Complete pathologic response rate to neoadjuvant chemotherapy increases with increasing HER2/CEP17 ratio in HER2 overexpressing breast cancer: analysis of the National Cancer Database (NCDB).

BACKGROUND: HER2-positive breast cancer is an aggressive subtype of breast cancer that overexpresses human epidermal growth factor receptor 2 promoting cancer cell growth. Monoclonal antibodies targeting the HER2 receptor have improved survival for this patient population. Achieving pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) has correlated with disease-free survival in multiple trials, but we do not know why some HER2-positive tumors respond better to these therapies. We evaluated the correlation between HER2/CEP17 ratio and partial versus complete response following NAC. We evaluated whether patients with higher HER2/CEP17 ratios would have higher rates of pCR after NAC. METHODS: Using the National Cancer Database (NCDB), we performed a retrospective review comparing pCR rates after NAC based on HER2 ratio between 2005 and 2014. Patients were excluded if they were HER2 negative, did not undergo NAC, or if the HER2 ratio was not recorded. Trends in percentage of pCR versus partial response were analyzed using SPSS. RESULTS: The NCDB included 237,118 patients with HER2 equivocal or HER2-positive breast tumors. 29,291 of these patients underwent NAC, and HER2/CEP17 ratios were recorded in 14,597 of the NAC cases. A pCR was noted in 9752 patients and 11,402 patients had a partial response. The ratios were significantly different between complete vs. partial response groups (include ratios), P < 0.001. Using linear regression analysis, we identified a direct relationship between increasing the ratio and response to NAC. CONCLUSION: Our study demonstrates a linear relationship between HER2/CEP17 ratio and pCR to NAC in patients included in the NCDB. The NCDB reflects current clinical practices across the country, and in this patient population, higher HER2 ratio is predictive of pCR to NAC and thus may be used in guiding decisions regarding the therapies that a patient receives in order to enhance pCR.

Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue of the Salivary Glands: A Multicenter, International Experience of 248 Patients (IELSG 41).

BACKGROUND: The salivary gland is one of the most common sites involved by nongastric, extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). A large series of patients with long-term follow-up has not been documented. This multicenter, international study sought to characterize the clinical characteristics, treatment, and natural history of salivary gland MALT lymphoma. METHODS: Patients with biopsy-confirmed salivary gland MALT lymphoma were identified from multiple international sites. Risk factors, treatment, and long-term outcomes were evaluated. RESULTS: A total of 247 patients were evaluated; 76% presented with limited-stage disease. There was a history of autoimmune disorder in 41%, with Sjögren disease being the most common (83%). Fifty-seven percent of patients were initially treated with local therapy with surgery, radiation, or both; 37 of patients were treated with systemic therapy initially, with 47% of those receiving rituximab; and 6% of patients were observed. The median overall survival (OS) was 18.3 years. The median progression-free survival (PFS) following primary therapy was 9.3 years. There was no difference in the outcomes between patients receiving local or systemic therapy in first-line management. On multivariate analysis, age <60 years and low to intermediate international prognostic index were associated with improved OS and PFS; Sjögren disease was associated with improved OS. CONCLUSION: Salivary gland MALT lymphoma has an excellent prognosis regardless of initial treatment, and patients with Sjögren disease have improved survival. Risks for long-term complications must be weighed when determining initial therapy.

Spectrum of myeloid neoplasms and immune deficiency associated with germline GATA2 mutations.

Guanine-adenine-thymine-adenine 2 (GATA2) mutated disorders include the recently described MonoMAC syndrome (Monocytopenia and Mycobacterium avium complex infections), DCML (dendritic cell, monocyte, and lymphocyte deficiency), familial MDS/AML (myelodysplastic syndrome/acute myeloid leukemia) (myeloid neoplasms), congenital neutropenia, congenital lymphedema (Emberger's syndrome), sensorineural deafness, viral warts, and a spectrum of aggressive infections seen across all age groups. While considerable efforts have been made to identify the mutations that characterize this disorder, pathogenesis remains a work in progress with less than 100 patients described in current literature. Varying clinical presentations offer diagnostic challenges. Allogeneic stem cell transplant remains the treatment of choice. Morbidity, mortality, and social costs due to the familial nature of the disease are considerable. We describe our experience with the disorder in three affected families and a comprehensive review of current literature.

The utility of restaging bone marrow biopsy in PET-negative patients with diffuse large B-cell lymphoma and baseline bone marrow involvement.

Patients with diffuse large B-cell lymphoma (DLBCL) and pre-treatment bone marrow (BM) involvement require a restaging BM biopsy to document complete remission (CR). We investigated whether BM assessment by restaging PET-CT could obviate the need for a repeat BM biopsy. Patients with DLBCL and a positive BM biopsy at diagnosis were identified from the Mayo Clinic Lymphoma Data Base. The concordance of BM status on restaging histopathology and PET-CT reports and the positive (PPV) and negative predictive value (NPV) of PET-CT were determined. One thousand eighty patients with DLBCL were evaluated and 69 patients (6%) had DLBCL involving the BM at diagnosis. Of 46 patients who completed frontline chemoimmunotherapy, 34 had a restaging PET-CT and BM biopsy and were included in the analysis. Thirty-three patients had a negative BM by both PET-CT and BM biopsy; one patient had persistent BM involvement by biopsy and PET-CT. Thus, restaging PET-CT had 100% PPV and 100% NPV for assessing residual BM disease. The findings were validated in a prospective cohort of 68 DLBCL patients treated on a phase II clinical trial where four patients (6%) had DLBCL involving the BM at diagnosis. All had a negative BM by both restaging BM biopsy and PET-CT. Compared with the gold standard of BM biopsy, PET-CT had a 100% NPV to exclude residual BM disease after frontline therapy. If further validated, DLBCL practice guidelines and response criteria could be modified so that BM biopsy is no longer required to document CR if the restaging PET-CT is negative.

Causes and palliation of transfusion-associated vaginal bleeding in patients with metastatic cancer.

PURPOSE: The current study was undertaken (1) to capture a clinically relevant, systematically collected series of patients with metastatic cancer and transfusion-associated vaginal bleeding and (2) to provide insight into how best to palliate this bleeding. METHODS/RESULTS: As part of a single-institution review, 46 patients with metastatic cancer and transfusion-associated vaginal bleeding were identified. In a minority, 14 (30%), the cancer itself was directly responsible for the bleeding, and under these circumstances, gynecological cancer was the most frequent cause. In 13 patients (28%), more than 1 palliative intervention was attempted. Of all the interventions, a hysterectomy was performed most frequently and was successful in 11 patients. The use of ablation or embolization procedures was rarely tried but successful in 4 patients. However, 2 patients died of vaginal bleeding, despite multiple palliative procedures to control bleeding, including tumor embolization in one. CONCLUSIONS: Transfusion-associated vaginal bleeding in patients with metastatic cancer can arise from nonmalignant causes and often assumes an uneventful course but can, at times, be serious and difficult to control.

Body mass index underestimates adiposity in women with spinal cord injury.

OBJECTIVE: To assess the relationship between body mass index (BMI) and adiposity as well as the influence of injury level on this relationship in 24 women with spinal cord injury (SCI) and 23 able-bodied (AB) women with similar age, race, and BMI. DESIGN AND METHODS: Body composition was measured by dual energy X-ray absorptiometry (DXA). Analysis of covariance was performed to compare total and regional soft tissue percent fat (PF) measures between groups. RESULTS: Women with SCI had a higher soft tissue PF than AB women at any given BMI. The BMI-adjusted soft tissue PF (mean ± SE) was (44.4 ± 1.8)%, (37.8 ± 1.3)%, and (35.9 ± 1.1)% for tetraplegic, paraplegic, and AB women, respectively. The BMI explained about equal amounts of the variance in soft tissue PF among paraplegic and AB women (65%), but only 28% in tetraplegic women. CONCLUSION: This study confirms a limited use of BMI in measuring adiposity in women with SCI, particularly among those with tetraplegia. Our observation of lower BMI cutoff points for defining obesity (28 kg/m(2) for paraplegia and 21 kg/m(2) for tetraplegia) needs further confirmation. The underweight/malnutrition issue also deserves the consideration while proposing the ideal weight and BMI range for persons with SCI.

Future directions for spinal cord injury research: recent developments and model systems contributions.

The authors look forward and discuss future directions in spinal cord injury (SCI) from a perspective of biomedical, psychosocial and technologic research. This discussion is based both on recent developments from various fields of knowledge and, more specifically, on SCI Model Systems' research contributions to medical rehabilitation. Biomedical research, as described here, includes (1) the process of moving from the "bench to bedside" and harnessing knowledge from basic science to produce new clinical treatment options for SCI during the life span; (2) the rapid proliferation of clinical trials aimed at neurologic recovery; (3) the growth of new technologies to restore and improve function; and (4) the challenges of developing relevant outcome measures to evaluate efficacy and effectiveness of interventions. Recent progress in psychosocial research has contributed significantly to understanding of the many factors associated with disability during the life course, the importance of quality of life issues, and the value of activity, participation, and the environment in promoting successful rehabilitation outcomes following SCI. Technology and bioengineering advances are discussed in relation to access to high-quality technology; restoration and replacement of movement; and technology to enhance rehabilitation outcomes.

Measurement of sexual functioning after spinal cord injury: preferred instruments.

BACKGROUND/OBJECTIVE: To determine the utility of certain instruments to assess sexuality and fertility after SCI, an expert panel identified key areas to study and evaluated available instruments. These were rated according to certain predefined criteria. METHODS: The authors divided sexual issues into male and female sexual function, male reproductive function, and female reproductive function. The instruments that have been used most frequently to measure these aspects of sexual function over the past 5 years were identified by expert consensus. Finally, these instruments were subjected to a critical review. RESULTS: The Female Sexual Function Index (FSFI), measurement of vaginal pulse amplitude (VPA), the International Index of Erectile Function (IIEF), and the measurement of ejaculatory function and semen quality were considered appropriate measures to assess sexual responses and reproductive function after SCI. There were no measures identified to assess female reproductive function. CONCLUSIONS: For clinical trials aiming to improve sexual function after SCI, the FSFI or the IIEF is currently preferred. Although VPA is an appropriate means to assess female sexual responses, it is only useful for laboratory studies and is too invasive for use in clinical trials. For assessment of male fertility potential, assessment of ejaculatory capacity and semen analysis are recommended.

Outcome measures for gait and ambulation in the spinal cord injury population.

BACKGROUND: At the 2006 National Institute on Disability and Rehabilitation Research (NIDRR) sponsored pre-conference on spinal cord injury (SCI) outcomes, several gait and ambulation measures were evaluated for utility in clinical practice, validity, and reliability as research measurement tools. The Conference Subcommittee on Gait and Ambulation chose to review the Walking Index for Spinal Cord Injury II (WISCI II), 50-Foot Walk Test (50FTWT), 6-Minute Walk Test (6MWT), 10-Meter Walk Test (10MWT), and Functional Independence Measure-Locomotor (FIM-L). METHODS: A subcommittee of international experts evaluated each instrument for test construct, administration, population applicability, reliability, sensitivity to change, and validity. Evaluations for each outcome measure were compiled, distributed to the whole committee, and then further reviewed with addition of comments and recommendations for consensus. An audience of experts voted on the validity and usefulness of each measure. RESULTS: WISCI II and 10MWT were found to be the most valid and clinically useful tests to measure improvement in gait for patients with SCI. FIM-L had little utility and validity for research in SCI. 6MWT and 50FTWT were found to be useful but in need of further validation or changes for the SCI population. CONCLUSION: A combination of the 10MWT and WISCI II would provide the most valid measure of improvement in gait and ambulation in as much as objective changes of speed, and functional capacity allow for interval measurement. To provide the most comprehensive battery, however, it will be important to include a measure of endurance such as the 6MWT. Further validation and study should be devoted to WISCI II, 10MWT, and 6MWT as primary outcome measures for gait in SCI.

Reproductive health care for women with spina bifida.

Women with spina bifida have unique health care concerns and as the life expectancy of this population increases, they are transitioning from adolescence to womanhood and entering their reproductive years with little information about what to expect. Likewise, their health care providers do not have the benefit of evidence-based research that comprehensively addresses the issues these women may face related to reproduction or aging. Few studies have focused on the effects that spina bifida may have on these women's reproductive systems, nor has attention been paid to the effects that possible reproductive endocrine changes may have on their disability. Needless to say, concerns about sexuality, sexual function, and pregnancy are just as important to these women as they are to their able-bodied counterparts.

Development of international standards to document sexual and reproductive functions after spinal cord injury: preliminary report.

Clinicians need standard terminology to communicate effectively about remaining autonomic function in persons after spinal cord injury. This article illustrates the development of standard nomenclature that describes the impact of injury on sexual functioning. A standard anatomic diagnosis and a secondary means of describing the presence of male and female sexual dysfunction, genital arousal, and orgasmic function are discussed.

Pressure ulcer prevalence in people with spinal cord injury: age-period-duration effects.

OBJECTIVE: To examine age-period-duration patterns of the prevalence of pressure ulcers in community-residing people with spinal cord injury (SCI). DESIGN: Multicenter cohort study. SETTING: Nine Model Spinal Cord Injury Systems throughout the United States. PARTICIPANTS: People with SCI (N=3361) injured between 1986 and 1995 and followed up thereafter on a yearly basis through 2002. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Physician-confirmed pressure ulcers of stage II or greater at the follow-up visits. RESULTS: The multivariable generalized estimating equations model showed a significant trend toward increasing pressure ulcer prevalence in the recent years (1994-2002 vs 1984-1993: odds ratio=1.4; 95% confidence interval, 1.2-1.6) not explained by aging, years since injury, or demographic and clinical factors. The risk of pressure ulcers appeared to be steady during the first 10 years and increased 15 years postinjury. Pressure ulcers were more common among the elderly, men, African Americans, singles, subjects with education less than high school, unemployed, subjects with complete injury, and subjects with history of pressure ulcers, rehospitalization, nursing home stay, and other medical conditions. Injury cause and level had no significant effect. CONCLUSIONS: These results highlight the need for research into factors that contribute to the increasing pressure ulcer prevalence.

Reproductive issues for women with spina bifida.

BACKGROUND/OBJECTIVES: Few studies have adequately examined the unique issues of women with spina bifida as they enter their reproductive years. Most studies are anecdotal, retrospective case studies that contribute little to our understanding of the physiological effects of the disability on the reproductive system and, conversely, the effects of the reproductive endocrine changes on the woman's disability. The purpose of this article was to review previously published reports on the reproductive issues facing female adolescents and women and to ascertain the current knowledge so that future research needs can be established. METHODS: Multiple MEDLINE searches were performed for publications from 1957 through the present pertaining to females/women with spina bifida and/or disabilities. Papers were then chosen if information was provided on menarche, menstruation and sexual maturation, gynecologic issues, sexual function, birth control, pregnancy outcomes, and menopause. These were then reviewed and classified according to the level of evidence (as defined by Ball et al). RESULTS: More than 150 titles and abstracts were reviewed for inclusion. Of these, 75 papers met the guidelines for the subject content. Studies were stratified by level of evidence and included 1 study at level 3, 71 studies at level 4, and 3 studies at level 5. CONCLUSION: Little research has examined the reproductive issues of women with spina bifida and women with other neurologic disabilities. Future controlled prospective research studies are needed to examine issues related to puberty and sexual and gynecologic issues throughout the life span and pregnancy in these populations.

Research from the Model Spinal Cord Injury Systems: findings from the current 5-year grant cycle.

This issue of the Archives of Physical Medicine and Rehabilitation is dedicated to current research findings of the Model Spinal Cord Injury Systems (MSCIS) program. The MSCIS grants were established by the Rehabilitation Services Administration in the 1970s. Now administered by the National Institute on Disability and Rehabilitation Research within the Office of Special Education and Rehabilitation Services in the US Department of Education, the program has included 27 spinal cord injury centers in the United States over the years. In the current 5-year grant cycle (2000-2005), there are 16 designated regional MSCIS centers. In addition to establishing a comprehensive system of care, the grantees contribute patient data to the National Spinal Cord Injury Database (which now contains data on 30,532 subjects with follow-up of up to 30 y). In addition, the MSCIS grants enable the conduct of site-specific and collaborative research projects. To highlight the research findings of the program, the MSCIS have produced a special dissemination effort during each of the previous 5 grant cycles, with this issue of the Archives representing the latest of these endeavors. This article provides a brief history of the MSCIS program and highlights the important findings of the 17 original research articles contained in this issue.

A demographic profile of new traumatic spinal cord injuries: change and stability over 30 years.

OBJECTIVE: To evaluate epidemiologic trends in new spinal cord injuries (SCIs) in the United States over 3 decades. DESIGN: Consecutive case series. SETTING: Model Spinal Cord Injury Systems (MSCIS) facilities. PARTICIPANTS: Persons (N=30,532) admitted to MSCIS facilities within 365 days of injury between 1973 and 2003, and enrolled in the National Spinal Cord Injury Database. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Data were collected at MSCIS admission and rehabilitation discharge. Variables included age, gender, race and ethnic group, year of injury, and level and extent of injury. Specific etiologies were grouped as motor vehicle collisions (MVCs), violence, falls, sports, and other. Demographic and injury severity trends were analyzed by year of injury groupings according to decades (1973-1979, 1980-1989, 1990-1999, 2000-2003.) Chi-square tests assessed statistical significance. One-way analysis of variance compared mean ages. RESULTS: The male/female ratio remained fairly stable at 4:1, but the percentage of women increased slightly over time, especially from MVC etiologies ( P <.001). Over time, the mean age at injury increased significantly ( P <.001); it was 37.7+/-17.5 years in 2000-2003. The majority of cases were white (66.1%). Tetraplegia (54.1%) and complete injuries (55.6%) occurred more than paraplegia and incomplete injuries, respectively. MVCs (45.6%) remained the most common etiology; falls (19.6%) held the second position over violence (17.8%), except for the 1990-1999 period when the positions were reversed. Significantly increasing percentages of new injuries were seen for SCI due to automobile, motorcycle, bicycle, and all-terrain vehicle crashes, blunt object attacks, snow skiing, and medical and surgical mishaps. CONCLUSIONS: Many previously seen SCI demographic trends continued into the 2000 decade.

Health status, community integration, and economic risk factors for mortality after spinal cord injury.

OBJECTIVE: To examine the association of health, community integration, and economic status with subsequent mortality and life expectancy among persons with spinal cord injury. DESIGN: Cohort study. SETTING: Model Spinal Cord Injury Systems (MSCIS) hospitals. PARTICIPANTS: A total of 5947 persons injured since 1973 who were enrolled in the National Spinal Cord Injury Database and who were still alive and received an annual evaluation from November 1995 through March 2002. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Mortality was determined by routine follow-up supplemented by information from the Social Security Death Index. A logistic regression model based on the full set of predictor variables was developed to estimate the chance of dying in any given year. RESULTS: After adjusting for demographic characteristics and injury severity, health status indicators, measures of community integration, and economic status indicators all had relatively small but statistically significant effects (20%-70% increases) on the likelihood of dying during the next year. Inclusion of these factors may result in higher life expectancy estimates under highly favorable conditions. CONCLUSIONS: Whereas previous reports of the MSCIS data have identified the life expectancies associated with a particular set of demographic (eg, age, gender) and injury-related characteristics (level and completeness of injury; ventilator dependence), the current analysis suggests that consideration of health, economic, and psychosocial factors may make computations of life expectancy more accurate.

Effects of gender on neurologic and functional recovery after spinal cord injury.

OBJECTIVE: To assess gender differences in neurologic and functional outcome measures in persons with spinal cord injury (SCI). DESIGN: Case series. SETTINGS: Model Spinal Cord Injury Systems (MSCIS) throughout the United States. PARTICIPANTS: People (N=14,433) admitted to an MSCIS within 30 days of injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Improvement in American Spinal Injury Association (ASIA) motor index score, ASIA Impairment Scale, level of injury, and FIM instrument scores after SCI. RESULTS: When examining subjects grouped by severity of injury, changes in ASIA motor index total scores, from system admission to 1-year anniversary, were significantly greater for women than men with either complete ( P =.035) or incomplete ( P =.031) injuries. Functional comparison of men and women, using the FIM motor subscale, revealed that men had higher FIM motor scores at rehabilitation discharge among those with motor-complete injuries, except for those with C1-4 and C6 neurologic levels. Women with motor-incomplete high tetraplegia (C1-4 levels) had higher discharge FIM motor scores than did similarly afflicted men. There were no significant differences in FIM motor scores among men and women with other levels of motor incomplete SCI. CONCLUSIONS: Gender differences in SCI were seen in several areas. Women may have more natural neurologic recovery than men; however, for a given level and degree of neurologic injury, men tend to do better functionally than women at time of discharge from rehabilitation. Future prospective study of the effects of estrogen on neurologic recovery and the effects of gender on functional potential are recommended.