In a population-based study, we examined the relationship between the risk of myocardial infarction (MI) among young women and plasma total homocysteine (tHCY), folate, vitamin B12, and a common ...cytosine (C) to thymine (T) polymorphism in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR).
In-person interviews and nonfasting blood samples were obtained from 79 women < 45 years old diagnosed with MI and 386 demographically similar control subjects living in western Washington state between 1991 and 1995. Compared with control subjects, case patients had higher mean tHCY concentrations (13.4+/-5.2 versus 11.1+/-4.4 micromol/L, P=.0004) and lower mean folate concentrations (12.4+/-13.4 versus 16.1+/-12.2 nmol/L, P=.018). There was no difference in vitamin B12 concentrations between case patients and control subjects (346.8+/-188.4 versus 349.7+/-132.4 pmol/L, P=.90). After adjusting for cardiovascular risk factors, we found that women with tHCY > or = 15.6 micromol/L were at approximately twice the risk of MI as women with tHCY < 10.0 micromol/L (OR, 2.3; 95% CI, 0.94 to 5.64). Women with folate > or = 8.39 nmol/L had an approximately 50% lower risk of MI than women with folate < 5.27 nmol/L (OR, 0.54; 95% CI, 0.23 to 1.28). There was no association with vitamin B12 concentration. Among control subjects, 12.7% were homozygous for the MTHFR T677 allele, and these women had higher plasma tHCY and lower plasma folate than women with other genotypes. Ten percent of case patients were homozygous for the T677 allele, and there was no association of homozygosity for T677 with MI risk (OR, 0.90; 95% CI, 0.31 to 2.29).
These data support the hypothesis that elevated plasma tHCY and low plasma folate are risk factors for MI among young women. Although homozygosity for MTHFR T677 is related to increased plasma tHCY and low plasma folate, this genetic characteristic is not a risk factor for MI in this population.
Diagnostic strategies designed to identify the underlying primary malignancies in patients with unknown primary tumors (UPTs) have relied on retrospective analyses. We analyzed 879 consecutive ...patients referred with suspected UPTs to determine the yield and cost of a limited diagnostic evaluation, assess the contribution of specific studies to diagnosis, and analyze the survival patterns of patients in whom the primary tumor was diagnosed.
Data from patients with a suspected UPT were entered into a computerized data base, and the patients underwent a predefined limited diagnostic evaluation. Primary malignancies were diagnosed by pathologic review alone or by pathologic criteria plus a physical or radiographic finding. Survival was measured from diagnosis, estimated using the Kaplan-Meier method, and compared using the Cox-Mantel log-rank test.
A primary tumor was found in 179 of 879 patients (20%). The survival duration of patients in whom the primary tumor was diagnosed was superior to that of patients in whom the primary tumor remained unknown. Specific patient subsets contributed most to the improved survival duration of the group in which the primary tumor was found, including lymphoma patients diagnosed solely by pathologic criteria and female patients with primary breast or ovarian cancer. The cost of diagnosis was mostly due to the extensive use of computed tomography. Except for ovarian cancer, computed tomography rarely identified treatable primary tumors.
The limited diagnostic evaluation used in this study identified patients with treatable malignancies and increased the survival duration of a population of suspected UPT patients. Primary malignancies with the best survival can be diagnosed through careful pathologic review and focused evaluations for breast and ovarian cancer in women.
Abstract
Background: Gene expression profiling (GEP) has identified several molecularly distinct subtypes of triple negative breast cancer (TNBC). Currently, GEP-based molecular diagnostics are not ...routinely used in clinical decision making due to the lack of proven benefit, costs involved and long turnaround time. However, two molecularly distinct subtypes of TNBC, the luminal androgen receptor (AR) and mesenchymal subtypes, have surrogate CLIA-certified immunohistochemical (IHC) markers, AR and vimentin (VM), respectively, which have the potential for application in the clinic. Here we report the rates of AR and VM positivity and their association with clinicopathological characteristics in a cohort of TNBC pts receiving NACT.
Methods: As part of an ongoing molecular triaging protocol, 144 pts with stage I-III TNBC underwent a pretreatment biopsy for molecular characterization (MC) prior to initiating neoadjuvant chemotherapy (NACT). IHC for AR and VM were performed using commercially available antibodies. AR+ and VM+ were defined as ≥10% and ≥50% staining, respectively. Pts were randomized 2:1 to know (intervention arm, n=93) and not know (control arm, n=51) the MC results. The charts of pts randomized to the intervention arm were reviewed. Categorical variables were analyzed using Fisher's exact test. Ordinal and continuous variables were analyzed using the Wilcoxon rank-sum test and Student's t test as appropriate.
Results: 31% (29/93) and 16% (15/93) of pts were AR+ and VM+, respectively. Only 4% (4/93) of pts were both AR+ and VM+. Clinicopathological characteristics are summarized in Table 1. AR+ pts were more likely to have clinically node positive disease as compared to AR- pts (66% vs 34%, p=0.007). There were no significant differences in clinical tumor size or grade between AR+ and AR- pts. VM+ and VM- pts had similar clinicopathological characteristics.
Conclusion: Pts with AR+ TNBC were more likely to have node positive disease. The impact of AR+ on long term outcomes should be investigated in prospective studies.
Table 1: Association between patient characteristics and AR/VM status AR VM AR+ (n=29)AR- (n=64)p-valueVM+ (n=15)VM- (n=78)p-valueAge - Median (years, interquartile range)58 (48-65)52 (46-61)0.05855 (48-64)56 (47-62)0.88Clinical Tumor Size Mean (cm, standard deviation)3.5 (1.8)3.0 (1.8)0.2872.7 (1.7)3.3 (1.9)0.31T1 – n(%)5 (17)21 (33)0.2307 (47)19 (24)0.098T2 – n(%)21 (72)36 (56) 7 (47)50 (64) T3 – n(%)3 (10)7 (11) 1 (7)9 (12) Clinical Nodal Status Negative – n(%)10 (34)42 (66)0.0078 (53)44 (56)1.00Positive – n(%)19 (66)22 (34) 7 (47)34 (44) Grade 2 – n(%)6 (21)5 (8)0.0763 (20)8 (10)0.293 – n(%)23 (79)59 (92) 12 (80)70 (90)
Citation Format: Yam C, Huo L, Hess KR, Litton JK, Yang W, Piwnica-Worms H, Mittendorf EA, Ueno NT, Lim B, Murthy RK, Damodaran S, Helgason T, Thompson AM, Santiago L, Candelaria RP, Rauch GM, Adrada BE, Symmans WF, Gilcrease MZ, Moulder SL. Androgen receptor positivity is associated with nodal disease in triple negative breast cancer abstract. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-22.
Abstract
Background: Image-guided percutaneous needle biopsy of the breast is a common procedure. In breast cancer patients (pts) undergoing core biopsies and surgical resection on the same day, the ...rate of tumor cell displacement along the needle track has been reported to be up to 50%. However, the clinical significance of this finding in triple negative breast cancer (TNBC) patients (pts) undergoing serial biopsies while receiving neoadjuvant chemotherapy (NACT) is unknown. Here we report the incidence of needle-track seeding (NTS) in a cohort of TNBC pts enrolled on a molecular triaging protocol involving serial biopsies of the index breast lesion.
Methods: We reviewed the clinical records of 144 consecutive TNBC pts enrolled on a molecular triaging protocol at MD Anderson Cancer Center. Per protocol, all pts underwent a pre-treatment research biopsy and were initiated on anthracycline based NACT (AC). Pts with inadequate response to front-line NACT were encouraged to undergo additional biopsies of the index breast lesion prior to switching therapies. Serial breast ultrasound (US) was performed to monitor therapeutic response and incidental evidence of needle-track seeding noted on US was documented.
Results: Clinicopathological characteristics of the pts are summarized in Table 1. 89% (128/144) of pts had a diagnostic breast biopsy done at another center prior to presenting at MDACC. To date, we have performed 209 US guided biopsies of index breast lesions in 144 pts. 92% (193/209) of these biopsies were done mainly for research purposes. 1.4% (2/144) of pts were found to have evidence of NTS on follow up US. The first pt had a T1N0 (1.9cm), grade 3, invasive ductal carcinoma (IDC) at diagnosis. She underwent a diagnostic biopsy followed by a research biopsy before initiating AC. She was found to have NTS as well as progression of disease (PD) on follow up US after 2 cycles of AC. The second pt had a T2N0 (3cm), grade 3 IDC at diagnosis. She underwent a diagnostic biopsy at another center, followed by a research biopsy before initiating AC. Like the first pt, she was found to have NTS and PD on follow up US after 2 cycles of AC. Both pts are currently on neoadjuvant clinical trials of novel agents.
Conclusion: The rate of NTS detected on US in TNBC pts undergoing serial biopsies of index breast lesions while receiving NACT is low and further studies are needed to determine the impact of serial biopsies on long term outcomes in TNBC.
Table 1: Patient CharacteristicsCharacteristicN=144Age - Median (years, interquartile range)55 (46-62)Tumor Size Mean (cm, standard deviation)3.4 (2.2)T1 – n(%)35 (24)T2 – n(%)89 (62)T3 – n(%)19 (13)T4 – n(%)1 (1)Clinical Nodal Status Negative – n(%)74 (51)Positive – n(%)70 (49)Grade 1 – n(%)1 (1)2 – n(%)17 (12)3 – n(%)124 (86)Unknown – n(%)2 (1)Histologic Subtype Invasive ductal carcinoma – n(%)121 (84)Invasive lobular carcinoma – n(%)2 (1)Mixed ductal and lobular carcinoma – n(%)3 (2)Metaplastic carcinoma – n(%)13 (9)Not specified – n(%)5 (3)Laterality Right – n(%)72 (50)Left – n(%)72 (50)
Citation Format: Yam C, Santiago L, Candelaria RP, Adrada BE, Rauch GM, Hess KR, Litton JK, Piwnica-Worms H, Mittendorf EA, Ueno NT, Lim B, Murthy RK, Damodaran S, Helgason T, Huo L, Thompson AM, Gilcrease MZ, Symmans WF, Moulder SL, Yang W. Risk of needle-track seeding with serial ultrasound guided biopsies in triple negative breast cancer abstract. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-03-05.
Preclinical studies suggest that combining vandetanib (VAN), a multi-tyrosine kinase inhibitor of rearranged during transfection (RET) proto-oncogene, vascular endothelial growth factor receptor ...(VEGFR), and epidermal growth factor receptor (EGFR), with everolimus (EV), a mammalian target of rapamycin (mTOR) inhibitor, may improve antitumor activity. We determined the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of VAN + EV in patients with advanced solid cancers and the effect of combination therapy on cancer cell proliferation and intracellular pathways.
Patients with refractory solid tumors were enrolled in a phase I dose-escalation trial testing VAN (100-300 mg orally daily) + EV (2.5-10 mg orally daily). Objective responses were evaluated using RECIST v1.1. RET mutant cancer cell lines were used in cell-based studies.
Among 80 patients enrolled, 72 (90%) patients were evaluable: 7 achieved partial response (PR) (10%) and 37 had stable disease (SD) (51%; duration range: 1-27 cycles). Clinical benefit (SD or PR ≥ 6 months) was observed in 26 evaluable patients 36%, 95% confidence intervals (CI) (25% to 49%). In 80 patients, median overall survival (OS) was 10.5 months 95% CI (8.5-16.1) and median progression-free survival (PFS) 4.1 months 95% CI (3.4-7.3). Six patients (7.5%) experienced DLTs and 20 (25%) required dose modifications. VAN + EV was safe, with fatigue, rash, diarrhea, and mucositis being the most common toxicities. In cell-based studies, combination therapy was superior to monotherapy at inhibiting cancer cell proliferation and intracellular signaling.
The MTDs and RP2Ds of VAN + EV are 300 mg and 10 mg, respectively. VAN + EV combination is safe and active in refractory solid tumors. Further investigation is warranted in RET pathway aberrant tumors.
•VAN + EV is safe, active and provides clinical benefit in some patients with refractory solid cancers.•Dual therapy is superior to monotherapy at inhibiting proliferation and intracellular signaling of RET mutant cancer cells.•This study highlights the importance of identifying novel combination therapies to overcome therapeutic resistance.•Next-generation sequencing of advanced solid tumors may inform treatment strategies and guide future drug development.
Purpose: This study was conducted to evaluate the role of cerebrospinal fluid (CSF) drainage and distal aortic perfusion (DAP) in the prevention of postoperative neurologic complications for ...high-risk patients who had undergone type I and type II thoracoabdominal aortic aneurysm (TAAA) repair.
Methods: CSF drainage and DAP were used as an adjunct in the treatment of 94 patients with TAAA (31 type I, 63 type II) between September 1992 and December 1994; 67 were men and 27 were women. The median age was 64 years (range, 28 to 88 years). Aortic dissection occurred in 35 of 94 patients (37%). Thirty-six of 94 patients (38%) had previously undergone proximal aortic surgery. All patients underwent intraoperative DAP and perioperative CSF drainage. Median aortic cross-clamp time was 67 minutes (range, 20 to 131 minutes).
Results: The 30-day survival rate was 90% (85 of 94 patients). Early neurologic complications occurred in 5 of 94 patients (5%), and late neurologic complications occurred in 3 of 94 patients (3%). We compared the neurologic complications of our current group of 94 patients with the data from 42 patients (control group) who also underwent repair of TAAA type I and type II with only simple cross-clamp and without CSF drainage or DAP. Both groups were treated by the senior author (HJS) at the same institution. Total neurologic complications for the current group occurred in 8 of 94 patients (9%) versus 8 of 42 patients (19%) for the control group (
p = 0.090). Neurologic complications for patients with type II TAAA occurred in 8 of 63 patients (13%) versus 17 of 42 patients (41%) (
p = 0.014). For all patients with aortic clamp times ≥45 minutes, neurologic complications occurred in 7 of 55 (13%) versus 7 of 18 (39%) (
p = 0.033).
Conclusion: The period of risk during aortic cross-clamp time is reduced with the adjuncts of CSF drainage and DAP, which significantly lower the incidence of neurologic complications after repair of TAAA types I and II. (J V
ASC S
URG 1996;23:223-9.)
Aquaflor is a feed premix for fish containing the broad spectrum antibacterial agent florfenicol (FFC) incorporated at a ratio of 50% (w/w). To enhance the effectiveness of FFC for salmonids infected ...with certain isolates of Flavobacterium psychrophilum causing coldwater disease, the FFC dose must be increased from the standard 10 mg·kg−1 body weight (BW)·d−1 for 10 consecutive days. A residue depletion study was conducted to determine whether FFC residues remaining in the fillet tissue after treating fish at an increased dose would be safe for human consumption. Groups of Rainbow Trout Oncorhynchus mykiss (total n = 144; weight range, 126–617 g) were treated with FFC at 20 mg·kg−1 BW·d−1 for 10 d in a flow‐through system (FTS) and a recirculating aquaculture system (RAS) each with a water temperature of ∼13°C. The two‐tank RAS included a nontreated tank containing 77 fish. Fish were taken from each tank (treated tank, n = 16; nontreated tank, n = 8) at 6, 12, 24, 48, 72, 120, 240, 360, and 480 h posttreatment. Florfenicol amine (FFA) concentrations (the FFC marker residue) in skin‐on fillets from treated fish were greatest at 12 h posttreatment (11.58 μg/g) in the RAS and were greatest at 6 h posttreatment (11.09 μg/g) in the FTS. The half‐lives for FFA in skin‐on fillets from the RAS and FTS were 20.3 and 19.7 h, respectively. Assimilation of FFC residues in the fillets of nontreated fish sharing the RAS with FFC‐treated fish was minimal. Florfenicol water concentrations peaked in the RAS‐treated tank and nontreated tanks at 10 h (453 μg/L) and 11 h (442 μg/L) posttreatment, respectively. Monitoring of nitrite concentrations throughout the study indicated the nitrogen oxidation efficiency of the RAS biofilter was minimally impacted by the FFC treatment.
Received January 8, 2014; accepted July 7, 2014
•Patients with MCL experiencing late relapse benefit from BTK-inhibitors over immunochemotherapies.•Overall, immunochemotherapies as second-line treatment are discouraged in the era of chimeric ...antigen receptor T-cell therapies.
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Patients with mantle cell lymphoma (MCL) who experience first relapse/refractoriness can be categorized into early or late progression-of-disease (POD) groups, with a threshold of 24 months from MCL diagnosis. Bruton tyrosine kinase inhibitors (BTKi) are the established standard treatment at first relapse, but their effectiveness compared with chemoimmunotherapy (CIT) in late-POD patients remains unknown. In this international, observational cohort study, we evaluated outcomes among patients at first, late POD beyond 24 months. The primary objective was progression-free survival from the time of second-line therapy (PFS-2) of BTKi vs CIT. Overall, 385 late-POD patients were included from 10 countries. Their median age was 59 years (range, 19-70), and 77% were male. Median follow-up from the time of second-line therapy was 53 months (range, 12-144). Overall, 114 patients had second-line BTKi, whereas 271 had CIT, consisting of rituximab-bendamustine (R-B; n = 101), R-B and cytarabine (R-BAC; n = 70), or other regimens (mostly cyclophosphamide-hydroxydaunorubicin-vincristine-prednisone- or platinum-based; n = 100). The 2 groups were balanced in clinicopathological features and median time to first relapse. Overall, BTKi was associated with significantly prolonged median PFS-2 than CIT (not reached NR vs 26 months, respectively; P = .0003) and overall survival (NR and 56 months, respectively; P = .03). Multivariate analyses showed that BTKi was associated with lower risk of death than R-B and other regimens (hazard ratio, 0.41 for R-B and 0.46 for others), but similar to R-BAC. These results may establish BTKi as the preferable second-line approach in patients with BTKi-naïve MCL.
Purpose:
To conduct a Phase II one-arm study to evaluate the long-term efficacy and safety of accelerated fractionated radiotherapy combined with i.v. carboplatin for patients with previously ...untreated anaplastic gliomas.
Methods and Materials:
Between 1988 and 1992, 90 patients received 1.9–2.0-Gy radiation 3 times a day with 2-h infusions of 33 g/m
2 carboplatin for two 5-day cycles separated by 2 weeks. After radiotherapy, patients received procarbazine, lomustine (CCNU), and vincristine (PCV) for 1 year or until the tumor progressed.
Results:
Ninety patients were evaluable for analysis. Histologically, 69 had anaplastic astrocytoma; 14, anaplastic oligoastrocytoma; and 7, anaplastic oligodendroglioma. Gross total resection was performed in 20 (22%), subtotal resection in 45 (50%), and biopsy in 25 (28%); reoperation (total or subtotal resection) was performed in 50 (56%) patients. A multivariate analysis showed that a younger age (
p = 0.026), Karnofsky performance score (KPS;
p = 0.009), and brain necrosis (
p = 0.0002) were predictive of a better survival. Results from analysis of extent of surgery (biopsy, subtotal resection, gross total resection) approached significance (
p = 0.058). Radiation dose, irradiated tumor volume, and techniques used (boost and fields) were not significant variables. The median survival (MS) of all anaplastic glioma patients was 28.1 months; for anaplastic astrocytoma patients, MS was 28.7 months and 40.8 months for the combined anaplastic oligodendroglioma/oligoastrocytoma patients. Long-term survival occurred in 25% of anaplastic glioma patients who were alive 8.6 years after treatment was initiated. Treatment-induced necrosis was documented by surgery or autopsy in 19 (21%) patients; 21 (23%) had a mixed pattern of necrosis and tumor; and an additional 13 (14%) patients who did not have surgical or autopsy demonstration of predominant radiation necrosis had magnetic resonance imaging (MRI) evidence of radiation necrosis. Serious clinical neurologic deterioration and/or dementia requiring full-time caregiver attention were observed in 9 (10%) patients.
Conclusion:
When comparable selection criteria are applied, the rate of MS in this study is inferior to results attainable with current radiation and chemotherapy approaches, although the rates of long-term survival are comparable. Theoretically, patients failing therapy and dying earlier than anticipated may be because of excessive central nervous system (CNS) toxicity resulting from the combination of accelerated fractionated irradiation, intensive carboplatin chemotherapy before each radiation fraction, and postirradiation PCV chemotherapy. On the other hand, patients with treatment-induced necrosis survived significantly longer than patients who did not demonstrate MRI or histologic evidence of necrosis (MS, 106 months vs. 18–33 months).
To evaluate the natural history, validate previous observations, and identify prognostic factors in patients with unknown primary carcinoma (UPC).
Nine hundred twenty-seven consecutive patients ...referred to the M.D. Anderson Cancer Center with a preliminary diagnosis of UPC were prospectively identified. A standardized evaluation narrowed the study population to 657 patients with UPC. All data were recorded and computerized for storage, retrieval, and analysis. The primary end point for the study was survival, which was calculated from the first day of patient registration. Survival curves were estimated using the Kaplan-Meier method and compared using the Cox-Mantel log-rank test. To identify important prognostic factors, univariate and multivariate analyses were conducted.
The demographics of the UPC patient population mirrored those of the general population of patients referred to our cancer center except for an excess of men among the UPC patients. Most patients had histologic or cytologic evidence of adenocarcinoma and had more than one organ site metastatically involved. Univariate and multivariate analyses identified numerous important prognostic factors with a significant influence on survival, including sex, number of organ sites involved, specific organ sites involved, and pathologic subtypes.
This study validated previously identified important prognostic factors for survival in UPC. Additional variables that had an impact on survival were identified and the complex interaction of the factors was explored. As patient numbers increase, this database will be able to provide further analyses of patient subsets and potentially relate specific clinical features to the evolving molecular and biochemical understanding of these malignancies.
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