Evaluation of Alisertib Alone or Combined With Fulvestrant in Patients With Endocrine-Resistant Advanced Breast Cancer: The Phase 2 TBCRC041 Randomized Clinical Trial

IMPORTANCE: Aurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i-resistant MBC is unknown. OBJECTIVE: To assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)-negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement ( INTERVENTIONS: Alisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2). MAIN OUTCOMES AND MEASURES: Improvement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%. RESULTS: All 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%]). CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i-resistant MBC. The overall safety profile was tolerable

Case Report Safety of Pegfilgrastim (Neulasta) in Patients with Sickle Cell Trait/Anemia

Pegfilgrastim (Neulasta) is a recombinant filgrastim (human granulocyte colony-stimulating factor (G-CSF)) attached to a polyethylene glycol (PEG) molecule and is given as part of chemotherapy regimens that are associated with significant myelosuppression and risk for febrile neutropenia. Prescribing information available on manufacturer's website for the drug warns us about possible severe sickle cell crises related to the medication but does not report the actual incidence or the use in patients with sickle cell trait. Caution is advised when using it in patients with sickle cell disease. Here we present a case of a Caucasian female with known sickle cell trait (SCT) with no prior complications who developed a presumed sickle cell crisis after getting Neulasta, as a part of the chemotherapy regimen used to treat her breast cancer. Based on our literature review, this appears to be the first case report of a patient with SCT developing a sickle cell crisis with the pegylated form of recombinant filgrastim. Given the dearth of literature regarding the use of G-CSF and its related pegylated forms in patients with sickle cell anemia and sickle cell trait, a discussion of potential mechanisms and review of current literature and guidelines is also presented. Background Pegfilgrastim is a recombinant filgrastim (human granulocyte colony-stimulating factor (G-CSF)) attached to a polyethylene glycol (PEG) molecule and is given as part of chemotherapy regimens that are associated with significant myelosuppression and febrile neutropenia The heterozygous form of sickle cell anemia, sickle cell trait (SCT), is present in up to 8% of African-Americans in the United States With respect to administration of colony stimulating factors in patients with sickle cell trait, as pointed out by Kang and colleagues, "the use of G-CSF may represent another form of stressor" Case Presentation A 54-year-old Caucasian woman with sickle cell trait and no other comorbidities presented to the medical oncology clinic for further management of her recently diagnosed breast cancer. Case Reports in Hematology Her oncological history dates back to March 2013 when she initially underwent a left total mastectomy with sentinel lymph node biopsy for an infiltrating ductal carcinoma, grade 3 (of 3), measuring 1.4 × 1.2 × 0.9 cm in the upper outer quadrant of the left breast. There were two other separate foci of ductal carcinoma in situ, low nuclear grade, involving radial scars: one in the lower outer quadrant measuring 0.7 × 0.5 cm and one in the central aspect measuring 0.5 × 0.5 cm. There was no angiolymphatic invasion. All the margins were noted to be negative for tumor with the nearest tumor-free margin of 1.7 cm for the in-situ carcinoma and 1.8 cm for the invasive carcinoma. Three sentinel lymph nodes were noted to be negative for tumor. Estrogen Receptor and Progesterone Receptor status were checked on the specimen and were negative with less than 1% tumor nuclei staining. HER-2/neu overexpression was negative with a score of 1+. Ki-67 was 81.4%. Given the profile, adjuvant Docetaxel (Taxotere) and Cyclophosphamide (Cytoxan) was started, April 18, 2013. The first cycle of chemotherapy was complicated by neutropenic fever requiring hospitalization; therefore, Pegfilgrastim (Neulasta) was added to her regimen. Cycles two and three were essentially uneventful. In June, after receiving her fourth and final cycle of Docetaxel and Cyclophosphamide followed by Neulasta she developed shortness of breath, severe substernal chest pain, and diffuse body aches. Due to persistent symptoms she was hospitalized. Cardiac enzymes, a transthoracic echocardiogram, and a CT scan of the chest PE protocol were normal. There was no evidence for infection. Her CBC revealed a hemoglobin of 11.2 g/dL on day of admission with a white count of 17.4 × 10 9 /L, with 16.9 × 10 9 /L neutrophils. Given her history of sickle cell trait and her presentation mimicking a sickle cell crisis, she was given supportive therapy in the form of intravenous hydration and pain control to which she responded wel

Safety of Pegfilgrastim (Neulasta) in Patients with Sickle Cell Trait/Anemia

Pegfilgrastim (Neulasta) is a recombinant filgrastim (human granulocyte colony-stimulating factor (G-CSF)) attached to a polyethylene glycol (PEG) molecule and is given as part of chemotherapy regimens that are associated with significant myelosuppression and risk for febrile neutropenia. Prescribing information available on manufacturer’s website for the drug warns us about possible severe sickle cell crises related to the medication but does not report the actual incidence or the use in patients with sickle cell trait. Caution is advised when using it in patients with sickle cell disease. Here we present a case of a Caucasian female with known sickle cell trait (SCT) with no prior complications who developed a presumed sickle cell crisis after getting Neulasta, as a part of the chemotherapy regimen used to treat her breast cancer. Based on our literature review, this appears to be the first case report of a patient with SCT developing a sickle cell crisis with the pegylated form of recombinant filgrastim. Given the dearth of literature regarding the use of G-CSF and its related pegylated forms in patients with sickle cell anemia and sickle cell trait, a discussion of potential mechanisms and review of current literature and guidelines is also presented

Balancing Service and Education: Improving Internal Medicine Residencies in the Managed Care Era.

BACKGROUND: Internal medicine training programs must adapt to health care systems faced with balancing the competitive priorities of patient-care responsibilities and educational needs. OBJECTIVE: To evaluated the effects of a major organizational change on the inpatient service of an internal medicine residency program in a vertically integrated health system. METHODS: We changed the structure of our program from a system in which the hospitalized patients\u27 primary physicians were responsible for daily inpatient management, while teaching was assigned to a defined teaching rounder, to a method in which the rounding attending was responsible for both teaching and patient care. Measurements before and after the change in the rounding system included: the McGill University clinical tutor evaluations, time-motion observations of house staff, patient satisfaction surveys, average length of stay data, and physician focus groups to assess physician satisfaction. RESULTS: The rounding attendings consistently received excellent to superior ratings by the house staff both before and after the implemented change. Compared to time-motion observations performed before the change, observations recorded after the change suggested that a greater percent of house staff time was spent on educational activities. The responses of patient satisfaction surveys indicated that the perception of quality of care remained high after the system change. Lastly, the average length of stay for patients on the general internal medicine and subspecialty services was reduced from 7.6 days before the change to 6.6 days after the change, a difference of 0.92 day (95% confidence interval 1.3 to 0.6, P \u3c 0.001). CONCLUSIONS: Through organizational restructuring, it is possible to improve the quality of patient care and improving the efficiency of patient-care management

Elevated serum levels of IL-10 are associated with inferior progression-free survival in patients with Hodgkin's disease treated with radiotherapy

Elevated pretreatment serum interleukin-10 (IL-10) is associated with inferior progression-free survival (PFS) in patients with Hodgkin's disease (HD) treated with ABVD or equivalent regimens. Therefore, we explored the association of serum IL-10 with presenting features and PFS in HD patients treated only by radiotherapy (RT) with curative intent. Eligible patients were previously untreated, had biopsy-proven HD, were older than 16 years, HIV-negative, and had unthawed pretreatment serum. Serum IL-10 levels were measured with ELISA and were considered high if > or = 10 pg/ml. We identified 69 patients with median age of 34 years (range 16 - 74), of who 52% were males, and 3% had B-symptoms. Ann Arbor Stage was I in 35%, II in 58%, and III in 7% of the patients. Histology was lymphocyte predominance in 26%, and classical HD in 74% of the patients. Serum IL-10 was elevated in 35% of the patients. After a median follow-up of 67 months for survivors, the 5-year PFS of patients with high vs. normal serum IL-10 was 50% vs. 81% (all patients, P = 0.006), and 43% vs. 77% for the subset with classical HD (P = 0.008). Multivariate analysis revealed that high serum IL-10 and beta2-microglobulin were independently associated with inferior PFS. Patients with none, 1, or 2 adverse features comprised 57%, 36%, and 7% of the population, and their 5-year PFS was 80%, 63%, and 0%, respectively (P < 0.0001). In conclusion, high serum IL-10 is independently associated with inferior PFS in patients with HD treated with RT

Very high levels of soluble CD30 recognize the patients with classical Hodgkin&apos;s lymphoma retaining a very poor prognosis

Objectives: To evaluate the prognostic role of pretreatment serum levels of soluble CD30 (sCD30) in patients with advanced stage classical Hodgkin’s lymphoma (cHL) treated with adriamycin, bleomycin, vinblastine, and dacarbazine or equivalent regimens. Methods: We identified 321 previously untreated patients with cHL who presented to the participating centers between 1985 and 2002, and had serum samples available for the determination of sCD30 levels. Results: With a median follow-up of 72 months, the actuarial 5-year overall survival was 82%, and failure-free survival (FFS) was 71%. The median serum level of sCD30 was 65 U/mL (range: 1-2230), and was significantly higher (P &lt; 0.0001) when compared with a group of 113 healthy controls (4 U/mL, range: 0-20). Increasing level of sCD30 was associated with a continuous worsening of FFS and OS, and patients with sCD30 &gt;= 200 U/mL had a 5-year FFS of 39%. With multivariate analysis, sCD30, Ann Arbor stage, and lactic acid dehydrogenase were significant independent factors in terms of FFS. The association of the above-mentioned three independent prognostic variables could discriminate 22% of patients with 5-year FFS of 40%. Conclusions: Our data confirm the independent prognostic role of sCD30 in identifying the patients with high risk of treatment failure, and show that its association with other variables can recognize patients with FFS considerably lower than 50%