation of population-enriched clinical trials that utilized genetic targets such as somatic EGFR mutations and ALK-EML4 mutations. In this review we will discuss the available information about the key genetic markers of non-small cell lung cancer and the pivotal clinical trials that validate the use of those genetic markers in non-small cell lung cancer patients.

Perceived levels of pain associated with bone marrow aspirates and biopsies.

BACKGROUND: Little is known about the degree of pain experienced by patients undergoing a bone marrow aspiration and biopsy (BMAB). OBJECTIVE: To evaluate the effectiveness of several strategies aimed at reducing the pain score. METHODS: We conducted a retrospective analysis of 258 consecutive adult patients who underwent BMAB via 6 different approaches, the first 5 of which were performed by one physician. Group A received local anesthesia with 1% lidocaine hydrochloride (5 mL) and a 5-minute wait time before the procedure; group B received local anesthesia with a double dose (10 mL) of lidocaine; group C received 5 mL of local anesthesia with a 10-minute wait; group D received 5 mL of local anesthesia plus a topical spray with ethyl chloride; group E received oral analgesia and anxiolysis 30 minutes before the procedure in addition to the group A dosage of lidocaine; and group F received the same anesthesia as did group A, but the BMAD was performed by a less experienced practitioner. RESULTS: On a 0 to 10 scale, the mean pain level among the 258 patients was 3.2 (standard deviation = 2.6). Rate of complications was low (<1%). Several strategies failed to improve the pain level, including the administration of a double dose of local anesthesia, waiting longer for the anesthesia effect, and the additional use of a topical anesthetic spray or oral analgesia and anxiolysis. Pain levels were not increased when the procedure was done by a less experienced practitioner. Younger age and female gender were associated with higher pain levels. CONCLUSIONS: Given that the average level of perceived pain during BMAB is low to moderate (approximately 3 on a 0-10 scale), the routine use of conscious sedation for this procedure may not be indicated. Several strategies aimed at reducing the pain level, including doubling the dose of anesthesia and using an oral prophylactic regimen of analgesia and anxiolysis, failed to improve pain scores.