St. Mary's Health Center

OBJECTIVE: To provide evidence-based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). METHODS: Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel. RESULTS: We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low-quality evidence supporting the recommendations. CONCLUSION: This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases.

OBJECTIVE: To provide evidence-based recommendations and expert guidance for the management of giant cell arteritis (GCA) and Takayasu arteritis (TAK) as exemplars of large vessel vasculitis. METHODS: Clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for GCA and TAK (27 for GCA, 27 for TAK). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. Recommendations were developed by the Voting Panel, comprising adult and pediatric rheumatologists and patients. Each recommendation required ≥70% consensus among the Voting Panel. RESULTS: We present 22 recommendations and 2 ungraded position statements for GCA, and 20 recommendations and 1 ungraded position statement for TAK. These recommendations and statements address clinical questions relating to the use of diagnostic testing, including imaging, treatments, and surgical interventions in GCA and TAK. Recommendations for GCA include support for the use of glucocorticoid-sparing immunosuppressive agents and the use of imaging to identify large vessel involvement. Recommendations for TAK include the use of nonglucocorticoid immunosuppressive agents with glucocorticoids as initial therapy. There were only 2 strong recommendations; the remaining recommendations were conditional due to the low quality of evidence available for most PICO questions. CONCLUSION: These recommendations provide guidance regarding the evaluation and management of patients with GCA and TAK, including diagnostic strategies, use of pharmacologic agents, and surgical interventions.

OBJECTIVE: This study assessed whether a weight-gain restriction regimen, with or without exercise, would impact glycemic control, pregnancy outcome, and total pregnancy weight gain in obese subjects with gestational diabetes mellitus (GDM). A total of 96 subjects with GDM met the inclusion criteria and were sequentially recruited, with 39 subjects self-enrolled in the exercise and diet (ED) group, and the remaining 57 subjects self-enrolled in the diet (D) group owing to contraindications or a lack of personal preference to exercise. All patients were provided a eucaloric or hypocaloric consistent carbohydrate meal plan and instructed in the self-monitoring of blood glucose. In addition, all ED subjects were prescribed an exercise routine equivalent to a 60% symptom-limited VO2 max. Subjects were followed at weekly or biweekly office visits. Results showed maternal weight and body mass index (35.2+/-7.2 (ED) vs. 33.5+/-9.2 (D)) at study entry as well as number of weeks into the study (7.7+/-5.7 (ED) vs. 9.4+/-4.7 (D)) were similar in both the ED and D groups. Weight gain per week was significantly lower in the ED group than in the D group (0.1+/-0.4 kg vs. 0.3+/-0.4 kg; p<0.05). Subjects (either ED or D) who gained weight had a higher percentage of macrosomic infants than those subjects who lost weight or had no weight change during pregnancy. Other pregnancy and fetal outcomes such as complications, gestational age at delivery, and rate of cesarean delivery were similar in both groups. Conclusions of this study were that caloric restriction and exercise result in limited weight gain in obese subjects with GDM, less macrosomic neonates, and no adverse pregnancy outcomes. Pregnancy is an ideal time for behaviour modification, and this intervention may also help promote long-term healthy lifestyle changes.

Intimate partner violence (IPV) is a common occurrence in pregnancy and results in an increased risk of adverse outcomes. Homicide may be the most common cause of maternal death. Women who are pregnant and the victims of IPV have high rates of stress, are more likely to smoke or use other drugs, deliver a preterm or low birth weight infant, have an increase in infectious complications, and are less likely to obtain prenatal care. The IPV continues in the postpartum period. Adolescents may be at even higher risk than their adult counterparts. Children raised in violent homes have both immediate and life long adverse health outcomes as a result of their exposure to IPV. IPV adds substantially to healthcare costs both for direct services to treat the injuries and higher utilization of a wide range of healthcare services. Healthcare providers, particularly those who care for pregnant women, are in a unique position to identify these women and direct them and their families to the help they need to end the violence in their lives.

OBJECTIVE: To determine risk factors for a prolonged second stage of labor and evaluate the maternal and neonatal outcomes of such pregnancies. METHODS: We reviewed all 7818 patients who delivered at the University of Illinois at Chicago from 1996 to 1999. Excluding nonvertex and multiple gestations, 6791 reached the second stage. Group 1 (n = 6259) consisted of patients with a second stage of 120 minutes or less; group 2, greater than 120 minutes (n = 532 [7.8%]); group 2A, 121-240 minutes (n = 384 [5.7%]); and group 2B, greater than 240 minutes (n = 148 [2.2%]). We compared pregnancy outcomes for these groups with respect to maternal and neonatal morbidity factors using chi(2), Student t, and Wilcoxon rank-sum tests (significance, P <.05). RESULTS: Vaginal delivery rates were 98.7% (group 1), 84.0% (group 2), 90.2% (group 2A), and 65.5% (group 2B). Group 2 had higher rates of perineal trauma, episiotomy usage, chorioamnionitis, postpartum hemorrhage, and operative vaginal delivery than group 1 (P <.001, all comparisons). Group 2B had higher rates of episiotomy usage, operative vaginal deliveries, and perineal trauma than group 2A (P <.001, all comparisons). The neonatal morbidity rates were similar for the three groups. Diabetes, preeclampsia (P <.023), macrosomia, nulliparity, chorioamnionitis, oxytocin usage, and labor induction were each independently associated with an increased risk of a prolonged second stage (all but preeclampsia, P <.001). CONCLUSION: A prolonged second stage is associated with a high rate of vaginal delivery, but a high rate of maternal, though not neonatal, morbidity was observed. Certain antenatal and intrapartum conditions are associated with a prolonged second stage of labor.

OBJECTIVE: To provide evidence-based recommendations and expert guidance for the management of giant cell arteritis (GCA) and Takayasu arteritis (TAK) as exemplars of large vessel vasculitis. METHODS: Clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for GCA and TAK (27 for GCA, 27 for TAK). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. Recommendations were developed by the Voting Panel, comprising adult and pediatric rheumatologists and patients. Each recommendation required ≥70% consensus among the Voting Panel. RESULTS: We present 22 recommendations and 2 ungraded position statements for GCA, and 20 recommendations and 1 ungraded position statement for TAK. These recommendations and statements address clinical questions relating to the use of diagnostic testing, including imaging, treatments, and surgical interventions in GCA and TAK. Recommendations for GCA include support for the use of glucocorticoid-sparing immunosuppressive agents and the use of imaging to identify large vessel involvement. Recommendations for TAK include the use of nonglucocorticoid immunosuppressive agents with glucocorticoids as initial therapy. There were only 2 strong recommendations; the remaining recommendations were conditional due to the low quality of evidence available for most PICO questions. CONCLUSION: These recommendations provide guidance regarding the evaluation and management of patients with GCA and TAK, including diagnostic strategies, use of pharmacologic agents, and surgical interventions.

BACKGROUND: Early case reports suggest more frequent and rapid recurrences of carcinoma of the gallbladder after laparoscopic cholecystectomy (LC) than after open cholecystectomy. This cancer has a poor prognosis and occurs in 1 percent of patients who undergo cholecystectomies. STUDY DESIGN: A recent community hospital series of gallbladder carcinoma (GBC) was reviewed and the total reported experience of GBC after LC was compiled. Diagnostic findings were compared for patients with GBC and a consecutive series of 24 patients who had LC for benign disease. RESULTS: Nine patients with GBC were found among 928 patients who had undergone cholecystectomy (0.97 percent incidence). Compared to patients without GBC, patients with carcinoma were older, had thicker gallbladder walls, and had more abnormalities detected intraoperatively (all p < or = 0.05). Recurrence of GBC occurred more rapidly after LC, and in diffuse peritoneal and port sites when compared with recurrence patterns after open cholecystectomy. CONCLUSIONS: In patients with GBC, LC may be sufficient when the disease is confined to the gallbladder mucosa and the gallbladder is excised intact without bile spillage. However, patients whose gallbladders are torn during dissection or patients who have invasive tumors should undergo laparotomy and local reexcision. In situ GBC can be implanted if the organ is torn during dissection. When gallbladders with suspicious wall thickening or adhesions are noted at LC, especially in older patients, the procedure should be converted to open cholecystectomy.

The literature on pulmonary gas exchange at rest, during exercise, and with weight loss in the morbidly obese (body mass index or BMI > or = 40 kg m(-2)) is reviewed. Forty-one studies were found (768 subjects weighted mean = 40 years old, BMI = 48 kg m(-2)). The alveolar-to-arterial oxygen partial pressure difference (AaDO2) was large at rest in upright subjects at sea level (23, range 5-38 mmHg) while the arterial pressure of oxygen (PaO2) was low (81, range 50-95 mmHg). Arterial pressure of carbon dioxide (PaCO2) was normal. At peak exercise (162 W), gas exchange improves. Weight loss of 45 kg (BMI = -13 kg m(-2)) over 18 months is associated with an improvement in PaO2 (by 10 mmHg, range 1-23 mmHg), a reduction in AaDO2 (by 8 mmHg, range -3 to -16 mmHg), and PaCO2 (by -3 mmHg, range 3 to -14 mmHg) at rest. Every 5-6 kg reduction in weight increases PaO2 by 1 and reduces AaDO2 by 1 mmHg, respectively. Morbidly obese women have better gas exchange at rest compared with morbidly obese men which is likely due to lower waist-to-hip ratios in women than from differences in weight or BMI.

BACKGROUND: There is great debate about the costs and benefits of technology-driven medical interventions such as instrumented lumbar fusion. With most analyses using charge data, the actual costs incurred by medical institutions performing these procedures are not well understood. The object of the current study was to examine the differences in hospital operating costs between open and minimally invasive spine surgery (MIS) during the perioperative period. METHODS: Data were collected in the form of a prospective registry from a community hospital after specific Institutional Review Board approval was obtained. The analysis included consecutive adult patients being surgically treated for degenerative conditions of the lumbar spine, with either an MIS or open approach for two-level instrumented lumbar fusion. Patient outcomes and costs were collected for the perioperative period. Hospital operating costs were grouped by hospitalization/operative procedure, transfusions, reoperations, and residual events (health care interactions). RESULTS: One hundred and one open posterior lumbar interbody fusion (Open group) and 109 MIS patients were treated primarily for stenosis coupled with instability (39.6% and 59.6%, respectively). Mean total hospital costs were $27,055.53 for the Open group and $24,320.16 for the MIS group. This represents a statistically significant cost savings of $2,825.37 (10.4% [95% confidence interval: $522.51-$5,128.23]) when utilizing MIS over traditional Open techniques. Additionally, residual events, complications, and blood transfusions were significantly more frequent in the Open group, compared to the MIS group. CONCLUSIONS/LEVEL OF EVIDENCE: Utilizing minimally invasive techniques for instrumented spinal fusion results in decreased hospital operating costs compared to similar open procedures in the early perioperative period. Additionally, patient benefits of minimally invasive techniques include significantly less blood loss, shorter hospital stays, lower complication rate, and a lower number of residual events. Long-term outcome comparisons are needed to evaluate the efficacy of the two treatments. LEVEL OF EVIDENCE: III CLINICAL RELEVANCE: This work represents a true cost-of-operating comparison between open and MIS approaches for lumbar spine fusion, which has relevance to surgeons, hospitals and payers in medical decision-making.

OBJECTIVE: To provide evidence-based recommendations and expert guidance for the management of systemic polyarteritis nodosa (PAN). METHODS: Twenty-one clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for systemic, non-hepatitis B-related PAN. Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel. RESULTS: We present 16 recommendations and 1 ungraded position statement for PAN. Most recommendations were graded as conditional due to the paucity of evidence. These recommendations support early treatment of severe PAN with cyclophosphamide and glucocorticoids, limiting toxicity through minimizing long-term exposure to both treatments, and the use of imaging and tissue biopsy for disease diagnosis. These recommendations endorse minimizing risk to the patient by using established therapy at disease onset and identify new areas where adjunctive therapy may be warranted. CONCLUSION: These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and imaging for patients with PAN.

The effects of prostaglandin F2 alpha (PGF2 alpha) on intracellular Ca2+ concentration ([Ca2+]i) and inositol phosphate (IP) generation in human myometrial cells were evaluated and compared to the effects of oxytocin. Basal [Ca2+]i levels were 146 and 153 nM in the absence and presence of 1 mM extracellular Ca, respectively. In Ca-containing medium, both PGF2 alpha and oxytocin significantly (P less than 0.01) increased [Ca2+]i over control values, eliciting half-maximal stimulation (ED50) at 4 and 1 nM, respectively. In Ca-free medium the potency of PGF2 alpha to raise [Ca2+]i was drastically reduced (ED50, 2 microM), whereas that of oxytocin remained the same, although maximal responses were markedly decreased. PGF2 alpha had no effect on total IP production in the concentration range that significantly raised [Ca2+]i. However, at a 100 times higher concentration (10 microM), PGF2 alpha produced a maximum 48% increase in total IP, with a rapid (15-30 s) rise in IP3 and IP2, followed by IP1. A similar increase in IP production was obtained when [Ca2+]i levels were raised by A23187 to the same level as that obtained with 10-50 microM PGF2 alpha. The effect of PGF2 alpha was dependent on extracellular Ca and could be suppressed by verapamil, but not by pertussis toxin, or phorbol ester. In contrast, the potencies of oxytocin to raise IP and [Ca2+]i were similar and independent of extracellular Ca2+, and could be suppressed by pertussis toxin and phorbol ester, but not by verapamil. These data provide evidence that in isolated human myometrial cells, PGF2 alpha and oxytocin trigger an increase in [Ca2+]i by different mechanisms. The action of PGF2 alpha depends on extracellular Ca2+, whereas oxytocin activates the G-protein-dependent phospholipase-C-IP3-Ca2+ signal-transducing pathway, complemented by the influx of extracellular Ca2+.

Only 25% of boys with acute scrotal swelling have testicular torsion. A noninvasive test that reliably distinguishes torsed testes from all other acute scrotal conditions would benefit patients presenting with pain and swelling of the scrotum. Recent reports suggest that color Doppler ultrasound may be the long-awaited test that clearly differentiates testes with compromised blood flow from all other conditions. However, we report on 2 patients with positive blood flow on color Doppler ultrasonography who subsequently were found at surgery to have testicular torsion. Inability to distinguish normal testes and normal epididymis on physical examination is still the best indicator to proceed with surgical exploration in pediatric patients with acute scrotal swelling.

Cruzipain, the major cysteinyl proteinase of Trypanosoma cruzi, is expressed by all developmental forms and strains of the parasite and stimulates potent humoral and cellular immune responses during infection in both humans and mice. This information suggested that cruzipain could be used to develop an effective T. cruzi vaccine. To study whether cruzipain-specific T cells could inhibit T. cruzi intracellular replication, we generated cruzipain-reactive CD4(+) Th1 cell lines. These T cells produced large amounts of gamma interferon when cocultured with infected macrophages, resulting in NO production and decreased intracellular parasite replication. To study the protective effects in vivo of cruzipain-specific Th1 responses against systemic T. cruzi challenges, we immunized mice with recombinant cruzipain plus interleukin 12 (IL-12) and a neutralizing anti-IL-4 MAb. These immunized mice developed potent cruzipain-specific memory Th1 cell responses and were significantly protected against normally lethal systemic T. cruzi challenges. Although cruzipain-specific Th1 responses were associated with T. cruzi protective immunity in vitro and in vivo, adoptive transfer of cruzipain-specific Th1 cells alone did not protect BALB/c histocompatible mice, indicating that additional immune mechanisms are important for cruzipain-specific immunity. To study whether cruzipain could induce mucosal immune responses relevant for vaccine development, we prepared recombinant attenuated Salmonella enterica serovar Typhimurium vaccines expressing cruzipain. BALB/c mice immunized with salmonella expressing cruzipain were significantly protected against T. cruzi mucosal infection. Overall, these data indicate that cruzipain is an important T. cruzi vaccine candidate and that protective T. cruzi vaccines will need to induce more than CD4(+) Th1 cells alone.

Congenital diaphragmatic hernia complicating pregnancy is a rarity, accounting for only six out of 17 cases of diaphragmatic hernia reported in the English literature. This case report describes the first successful repair of an acutely symptomatic foramen of Bochdalek hernia during pregnancy, with maternal and fetal survival. In the asymptomatic patient, surgery should be performed promptly on an elective basis in the first and second trimesters. During the third trimester, an asymptomatic defect should be repaired at the time of elective cesarean section. Active labor should be avoided. If symptoms of obstruction arise, this lesion represents a true surgical emergency, and immediate operative intervention should be undertaken regardless of the stage of pregnancy. Delay can result in both fetal and maternal mortality in up to half of cases. Tube gastrostomy may be performed at the time of repair to avert a potential prolonged gastric ileus and gastric volvulus.

This phase II study to determine the safety and efficacy of denileukin diftitox (DD) and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) enrolled patients with newly diagnosed peripheral T-cell lymphoma (PTCL). Forty-nine received DD 18 μg/kg/day (days 1, 2) with CHOP (day 3) every 21 days for ≤ 6–8 cycles. Intent-to-treat (ITT) and safety populations comprised all patients. In the ITT population, the overall response rate was 65%, median duration of response was 30 months and median progression-free survival was 12 months. Median overall survival was not attained at the end of the study, and the overall survival rate was 63.3%. The two most frequent treatment-related adverse events (AEs) were fatigue and nausea. Most frequent AEs ≥ grade 3 within the hematologic system were lymphopenia (24.5%), neutropenia (20.4%) and leukopenia (18.4%). Three treatment-related deaths occurred. DD plus CHOP was well tolerated, and progression-free and overall survival improved versus historical comparison with CHOP alone. Confirmation in larger trials is warranted.

Two cases of primary linitis plastica of the large intestine will be presented and discussed. Characteristic clinical features of this type of adenocarcinoma of the large intestine include younger age of presentation, low incidence of hepatic metastasis and a high incidence of ovarian, lymph node and peritoneal metastasis. Pathological features reveal thickening of the intestinal wall by diffuse infiltrating tumor cells of the characteristic signet ring cells, abortive glands and undifferentiated or anaplastic cells. The prognosis is poor.

The intraaortic balloon pump is usually the first mechanical device inserted for perioperative cardiac failure; however, little current information is available regarding short- and long-term effectiveness. From January 1983 through November 1990, 6856 adult patients underwent cardiac surgical procedures, 580 of whom (8.5%) had an intraaortic balloon inserted preoperatively (107 patients), intraoperatively (419 patients), or postoperatively (54 patients). There were 374 men and 206 women with a mean age of 63.9 years (range 19 to 88). Operations included 376 coronary artery bypass grafts, 100 mitral valve replacements (with or without bypass grafting), 70 aortic valve replacements (with or without bypass grafting), 15 double valve replacements (with or without bypass grafting), and 32 other procedures. There were 72 (12.4%) complications related to the balloon pump, of which 42 necessitated surgical intervention including thrombectomy (21), vascular repair (13), fasciotomy (2), aortic repair (1), and amputation (4). Operative mortality for patients supported by the balloon pump was 44%. Multivariate stepwise analysis of 27 parameters revealed six independent predictors of mortality: preoperative New York Heart Association class, transthoracic intraaortic balloon insertion (both p < 0.0001), preoperative administration of intravenous nitroglycerin, age, female gender, and preoperative balloon insertion (p < 0.001). Balloon-related complications were not predictive of death. Of the 326 hospital survivors, only 34 were lost to follow-up. There were 75 late deaths, the cause of which was cardiac in 41 (55%), noncardiac in 20 (27%), and unknown in 14 (19%). Actuarial survivals at 1, 5, and 9 years are 51%, 42%, and 33%. Of the 217 hospital survivors still alive and contacted, 81% were in class I (114) or II (60). These data demonstrate (1) operative mortality for patients requiring an intraaortic balloon in the perioperative period remains high, (2) perioperative risk factors can be identified, (3) complications related to the balloon pump do not affect survival, (4) operative survivors can achieve prolonged survival with excellent functional results, and (5) consideration for alternative methods of circulatory support is justified.

Bacterial products are thought to induce labor by stimulating the production of pro-inflammatory cytokines and prostaglandins in gestational tissues, leading to the onset of preterm parturition. Progesterone withdrawal is a prerequisite of parturition in many species. Yet a role for progesterone in the mechanisms responsible for preterm parturition, in the setting of infection, is unclear. The current studies were conducted to determine if a fall in serum progesterone concentrations occurs before the onset of bacterial product-induced preterm parturition in animals. Accordingly, pregnant mice at day 15 (70% gestation) were injected i.p. with Escherichia coli lipopolysaccharide (LPS; 50 microg/mouse) and timed-pregnant rabbits were inoculated transcervically with a suspension of E. coli to cause an ascending intrauterine infection. Control animals in both groups received equal volumes of sterile phosphate-buffered saline (PBS) solution. Blood specimens were collected at regular intervals and serum progesterone levels were determined by RIA. Within 14 h of LPS administration, mice delivered their pups. The median concentrations of serum progesterone were significantly lower at 1 h, 4 h, 10 h, and at the onset of preterm parturition (11-12 h) after LPS injection, compared to that in animals given PBS. Similarly, E. coli-inoculated rabbits delivered 1-2 days posttranscervical inoculation and demonstrated 60% decrease in serum progesterone within 12-24 h of inoculation compared to those given PBS. Parturition in both control groups occurred at term, following typical progesterone withdrawal. It is concluded that LPS administration to pregnant mice and ascending intrauterine infection in pregnant rabbits is associated with a dramatic fall in serum progesterone concentrations prior to the onset of parturition.

PURPOSE: To explore the safety and tolerability of combining two epigenetic drugs: decitabine (a DNA methyltransferase inhibitor) and panobinostat (a histone deacetylase inhibitor), with chemotherapy with temozolomide (an alkylating agent). The purpose of such combination is to evaluate the use of epigenetic priming to overcome resistance of melanoma to chemotherapy. METHODS: A Phase I clinical trial enrolling patients aged 18 years or older, with recurrent or unresectable stage III or IV melanoma of any site. This trial was conducted with full Institutional Review Board approval and was registered with the National Institutes of Health under the clinicaltrials.gov identifier NCT00925132. Patients were treated with subcutaneous decitabine 0.1 or 0.2 mg/kg three times weekly for 2 weeks (starting on day 1), in combination with oral panobinostat 10, 20, or 30 mg every 96 h (starting on day 8), and oral temozolomide 150 mg/m(2)/day on days 9 through 13. In cycle 2, temozolomide was increased to 200 mg/m(2)/day if neutropenia or thrombocytopenia had not occurred. Each cycle lasted 6 weeks, and patients could receive up to six cycles. Patients who did not demonstrate disease progression were eligible to enter a maintenance protocol with combination of weekly panobinostat and thrice-weekly decitabine until tumor progression, unacceptable toxicity, or withdrawal of consent. RESULTS: Twenty patients were initially enrolled, with 17 receiving treatment. The median age was 56 years. Eleven (65%) were male, and 6 (35%) were female. Eleven (64.7%) had cutaneous melanoma, 4 (23.5%) had ocular melanoma, and 2 (11.8%) had mucosal melanoma. All patients received at least one treatment cycle and were evaluable for toxicity. Patients received a median of two 6-week treatment cycles (range 1-6). None of the patients experienced DLT. MTD was not reached. Adverse events attributed to treatment included grade 3 lymphopenia (24%), anemia (12%), neutropenia (12%), and fatigue (12%), as well as grade 2 leukopenia (30%), neutropenia (23%), nausea (23%), and lymphopenia (18%). The most common reason for study discontinuation was disease progression. CONCLUSIONS: This triple agent of dual epigenetic therapy in combination with traditional chemotherapy was generally well tolerated by the cohort and appeared safe to be continued in a Phase II trial. No DLTs were observed, and MTD was not reached.

PURPOSE: To develop a new quantitative global kinetic breast magnetic resonance imaging (MRI) features analysis scheme and assess its feasibility to assess tumor response to neoadjuvant chemotherapy. MATERIALS AND METHODS: A dataset involving breast MR images acquired from 151 cancer patients before neoadjuvant chemotherapy was used. Among them, 63 patients had complete response (CR) and 88 had partial response (PR) to chemotherapy based on the RECIST criterion. A computer-aided detection (CAD) scheme was applied to segment breast region depicted on the breast MR images and computed a total of 10 kinetic image features to represent parenchyma enhancement either from the entire two breasts or the bilateral asymmetry between the two breasts. To classify between CR and PR cases, we tested an attribution selected classifier that integrates with an artificial neural network and a Wrapper Subset Evaluator. The classifier was trained and tested using a leave-one-case-out (LOCO)-based cross-validation method. The area under a receiver operating characteristic curve (AUC) was computed to assess classifier performance. RESULTS: From the pool of initial 10 features, four features were selected by more than 90% times in the LOCO cross-validation iterations. Among them, three represent the bilateral asymmetry of kinetic features between two breasts. Using the classifier yielded AUC = 0.83 ± 0.04, which is significantly higher than using each individual feature to classify between CR and PR cases (P < 0.05). CONCLUSION: This study demonstrated that quantitative analysis of global kinetic features computed from breast MRI-acquired prechemotherapy has potential to generate a useful clinical marker that is associated with tumor response to neoadjuvant chemotherapy. J. Magn. Reson. Imaging 2016;44:1099-1106.