Dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (P) is superior to every 3-weekly AC followed by P. Given the demonstrated cardiac safety for trastuzumab (T) with ...conventionally scheduled AC followed by P, we tested the safety of dd AC followed by P with T. The primary end point was cardiac safety, and the secondary end points were time to recurrence and overall survival.
Patients with HER-2/neu immunohistochemistry (IHC) 3+ or fluorescent in situ hybridization (FISH)-amplified breast cancer and baseline left ventricular ejection fraction (LVEF) of >or= 55% were enrolled, regardless of tumor size or nodal status. Treatment consisted of AC (60/600 mg/m(2)) x 4 followed by P (175 mg/m(2)) x 4 every 2-weekly with pegfilgrastim (6 mg on day 2) + T x1 year. LVEF by radionuclide scan was obtained at baseline, at months 2, 6, 9, and 18.
From January 2005 to November 2005, 70 patients were enrolled. The median age was 49 years (range, 27 to 72 years); median LVEF at baseline was 68% (range, 55% to 81%). At month 2 in 70 of 70 patients, the median LVEF was 67% (range, 58% to 79%); at month 6 in 67 of 70 patients, it was 66% (range, 52% to 75%); at month 9 in 68 of 70 patients, it was 65% (range, 50% to 75%); and at month 18 in 48 of 70 patients, it was 66% (range, 57% to 75%). As of December 1, 2007, the median follow-up was 28 months (range, 25 to 35 months). One patient (1%) experienced congestive heart failure (CHF). There were no cardiac deaths.
Dose-dense AC followed by P/T followed by T is feasible and is not likely to increase the incidence of cardiac events compared to established regimens.
Background: Essential thrombocythemia (ET) is a BCL-ABL1-negative myeloproliferative neoplasm characterized by increased number of mature megakaryocytes in the bone marrow and sustained ...thrombocytosis in the peripheral blood. ET is associated with an increased risk of hemorrhagic and thrombotic complications and leukemic transformation. In addition to somatic mutations, microRNA (miRNA) deregulation has been proposed to play roles in the molecular pathogenesis and disease phenotype in ET patients. The aims of this study were to investigate the plasma miRNA profiles in ET patients with those obtained from healthy adults (HA) and its correlation with clinical and prognostic features.
Methods: ET patients seen at the MacKay Memorial Hospital were enrolled into this study. The clinical and laboratory characteristics at the time of diagnosis or referral were determined retrospectively by chart review. Total plasma miRNA was derived from bone marrow or peripheral blood in patients or HA. Mutational status of JAK2V617F,CALR and MPL were detected by Sanger sequencing and/or allele-specific PCR. Plasma miRNA profiling was carried out on PanelChip™ Analysis System (Quark Biosciences, Taiwan) using a customized miRNA panel including 165 miRNAs called mirSCAN™ PanCancer Chips 1 & 2. KEGG pathways that miRNAs were associated with were analyzed using DIANA TOOLS - mirPath v.3. Differentially expressed miRNAs were identified by student t-test (P < 0.05) and significantly affected miRNAs in ET were identified by a change in expression of two-fold or more compared to the expression in HA. Statistical analysis was performed using SPSS.
Results: A total of 53 ET patients (median age at diagnosis 59 years; 60.4% females) were enrolled. Frequency of the 3 driver mutations was 64% for JAK2V617F, 15% CALR, 4% JAK2V617F and CALR co-mutations, and none for MPL. 17% of patients were classified as triple-negative. A total of 40 differentially expressed miRNAs were identified (Figure left axis) including 4 miRNAs (hsa-miR-940, hsa-miR-411-5p, hsa-miR-596 and hsa-miR-376c-3p) with higher expression levels. The putative target genes of these 40 differentially expressed miRNAs were enriched in signaling pathway including TGF-beta signaling pathway (p-value = 1.86E-12), Hippo signaling pathway (p-value = 1.84E-07), MAPK signaling pathway (p-value = 0.03), and FoxO signaling pathway (p-value < 0.001). According to the expression levels of these 40 miRNAs, samples were grouped into two clusters, i.e. low expression group and high expression group. ET patients with JAK2V617F were significantly associated with high expression of 40 miRNAs (n = 31 of 34, 91%) when compared with triple-negative ET patients (n = 5 of 9, 56%) (p = 0.03). ET patients with low expression of 40 miRNAs were significantly associated with acute leukemia transformation (n = 2 of 11, 18%) when compared with high expression group (n = 0 of 42, 0%) (p = 0.04). However, the expression levels of 40 miRNAs were not statistically correlated with other clinical features including hemogram, secondary solid cancer, myelofibrosis transformation, or thrombotic/hemorrhagic events.
Conclusions: In this cohort of ET patients, distinct plasma miRNA profiles correlated with JAK2V617F mutation and leukemic transformation. Larger cohort is warranted to validate our findings.
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Chen:Quark Biosciences, Inc.: Employment. Kang:Quark Biosciences, Inc.: Employment. Huang:Quark Biosciences, Inc.: Employment. Lin:Quark Biosciences, Inc.: Employment. Wang:Quark Biosciences, Inc.: Employment.
APTO-253 is a novel anticancer small molecule currently in a multicenter open-label, Phase I dose escalation study in patients with relapsed or refractory hematologic malignancies. APTO-253 has ...potent cytotoxic activity against leukemia, lymphoma and myeloma cell lines IC50s of 6.9 - 305 nM. APTO-253 produces significant tumor growth inhibition in the KG-1, THP-1 and Kasumi-1 xenograft models of human acute myeloid leukemia (AML). The anticancer activity of APTO-253 is mediated through induction of Krüppel-like factor 4 (KLF4), a tumor suppressor that is epigenetically silenced in many solid tumors and hematologic cancers. KLF4 expression is often downregulated in AML due to repressive binding of CDX2 to the KLF4 promoter. Increased levels of CDX2 are found in the majority of patients with AML and ALL, as well as in 40% of MDS patients, whereas CDX2 is not expressed in normal hematopoietic cells. Treatment of cultured AML cells with APTO-253 reverses the KLF4 silencing, resulting in induction of p21 and cell death by apoptosis. KG-1 AML cells treated with APTO-253 showed time- and concentration-dependent induction of KLF4 and a concentration-dependent increase in p21 mRNA levels following induction of KLF4. APTO-253 treatment of KG-1 cells for 24 h induced a 14-fold increase in KLF4 mRNA and 16-fold increase in p21 mRNA over basal levels. Following washout of APTO-253, the level of KLF4 mRNA decayed to approximately 50% of maximum induction level over a 24 h period.
The potential for APTO-253 as a therapeutic option in AML was further supported by safety and pharmacokinetics data from an earlier Phase I trial of APTO-253 in patients with advanced or metastatic solid tumors during which APTO-253 was administered at doses of 20 - 387 mg/m2 using a dosing schedule of days 1 and 2, and 15 and 16 of a 28 day cycle. APTO-253 showed a dose-dependent increase in Cmax and AUC, and as the dose was escalated from 80 to 176 mg/m2 the Cmax ranged from 1,800 - 4,960 nM on day 1 and 1,600 - 6,100 nM on day 2. These results suggest that exposure levels from these doses of APTO-253 should be sufficient for single agent activity in patients with AML and other hematologic malignancies.
APTO-253 demonstrated a favorable safety profile when tested against 5 major cytochrome P450 enzymes (1A2, 2C19, 2C9, 2D6 and 3A4), against a panel of proteins and receptors, and in the hERG tail current density assay. Metabolic profiling of APTO-253 at 50 μM in human liver microsomes showed no glutathione or glucuronide conjugation and only a minor hydroxylated metabolite. Finally, 1 μM APTO-253 did not inhibit kinases in a safety panel (40 kinases) or in a broad oncology panel (98 kinases), demonstrating that APTO-253 activity is not driven by kinase inhibition.
Taken together, our results demonstrate that APTO-253 has substantial potential for the treatment of AML and other hematologic malignancies and is of particular interest due to its ability to modulate the expression of the KLF4 master transcription factor that plays a central role in restraining the growth of leukemic cells.
Howell:Aptose Biosciences: Consultancy, Equity Ownership; Angstrom: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abeoda: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; InhibRx: Equity Ownership.
In the second C4 article, contributors examine five issues, including timely access during the hospital discharge process, access to immunosuppressive medications for life after transplant, access to ...medications used for off‐label indications, access to drugs affected by drug shortages, and the patient perspective.
To assess whether transcutaneous retrobulbar amphotericin B injections (TRAMB) reduce exenteration rate without increasing mortality in rhino-orbital-cerebral mucormycosis (ROCM).
In this ...retrospective case-control study, 46 patients (51 eyes) with biopsy-proven ROCM were evaluated at 9 tertiary care institutions from 1998 to 2021. Patients were stratified by radiographic evidence of local orbital versus extensive involvement at presentation. Extensive involvement was defined by MRI or CT evidence of abnormal or loss of contrast enhancement of the orbital apex with or without cavernous sinus, bilateral orbital, or intracranial extension. Cases (+TRAMB) received TRAMB as adjunctive therapy while controls (−TRAMB) did not. Patient survival, globe survival, and vision/motility loss were compared between +TRAMB and -TRAMB groups. A generalized linear mixed effects model including demographic and clinical covariates was used to evaluate the impact of TRAMB on orbital exenteration and disease-specific mortality.
Among eyes with local orbital involvement, exenteration was significantly lower in the +TRAMB group (1/8) versus -TRAMB (8/14) (p = 0.04). No significant difference in mortality was observed between the ±TRAMB groups. Among eyes with extensive involvement, there was no significant difference in exenteration or mortality rates between the ±TRAMB groups. Across all eyes, the number of TRAMB injections correlated with a statistically significant decreased rate of exenteration (p = 0.048); there was no correlation with mortality.
Patients with ROCM with local orbital involvement treated with adjunctive TRAMB demonstrated a lower exenteration rate and no increased risk of mortality. For extensive involvement, adjunctive TRAMB does not improve or worsen these outcomes.
Bevacizumab confers benefits in metastatic breast cancer but may be more effective as adjuvant therapy. We evaluated the cardiac safety of bevacizumab plus dose-dense doxorubicin-cyclophosphamide ...(ddAC) → nanoparticle albumin-bound (nab)-paclitaxel in human epidermal growth factor receptor 2 normal early-stage breast cancer.
Eighty patients with normal left ventricular ejection fraction (LVEF) were enrolled. Bevacizumab was administered for 1 year, concurrently with ddAC → nab-paclitaxel then as a single agent. LVEF was evaluated at months 0, 2, 6, 9, and 18. This regimen was considered safe if fewer than three cardiac events or fewer than two deaths from left ventricular dysfunction occurred. Correlative studies of cardiac troponin (cTn) and plasma renin activity (PRA) were conducted.
The median age was 48 years (range, 27-75 years), and baseline LVEF was 68% (53%-82%). After 39 months' median follow-up (5-45 months): median LVEF was 68% (53%-80%) at 2 months (n = 78), 64% (51%-77%) at 6 months (n = 66), 63% (48%-77%) at 9 months (n = 61), and 66% (42%-76%) at 18 months (n = 54). One patient developed symptomatic LV dysfunction at month 15. Common toxicities necessitating treatment discontinuation were hypertension (HTN, 4%), wound-healing complications (4%), and asymptomatic LVEF declines (4%). Neither cTn nor PRA predicted congestive heart failure (CHF) or HTN, respectively.
Bevacizumab with ddAC → nab-paclitaxel had a low rate of cardiac events; cTn and PRA levels are not predictive of CHF or HTN, respectively. The efficacy of bevacizumab as adjuvant treatment will be established in several ongoing phase III trials.
Purpose:
The purpose of this study was to evaluate the age- and race-dependence of the breast fibroglandular tissue density based on three-dimensional breast MRI.
Methods:
The normal breasts of 321 ...consecutive patients including Caucasians, Asians, and Hispanics were studied. The subjects were separated into three age groups: Younger than 45, between 45 and 55, and older than 55. Computer algorithms based on body landmarks were used to segment the breast, and fuzzy c-means algorithm was used to segment the fibroglandular tissue. Linear regression analysis was applied to compare mean differences among different age groups and race/ethnicity groups. The obtained parameters were not normally distributed, and the transformed data, natural log (ln) for the fibroglandular tissue volume, and the square root for the percent density were used for statistical analysis.
Results:
On the average, the transformed fibroglandular tissue volume and percent density decreased significantly with age. Racial differences in mean transformed percent density were found among women older than 45, but not among women younger than 45. Mean percent density was higher in Asians compared to Caucasians and Hispanics; the difference remained significant after adjustment for age, but not significant after adjusted for both age and breast volume. There was no significant difference in the density between the Caucasians and the Hispanics.
Conclusions:
The results analyzed using the MRI-based method show age- and race-dependence, which is consistent with literature using mammography-based methods.
Abstract Purpose We conducted a pilot study of dose-dense epirubicin/cyclophosphamide (EC) × 6 → paclitaxel (P) × 6 with pegfilgrastim. A previous dose-dense trial of FEC (5-fluorouracil 5-FU/EC) × 6 ...with filgrastim → by weekly paclitaxel alternating with docetaxel × 18 was not feasible because of pneumonitis (with dose-dense FEC) and pericardial/pleural effusion (taxane phase). Dose-dense EC (without the 5-FU) is not associated with pneumonitis, and dose-dense paclitaxel (alone) is feasible. Primary objective was feasibility. Patients and Methods Patients with resectable breast cancer were enrolled, regardless of surgery status, tumor size, or nodal status. Treatment regimen consisted of every-2-week EC (100/600 mg/m2 ) × 6 → by 2-weekly P (175 mg/m2 ) × 6 with pegfilgrastim 6 mg on day 2. Results Between November 2004 and May 2005, 38 patients were enrolled. The median age was 47 years (range, 30-72 years); 33 of 38 (87%) were treated in the adjuvant setting and 27 of 33 (81%) had involved nodes (range, 1-46); 5 of 38 (13%) were treated pre-operatively; 33 of 38 (87%) completed all chemotherapy as planned; the remaining patients (13%) had treatment modifications for toxicity. Febrile neutropenia occurred in 6 of 38 patients (16 %) and only during EC. There were 12 hospitalizations in 9 of 38 patients (24%) enrolled. Conclusion Dose-dense every-2-week EC × 6 → P × 6 with pegfilgrastim is feasible based on our prospective definition.
This paper considers the problem of error correction for a cooperative data exchange (CDE) system, where some clients are compromised or failed and send false messages. Assuming each client possesses ...a subset of the total messages, we analyze the error correction capability when every client is allowed to broadcast only one linearly-coded message. Our error correction capability bound determines the maximum number of clients that can be compromised or failed without jeopardizing the final decoding solution at each client. We show that deterministic, feasible linear codes exist that can achieve the derived bound. We also evaluate random linear codes, where the coding coefficients are drawn randomly, and then develop the probability for a client to withstand a certain number of compromised or failed peers and successfully deduce the complete message for any network size and any initial message distributions.
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