Use of PRAME immunostaining to distinguish early melanoma in situ from benign pigmented conditions.

BACKGROUND: PRAME (PReferentially expressed Antigen in MElanoma) is an antigen that shows marked overexpression in melanoma compared to normal skin melanocytes. PRAME immunohistochemistry has proven effective in distinguishing melanocytic nevi from melanoma, but it is unclear if it may be used to distinguish melanoma in situ from other benign pigmented lesions. In particular, differentiating from melanocytic hyperplasia in sun-damaged skin is sometimes clinically and histopathologically challenging. We hypothesized that PRAME staining of solar lentigo, sun-damaged skin, and melanoma in situ would aid in setting a threshold of positivity that could be useful in evaluating such conditions. METHODS: We collected and stained typical examples of solar lentigo, melanoma in situ, and non-lesional sun-damaged skin by PRAME immunohistochemistry to assess a potential cutoff of PRAME positivity. RESULTS: Solar lentigo and non-lesional sun-damaged skin had 10 or fewer PRAME-positive cells per millimeter (mean 1.2), on the other hand melanoma in situ had at least 16 (mean 75.1). CONCLUSIONS: PRAME immunostaining appears sensitive and specific in the current series. This could be clinically useful for distinguishing melanoma in situ from benign melanocytic hyperplasia in sun-damaged skin. However, further studies are required to determine if 10 cells per millimeter is an acceptable threshold of positivity.

eHealth Activity among African American and White Cancer Survivors: A New Application of Theory.

eHealth is a promising resource for cancer survivors and may contribute to reducing racial disparities in cancer survivorship. This research applies the Unified Theory of Acceptance and Use of Technology (UTAUT) to examine eHealth activity among African American (AfAm) and White cancer survivors. In a population-based sample of AfAm and White survivors (n = 300), a Poisson regression tested whether UTAUT constructs (facilitating conditions, social influence, perceived ease of use, perceived usefulness) and beliefs about security/trustworthiness of eHealth were associated with the number of eHealth activities respondents had used. To test whether the effects varied across racial groups, interactions between each of these five facets and survivor race were included in the model. The model adjusted for demographic characteristics, cancer history, and internet access and use. Across racial groups, facilitating conditions (IRR = 1.44, 95%CI [1.17, 1.77]) and perceived usefulness (IRR = 1.16, 95%CI [1.08, 1.24]) were associated with increased eHealth activity. A marginally significant interaction between race and perceived ease of use (IRR = 1.17, 95%CI [0.99, 1.39]) indicated this perception was associated with decreased eHealth activity for White but not AfAm survivors. A significant interaction between race and perceived security/trustworthiness (IRR = 1.16, 95%CI [1.02, 1.32]) indicated this perception was associated with increased eHealth activity for AfAm but not White survivors. Social influence was not associated with eHealth use for either group (IRR = 1.07, 95%CI [0.98, 1.16]). Interventions targeting attitudes about eHealth may encourage its adoption and use. Furthermore, eHealth tools intended for use among AfAm cancer survivors should ensure they are secure and emphasize trustworthiness to intended users.

Delayed Granulocyte Colony-Stimulating Factor (G-CSF) Administration after Chemotherapy Reduces Total G-CSF Doses without Affecting Neutrophil Recovery in a Randomized Clinical Study in Children with Solid Tumors.

The use of G-CSF after myelotoxic chemotherapy accelerates neutrophil recovery reducing the risk of febrile neutropenia. Current guidelines recommend initiating G-CSF 24 hours after myelotoxic chemotherapy. However, the optimal timing of post-chemotherapy G-CSF administration has not been elucidated. Our previous work in murine models demonstrated that the reappearance of myeloid progenitors does not occur in bone marrow until 3-4 days after completion of chemotherapy suggesting that delayed G-CSF administration may be equally efficacious compared to current practice. We conducted a prospective, randomized, crossover study to compare the absolute neutrophil count (ANC) recovery after chemotherapy and a delayed G-CSF administration to a standard G-CSF administration schedule with early G-CSF start. A total of 21 children with solid tumors who received 2 identical cycles of myelotoxic chemotherapy were randomized to start receiving G-CSF either 24 hours after completion of chemotherapy or on the day that their ANC dropped below 1,000/mm3. There was no significant difference in the time to neutrophil recovery (ANC > 1,000/mm3 post nadir) between the two G-CSF administration schedules: 16.0 ± 0.5 days in the standard group compared to 16.7 ± 0.4 days in the delayed group (p = 0.36). The total number of G-CSF doses given, however, was significantly less in the delayed group: 6.7 ± 0.6 compared to 10.5 ± 0.6 doses in the standard group (p < 0.0001). Our data show that a delayed administration of post chemotherapy G-CSF resulted in a significant reduction in the number of G-CSF injections without compromising the G-CSF effects on neutrophil recovery.

Menopausal estrogen therapy and non-Hodgkin's lymphoma: A post-hoc analysis of women's health initiative randomized clinical trial.

Estrogens are important immunomodulators, exerting significant effects on cell proliferation, apoptosis, cytokine production and differentiation of hematopoietic cells. Estrogen receptors are expressed on normal B and T lymphocytes, bone marrow and in leukemia and lymphoma cell lines. Epidemiologic evidence for the association of menopausal hormone use with risk of non-Hodgkin's lymphoma (NHL) has been mixed; however, all of the investigations have been observational. We analyzed the data from Women's Health Initiative hormone therapy trials where conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 16,654) or CEE alone (women with prior hysterectomy) (n = 10,685) were tested against placebos and the intervention lasted a median of 5.6 years in the CEE + MPA trial and 7.2 years in the CEE alone trial. During 13 years of follow-up through September 20, 2013 383 incident NHL cases were identified. We used the intent-to-treat approach to calculate incidence rates of NHL, hazards ratios (HR) and 95% confidence intervals (CI) by treatment group. Incidence of NHL was virtually the same in the treatment and placebo groups. The HR was 1.02 (95%CI 0.74-1.39) for CEE alone, 0.98 (95% CI 0.76-1.28) for CEE+MPA, and 1.00 (95% CI 0.82-1.22) for both combined. There were no specific NHL subtypes associated with either type of the treatment, except a marginally decreased risk of plasma cell neoplasms (HR= 0.53 95% CI 0.27-1.03) in the CEE-alone group. These results do not support a role of estrogen alone or combined with progestin in the development of NHL among postmenopausal women.

Electric Blanket Use and Risk of Thyroid Cancer in the Women's Health Initiative Observational Cohort.

Thyroid cancer disproportionally affects more women than men. The aim of this study was to assess whether exposure to extremely low frequency electric magnetic fields from electric blankets (EBs) was associated with the development of thyroid cancer. Data were analyzed from 89,527 women who participated in the Women's Health Initiative Observational Study and who responded to questions concerning prior use of EBs. During a mean follow-up of 12.2 years, 190 incident cases of thyroid cancer were identified. We estimated the hazard ratio (HR) and 95 percent confidence interval (CI) of incident thyroid cancer associated with EB use by Cox's proportional hazard model, adjusted for selected covariates. A majority, 57 percent, of the women in the cohort reported the use of EBs while sleeping and/or for warming the bed before sleep. No association was found between use of EBs and subsequent risk of thyroid cancer (HR = 0.98, 95 percent CI 0.72-1.32). Duration of EB use measured in years, months, or hours had no effect on risk. These results did not change when the cases were limited to papillary thyroid cancer, the most frequently occurring histologic type. The results of this study do not support possible health hazards of EBs in regards to thyroid cancer risk.

A phase I dose-escalation trial of high-dose melphalan with palifermin for cytoprotection followed by autologous stem cell transplantation for patients with multiple myeloma with normal renal function.

Melphalan 200 mg/m(2) is the standard conditioning regimen for patients with multiple myeloma (MM) with normal renal function (NRF) undergoing autologous stem cell transplant (ASCT). In an effort to escalate the dose of melphalan and to improve the efficacy, we designed a dose-escalation study of melphalan in conjunction with palifermin in patients with NRF, with the hope that a higher dose of melphalan can be administered with an acceptable degree of oral mucositis (OM). We enrolled 19 patients (18 evaluable) with NRF. Dose-escalation of melphalan administered on day -2 began at 200 mg/m(2) with palifermin administered at a fixed dose of 60 mcg/kg/day. Palifermin was given as an i.v. bolus on day -5, -4, and -3, and then on day +1, +2, and +3. Subsequent dose escalations of melphalan were done at 20 mg/m(2) increments up to a maximum dose of 280 mg/m(2). Of 18 evaluable patients, there were no treatment-related deaths by day 100. The median age was 48.5 years (range, 33-65 years). The most common adverse events related to palifermin included rash (18 events, no ≥ grade 3 events), elevation of amylase (10 events, 4 were grade 3 but asymptomatic), and lipase (5 events, 2 were grade 3 but asymptomatic), edema (11 events, no ≥ grade 3). The overall incidence of OM grade 3 was 44% (8/18) with a median duration of severe mucositis of 5 days (range, 3-6 days). Eleven patients (61%) required opioid analgesics. None of the patients received total parenteral nutrition (TPN)/nasogastric feeding. Two of 6 patients who were given melphalan 280 mg/m(2) did not develop OM. Cardiac dose-limiting toxicity (DLT) in the form of atrial fibrillation did occur in 1 of 6 patients treated with melphalan 280 mg/m(2). Palifermin has permitted safe dose escalation of melphalan up to 280 mg/m(2), thus reaching the cumulative dosage of melphalan administered in tandem ASCT. This higher dose of melphalan has the potential to improve the efficacy and, hopefully, outcomes of patients with MM with a single ASCT. A phase 2 trial is necessary to better delineate the antimyeloma efficacy of this regimen.

Evaluating the effects of lenalidomide induction therapy on peripheral stem cells collection in patients undergoing autologous stem cell transplant for multiple myeloma.

INTRODUCTION: Lenalidomide (LEN) is a relatively new and very effective therapy for multiple myeloma (MM). Prior LEN therapy is associated with an increased risk of peripheral blood stem cell collection (PBSC) failure, particularly with filgrastim (G-CSF) alone. We performed a retrospective chart review of 319 consecutive MM patients who underwent apheresis to collect PBSCs for the first autologous stem cell transplant (ASCT). RESULTS: The median number of PBSCs collected in the LEN (+) group was significantly less than the LEN (-) group (6.34 vs. 7.52 × 10(6) CD34(+) cells/kg; p = 0.0004). In addition, the median number of apheresis sessions required for adequate PBSCs collection were significantly more in the LEN (+) group as compared to LEN (-) group (2 vs. 1 sessions; p = 0.002). In the LEN (+) group, there was a negative correlation between PBSCs collected and prior number of cycles of LEN (p = 0.0001). Rate of PBSC collection failure was 9% in the LEN (+) group and 5% in the LEN (-) group (p = 0.16). Only six patients who failed PBSC collection with G-CSF were able to collect adequate PBSCs with G-CSF + plerixafor. LEN exposure had no effect on neutrophil or platelet recovery post-ASCT. CONCLUSIONS: Up to four cycles of LEN exposure have minimal negative impact on PBSC collection. Despite prolong exposure of LEN, PBSC collection was adequate for two ASCTs in the majority of patients and post-ASCT engraftment was not longer than expected; however, clinical relevance (complication rate, quality of life, cost) of prolonged LEN exposure on both PBSC and ASCT, should be evaluated in prospective clinical trials.

PRAME immunohistochemistry compared to traditional FISH testing in spitzoid neoplasms and other difficult to diagnose melanocytic neoplasms.

PRAME (PReferentially expressed Antigen in Melanoma) is a gene first identified in melanoma. It has been proposed as a useful marker to differentiate melanoma from benign melanocytic neoplasms. Recently genomic testing using fluorescence in situ hybridization has been used to aid in the diagnosis of difficult melanocytic neoplasms. We have compared PRAME staining to FISH testing results in 83 difficult to classify melanocytic neoplasms which showed spitzoid histologic features. A relatively low sensitivity of 29.6% and high specificity of 76.8% is seen with PRAME staining as compared to genomic testing with fluorescence in situ hybridization. This study highlights the limitations of PRAME staining in spitzoid neoplasms.

The impact of high intensity interval training in a diverse group of cancer survivors: CAPABLE, a pilot study.

Purpose: Given the well-documented benefits of regular exercise to cancer survivors, current American Cancer Society guidelines recommend that patients engage in a minimum of 150 min per week of moderate-to-vigorous physical activity with a minimum of two days of strength training. However, few survivors meet this goal, particularly among minorities. Methods: The CAPABLE study is a single-arm, pilot exercise intervention that introduced 48 cancer survivors to a high intensity interval and strength training program three days a week for 12 weeks. We evaluated the impact of this unique training method on bodyweight, % body fat, serum markers correlated with an adverse cardiometabolic profile and health-related quality of life (HRQoL). Measures were summarized at baseline and program exit. Paired t-tests were used to assess change in each of these measures over time. Results: We observed losses in weight, body mass index, and % body fat, and glycosylated hemoglobin (HbA1c) levels over 12-weeks. There were also clinically meaningful improvements in reported overall HRQoL (FACTG total change +9.5 (95% CI, 4.6, 14.4)) and in each one of the individual domains (physical, social, emotional, and functional well-being). Conclusions: We observed meaningful improvements in body composition, HbA1c and quality of life over 12 weeks among cancer survivors participating in a high-intensity interval training program. Future work will include a control arm for comparison and address barriers to participation and adherence which will be important in using this intervention and others like it to improve outcomes and reduce cancer health disparities.

Induction of proapoptotic antibodies to triple-negative breast cancer by vaccination with TRAIL death receptor DR5 DNA.

TNF-related apoptosis-inducing ligand receptor 2 [TRAIL-R2 or death receptor 5 (DR5)] is expressed at elevated levels in a broad range of solid tumors to mediate apoptotic signals from TRAIL or agonist antibodies. We tested the hypothesis that DR5 DNA vaccination will induce proapoptotic antibody to trigger apoptosis of tumor cells. BALB/c mice were electrovaccinated with DNA-encoding wild-type human DR5 (phDR5) or its derivatives. Resulting immune serum or purified immune IgG induced apoptosis in triple-negative breast cancer (TNBC) cells, which were also TRAIL sensitive. The proapoptotic activity of immune serum at dilutions of 0.5-2% was comparable to that of 1-2 µg/ml of TRAIL. Apoptotic activity of immune serum was enhanced by antibody crosslinking. Apoptotic cell death induced by anti-DR5 antibody was shown by the cleavage of PARP and caspase-3. In contrast, immune serum had no effect on the proliferation of activated human T cells, which expressed low levels of DR5. In vivo, hDR5 reactive immune serum prevented growth of SUM159 TNBC cells in severe combined immune-deficient mice. DR5-specific IFN-γ-secreting T cells were also induced by DNA vaccination. Furthermore, the feasibility to overcome immune tolerance to self DR5 was shown by the induction of mouse DR5-binding antibody after electrovaccination of BALB/c mice with pmDR5ectm-Td1 encoding a fusion protein of mouse DR5 and an immunogenic fragment of tetanus toxin. These findings support DR5 as a promising vaccine target for controlling TNBC and other DR5-positive cancers.

Melphalan 180 mg/m2 can be safely administered as conditioning regimen before an autologous stem cell transplantation (ASCT) in multiple myeloma patients with creatinine clearance 60 mL/min/1.73 m2 or lower with use of palifermin for cytoprotection: results of a phase I trial.

UNLABELLED: High-dose melphalan 140 mg/m2 is the standard of care for patients with multiple myeloma (MM) with renal insufficiency (RI). Palifermin as a cytoprotective agent has demonstrated efficacy in reducing the intensity and duration of oral mucositis (OM) in patients who receive intensive chemotherapy/radiotherapy. There is no prospective data on the use of palifermin in patients with MM with RI. ELIGIBILITY CRITERIA: creatinine clearance ≤60 mL/minute/1.73 m2, age >18 years, no dialysis, no active OM, and a suitable candidate for autologous stem cell transplant (ASCT). Melphalan dose ranged from 140 to 200 mg/m2 and escalated at the increment of 20 mg/m2. Six dosages of palifermin 60 mcg/kg/day were given intravenously between day -5 to day +3. Dose escalations were to stop if dose-limiting toxicities (DLTs) occurred at melphalan dose in ≥2 of 3 patients, with that dose declared as the maximal administered dose and the level below where ≤1 of 6 patients had DLTs was considered the maximally tolerated dose (MTD). Nineteen patients were enrolled from June 2007 to June 2011. Data on 15 evaluable patients is reported as 4 patients were removed. Median age was 59 years (range, 36-67 years). The overall incidence of OM ≥ grade 3 was 53% (8 of 15) and a median duration of ≥grade 3 OM was 6.5 days (range, 3-42 days). One patient in L2 (melphalan 160 mg/m2) developed atrial fibrillation on day +9. Two patients in L4 (melphalan 200 mg/m2) developed grade 4 OM, hence reaching DLT. No DLT was observed in 6 patients enrolled in L3 (melphalan 180 mg/m2). Palifermin has permitted safe dose escalation of melphalan up to 180 mg/m(2) in patients with RI.

A phase II study of 17-allylamino-17-demethoxygeldanamycin in metastatic or locally advanced, unresectable breast cancer.

Heat shock protein 90 (Hsp90) is an attractive target for breast cancer treatment, as it is required for the proper folding and stabilization of several proteins known to be involved in breast cancer growth and development. These proteins include the epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), progesterone receptor (PR), and src. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is an intravenous Hsp90 inhibitor in development for breast cancer treatment. We conducted a phase II study of 17-AAG 220 mg/m(2) on days 1, 4, 8, and 11 every 21 days in patients with metastatic and locally advanced breast cancer. Since we expected the molecular effects of Hsp90 inhibition to extend beyond just ER, PR, and HER2 down regulation and to impact a variety of other cellular proteins, patients were not selected based on ER, PR, or HER2 status. Eleven patients, including 6 patients with triple negative breast cancer, were enrolled and treated. There were no responses and 3 patients had stable disease as their best response. Five patients developed grade 3/4 toxicities, which were primarily hepatic and pulmonary. Based on these results, we do not recommend further study of 17-AAG at this dosing schedule or in unselected breast cancer patients.

ERLIN2 promotes breast cancer cell survival by modulating endoplasmic reticulum stress pathways.

BACKGROUND: Amplification of the 8p11-12 region has been found in approximately 15% of human breast cancer and is associated with poor prognosis. Previous genomic analysis has led us to identify the endoplasmic reticulum (ER) lipid raft-associated 2 (ERLIN2) gene as one of the candidate oncogenes within the 8p11-12 amplicon in human breast cancer, particularly in the luminal subtype. ERLIN2, an ER membrane protein, has recently been identified as a novel mediator of ER-associated degradation. Yet, the biological roles of ERLIN2 and molecular mechanisms by which ERLIN2 coordinates ER pathways in breast carcinogenesis remain unclear. METHODS: We established the MCF10A-ERLIN2 cell line, which stably over expresses ERLIN2 in human nontransformed mammary epithelial cells (MCF10A) using the pLenti6/V5-ERLIN2 construct. ERLIN2 over expressing cells and their respective parental cell lines were assayed for in vitro transforming phenotypes. Next, we knocked down the ERLIN2 as well as the ER stress sensor IRE1α activity in the breast cancer cell lines to characterize the biological roles and molecular basis of the ERLIN2 in carcinogenesis. Finally, immunohistochemical staining was performed to detect ERLIN2 expression in normal and cancerous human breast tissues RESULTS: We found that amplification of the ERLIN2 gene and over expression of the ERLIN2 protein occurs in both luminal and Her2 subtypes of breast cancer. Gain- and loss-of-function approaches demonstrated that ERLIN2 is a novel oncogenic factor associated with the ER stress response pathway. The IRE1α/XBP1 axis in the ER stress pathway modulated expression of ERLIN2 protein levels in breast cancer cells. We also showed that over expression of ERLIN2 facilitated the adaptation of breast epithelial cells to ER stress by supporting cell growth and protecting the cells from ER stress-induced cell death. CONCLUSIONS: ERLIN2 may confer a selective growth advantage for breast cancer cells by facilitating a cytoprotective response to various cellular stresses associated with oncogenesis. The information provided here sheds new light on the mechanism of breast cancer malignancy.

Aprepitant for prevention of nausea and vomiting secondary to high-dose cyclophosphamide administered to patients undergoing autologous peripheral blood stem cells mobilization: a phase II trial.

This is a phase II trial evaluating efficacy and safety of aprepitant (AP) in combination with 5-HT3 antagonist and adjusted dose dexamethasone in patients receiving high-dose cyclophosphamide (CY) and filgrastim for stem cell mobilization. We used Simon's optimal two-stage design constrained to fewer than 40 patients with 10% type I error and 85% statistical power. The first stage of the study required accrual of 18 response-evaluable patients. The primary endpoint was the control of vomiting without the use of any rescue anti-emetics at 24 h after the administration of high dose CY (4 g/m(2)). If emesis was controlled in ≥9 patients, an additional cohort of 17 patients would be enrolled. The null hypothesis would be rejected if there were ≥20 responses among 35 patients. Forty patients were enrolled, five of whom were not evaluable for response. Eighteen evaluable patients were enrolled in the first stage. Acute emesis was controlled in 10 patients; therefore, enrollment proceeded to stage 2. An additional 17 patients were enrolled; 20/35 response-evaluable patients (57%) did not develop acute vomiting or require rescue anti-emetics, thus achieving the goal of the study. A total of 22/35 response-evaluable patients (63%) met the secondary endpoint of delayed emesis control (days 2-5). Thirty-three out of 35 patients underwent successful stem cell mobilization. No ≥ grade 3 AP-related adverse events were noted. The AP regimen can effectively control acute and delayed emesis in the majority patients receiving high-dose CY.

Financial Hardship by Age at Diagnosis Including in Young Adulthood among African American Cancer Survivors.

BACKGROUND: Financial hardship is most common among cancer survivors with the fewest financial resources at diagnosis; however, little is known about the financial outcomes of young adult (YA) survivors (ages 20-39 at diagnosis), despite their having fewer financial reserves than older adults. METHODS: We utilized data from 3,888 participants in the population-based Detroit Research on Cancer Survivors cohort. Participants self-reported several forms of material and behavioral financial hardship (MFH and BFH, respectively). Psychological financial hardship (PFH) was measured using the Comprehensive Score for financial Toxicity (COST) score. Modified Poisson models estimated prevalence ratios (PR) and 95% confidence intervals (CI) for financial hardship by age at diagnosis controlling for demographic, socioeconomic, and cancer-related factors. RESULTS: MFH prevalence was inversely associated with age such that 72% of YA survivors reported MFH, 62% ages 40 to 54, 49% ages 55 to 64, and 33% ages 65 to 79 (PRadjusted YA vs. 65+: 1.75; 95% CI, 1.49-2.04; Ptrend < 0.001). BFH was also more common among YA survivors (26%) than those ages 65 to 79 (20%; PRadjusted: 1.50; 95% CI, 1.08-2.08; Ptrend = 0.019). Age was positively associated with financial wellbeing. COST scores ranged from 20.7 (95% CI, 19.0-22.4) among YA survivors to 27.2 (95% CI, 26.1-28.2) among adults 65 to 79 years old (Ptrend < 0.001). CONCLUSIONS: In this population of African American cancer survivors, MFH and BFH were more common, and PFH was more severe, in YA survivors compared with those diagnosed as older adults. IMPACT: Young adulthood at diagnosis should be considered a risk factor for cancer-related financial hardship and addressed in work designed to reduce the adverse financial impacts of cancer.

Role of High-Dose Adjuvant Chemotherapy Followed by Autologous Stem Cell Transplantation in Locally Advanced Triple-Negative Breast Cancer: A Retrospective Chart Review.

Purpose: Women with locally advanced/high-risk triple-negative breast cancer treated with the current standard chemotherapy continue to have a poor prognosis. High-dose chemotherapy with autologous stem cell transplant as treatment for locally advanced/high-risk breast cancer remains controversial due to a lack of survival benefit seen in previous phase III trials. However, these trials evaluated a heterogeneous group of patients with different receptor subtypes. A marginal benefit was observed in certain subgroups. We report long-term outcomes of women with stage IIB or III triple-negative breast cancer treated with high-dose chemotherapy followed by autologous stem cell transplant at our institution between 1995 and 2001. Methods: This is a retrospective analysis of stage IIB or stage III triple-negative breast cancer treated with high-dose chemotherapy followed by autologous stem cell transplant. We excluded women with hormone-positive, HER2/neu-positive/unknown, and/or metastatic disease prior to transplant as per updated AJCC 7th edition guidelines. Patients underwent surgery and either neoadjuvant or adjuvant anthracycline and taxane-based chemotherapy and then proceeded to high-dose chemotherapy and autologous stem cell transplant using carmustine 600 mg/sqm, cyclophosphamide 5.6gm/sqm, and cisplatin 165 mg/sqm (STAMP 1 regimen) for consolidation. This was followed by locoregional breast and lymph node radiation per standard of care. Results: Twenty-nine women (2 stage IIB and 27 stage III) were evaluated. The median age at diagnosis was 43 years (IQR: 40, 51). Eleven patients had 4-9 regional lymph nodes (LN) involved and 16 had 10+ involved LNs. Four patients had T4 or inflammatory breast cancer and two had ipsilateral supraclavicular LNs involved. The median follow-up time is 16 years (95% CI: 12, 19, range <1-19 y) posttransplant. The median overall survival was 15 years (95% CI: 3, 19); the median DFS was 14 years (95% CI: 1, 19). Conclusions: This study of locally advanced/high-risk triple-negative breast cancer treated with adjuvant high-dose chemotherapy and autologous stem cell transplant reveals high overall survival rate. With the current improvement in treatment-related mortality, re-evaluating this approach in this subset of high-risk breast cancer in prospective randomized studies may be worthwhile.

Adverse Effects of Total Body Irradiation: A Two-Decade, Single Institution Analysis.

PURPOSE: Several adverse effects have been reported in the literature associated with total body irradiation (TBI). Reports of the adverse effects of TBI have been primarily drawn from single-institution retrospective analyses. We report, to our knowledge, one of the largest cohorts of patients treated with TBI using multiple preparative chemotherapy and radiation regimens. METHODS AND MATERIALS: A retrospective chart review was performed for all 705 patients treated with TBI at our institution from 1995 to 2017. Based on availability of TBI records, 622 patients (88%) had sufficient evaluable documentation for analysis. Patients received 1 of 4 conditioning regimens: busulfan-fludarabine, 2 Gy (BUFLU); fludarabine-melphalan, 2 Gy (FLUMEL); cyclophosphamide, 12 Gy fractionated (CY); or etoposide, 12 Gy fractionated (VP16). Individual patients were evaluated for 13 specific recognized adverse effects based on the Common Terminology Criteria for Adverse Events, version 5.0. RESULTS: Mucositis (grade 3) was the most common serious adverse effect and occurred most frequently in the group receiving the VP16 12 Gy regimen (40% vs less than 14% in each of the other groups). Serious febrile neutropenia (grade 3-5) was less frequent (24%) among patients receiving CY than among those receiving the other conditioning regimens (more than 38% in each of the other groups). The incidence of serious lung infection was less common (5%) in patients receiving CY than in those receiving VP16 (18%). There was a higher frequency of grade 3-5 diarrhea among those receiving FLUMEL (5%) and VP16 (4%) than in the other groups (<3%) (P = .034). Otherwise, there were no detectable differences in serious toxicity by regimen for the 13 adverse effects reviewed. Only 2 secondary malignancies were reported, and both were in the BUFLU group. Cataract formation occurred in approximately 16% of patients overall, and the rates were similar across regimens. Median time to cataract formation was 1 to 4 years across regimens, with cataracts occurring earlier in the 2-Gy regimens. The overall rate of grade ≥3 pneumonitis was approximately 2% across the entire cohort. CONCLUSIONS: Our nearly 20-year TBI experience showed relatively low rates of radiation-related toxicities. However, cataracts were common with a relatively short onset time.

Long term follow-up of allogeneic stem cell transplantation in patients with myelodysplastic syndromes using busulfan, cytosine arabinoside, and cyclophosphamide.

We report here the 10-year follow-up of 86 patients who underwent allogeneic stem cell transplantation (ASCT) for myelodysplastic syndrome (MDS). All patients received the busulfan, cytosine arabinoside, and cyclophosphamide (BAC) preparative regimen which consisted of busulfan 16 mg/kg, cytosine arabinoside 8 g/m(2) IV, and cyclophosphamide 120 mg/kg IV. Fifty-nine patients (69%) had de novo MDS; 26 (30%) had secondary MDS (treatment related), and one had a preceding aplastic anemia which progressed to MDS before transplant. Cytogenetics (80 patients) was classified as good (34%), intermediate (17%), or poor (42%). With a median follow-up for survivors of 124 months, the 10-year Kaplan-Meier estimates for overall survival (OS) was 43% (95% confidence interval [CI]: 31-53%). Cumulative nonrelapse mortality (NRM) and relapse was 43% (95% CI: 32-54%) and 19% (95% CI: 11-27%), respectively. No patient relapsed after 2 years. In patients with RAEB-T/AML, 10-year relapse-free survival (RFS), relapse, and NRM was 36%, 36%, and 27%, respectively. Younger age (P = 0.05), human leukocyte antigen (HLA) match (P = 0.002), good risk cytogenetics (P = 0.008), and having a related donor (P = 0.03) significantly improved overall and RFS in the multivariable analysis. The long-term follow-up of patients receiving the BAC regimen with ASCT in this study indicated durable relapse-free and OS with acceptable toxicity in this group of patients with high-risk features.

Analysis of citations to biomedical articles affected by scientific misconduct.

We describe the ongoing citations to biomedical articles affected by scientific misconduct, and characterize the papers that cite these affected articles. The citations to 102 articles named in official findings of scientific misconduct during the period of 1993 and 2001 were identified through the Institute for Scientific Information Web of Science database. Using a stratified random sampling strategy, we performed a content analysis of 603 of the 5,393 citing papers to identify indications of awareness that the cited articles affected by scientific misconduct had validity issues, and to examine how the citing papers referred to the affected articles. Fewer than 5% of citing papers indicated any awareness that the cited article was retracted or named in a finding of misconduct. We also tested the hypothesis that affected articles would have fewer citations than a comparison sample; this was not supported. Most articles affected by misconduct were published in basic science journals, and we found little cause for concern that such articles may have affected clinical equipoise or clinical care.

History of Inflammatory Bowel Disease and Self-Reported Oral Health: Women's Health Initiative Observational Study.

Background and Objective: Both periodontal disease and inflammatory bowel disease (IBD), are chronic inflammatory conditions, which are mediated by a complex interplay among a dysbiotic microbiota, dysregulated host immune-inflammatory responses, and lifestyle factors. Despite substantial differences in physical and chemical environments, rather strong correlations have been detected between microbial compositions of the oral cavity and stool. In this study, we tested the hypothesis that oral health conditions are affected by the presence of IBD. Materials and Methods: We analyzed the data from 73,621 women who were enrolled in the Women's Health Initiative observational cohort study and completed a follow-up questionnaire that surveyed oral health status specifically at year 5. Among these, 880 reported IBD at the baseline, including 47% who were symptomatic cases and 27% who were on immunosuppressive treatment. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for the association of IBD and medication status for self-reported oral health outcomes, using logistic regression models, adjusted for selected covariates. Results: IBD was not associated with periodontal disease history itself in a multivariable model; however, poorer self-rated oral health was modestly associated with the presence of IBD (OR = 1.15, 95% CI: 1.01-1.30). Likewise, more frequent eating limitations due to teeth were associated with the presence of IBD history (OR = 1.22, 95% CI: 1.07-1.39). When IBD cases were limited to those who were symptomatic, the associations with these two self-rated oral health outcomes were more pronounced with ORs of 1.28 (95% CI: 1.07-1.54) and 1.36 (95% CI: 1.07-1.54), respectively. Immunosuppressive treatment had little effect on these risk estimates. Conclusions: Among this nation-wide cohort of women 50-79 years of age, history of IBD was associated with poorer perceived oral health status.