Comparative study of dexamethasone premedication regimens with docetaxel chemotherapy in early HER-2 positive breast cancer: A safety net hospital experience.

INTRODUCTION: Docetaxel can cause fluid retention reactions (FRRs) and hypersensitivity reactions (HSRs). The manufacturer recommends a multi-day oral dexamethasone premedication to prevent these toxicities, but steroid related side effects and regimen compliance remain a concern. This study aimed to determine if modified dexamethasone premedication regimens resulted in differences in HSRs or FRRs to docetaxel. We also examined side effects of dexamethasone and delays in chemotherapy. METHODS: A retrospective chart review was conducted on 82 early breast cancer patients treated with docetaxel. Three steroid regimens were examined: IV 20 mg single-dose dexamethasone, or IV 12 mg dexamethasone with either dexamethasone 8 mg BID for three days starting the day before chemotherapy or dexamethasone 4 mg BID for three days following chemotherapy. Adverse effects, delays in chemotherapy, and reasons for delays in chemotherapy were recorded. RESULTS: The incidence and severity of FRRs and HSRs was low, with less than 10% incidence of HSRs or FRRs in any group. Delays were most common in the group receiving dexamethasone 8 mg BID for 3 days starting the day before chemotherapy (63.3%) (p < 0.05) and were most commonly due to patient noncompliance (26%). CONCLUSION: A single dose of intravenous dexamethasone alone or followed by lower doses of oral dexamethasone may improve patient compliance and avoid delays in chemotherapy, without an increase in docetaxel toxicity.

Triple pass laser therapy for recalcitrant facial port wine stains.

Patients with recalcitrant facial port wine stains (rfPWS) can be challenging to manage, often leaving the clinician with difficult decisions for treatment options. 'Triple therapy' consists of using three different laser wavelengths at each treatment setting. The evidence on outcomes is limited as this treatment approach has not been previously reported to the best of our knowledge. Children who received triple therapy at least once for rfPWS, and for whom SIAscopy readings had been taken, were retrospectively identified. SIAscope readings were compared before the first triple therapy treatment and at final the most recent clinical follow-up. The clinical appearance was also assessed using a Visual Analogue Scale comparing clinical photographs taken before triple therapy to those taken at the most recent clinical follow-up. A total of 47 children were identified and included in our review. The SIAscope readings showed an overall significant (p < 0.001) lightening with 39 (83%) showing lightening and 8 (17%) patients showing a darkening. Scores using the VAS also showed improvement with 55% experiencing an improvement in their clinical appearance, 38% showing no visible change and 6% appearing to have worsened. Triple therapy can offer improvement of rfPWS which have failed to respond to single wavelength laser therapy. SIAscopy and VAS scores correlate well in assessing clinical response; however, the added clinical benefit of SIAscopy in vascular laser clinics remains uncertain.

Clinicopathological Features and Outcomes in Individuals with Breast Cancer and ATM, CHEK2, or PALB2 Mutations.

INTRODUCTION: The moderate-penetrance germline mutations ATM, CHEK2, and PALB2 are implicated in an increased risk of the development of breast cancer. Whether these mutations provide clinical utility to guide treatment strategies and prognosis remains unknown. METHODS: A retrospective case-control study from a tertiary institution compared patients with stage 0-III breast cancer, and positive for ATM, CHEK2, or PALB2 mutations, with a matched cohort selected by randomization and negative for mutations. Data acquisition included demographics, histopathologic, treatment, and clinical outcome variables. RESULTS: A total of 145 patients with breast cancer (144 female and 1 male) were analyzed-74 mutation-positive patients (24 ATM, 26 CHEK2, 24 PALB2) and 71 mutation-negative patients. Mutation-positive patients compared with mutation-negative patients had increased family history of breast cancer (79.7 vs. 52.9%, p < 0.001) and tumor size > 2.0 cm (63.1% vs. 42.3%, p = 0.015). Patients with prior knowledge of mutational status were more likely to proceed with total mastectomy and prophylactic mastectomy (74.5% vs. 25.5%, p < 0.02; and 65.5% vs. 34.5%, p < 0.001, respectively). The unadjusted recurrence rate was higher in mutation-positive patients compared with mutation-negative patients (24.3 vs. 8.5%, p = 0.01), although mutation status was not predictive for recurrence in Cox regression analysis. CONCLUSIONS: Patients positive for ATM, CHEK2, or PALB2 mutations had increased tumor size and were more likely to undergo extensive surgeries. Mutation status was not predictive of recurrence, although this lack of effect may have been mitigated by lower rates of recurrence in those who pursued total mastectomy. Further studies are needed to confirm these findings.

Multidisciplinary Teams Improve Gastric Cancer Treatment Efficiency at a Large Safety Net Hospital.

BACKGROUND: Gastric cancer treatment initiation is a complex process. Inefficiencies in care coordination can lead to significant delays, which are often more prominent at safety net hospitals. Multidisciplinary teams (MDTs) have been proposed as an effective solution. METHODS: A retrospective review of sequential gastric cancer patients receiving treatment at Parkland Hospital (Dallas, TX) between 2013 and 2015 was performed before (n = 50) and after (n = 50) creation of a MDT and standardized care pathways. Patients undergoing urgent resection were excluded. Time to treatment (TTT) from initial endoscopy to initiation of chemotherapy was evaluated. The number of diagnostic tests performed and treatment variability also were compared. RESULTS: Groups were similar in terms of age, sex, stage distribution, tumor location, and type of presentation (outpatient vs. emergency room). Post-intervention, TTT decreased from 84.1 ± 12.3 to 32.5 ± 15.2 days (p < 0.02). This decrease was primarily related to parallel performance of subspecialty evaluations, staging studies, and procedures. MDT review reduced the number of unnecessary staging tests performed, leading to a decrease in the average number of studies from 3.8 per patient to 2.2 (p < 0.05). Use of diagnostic laparoscopy in patients with clinically locally advanced disease increased from 18 to 94% (p < 0.05). CONCLUSIONS: Creation of a gastric cancer MDT and uniform care pathways at a large safety net hospital expedited initiation of treatment, reduced unnecessary tests, and promoted consistent patient management.

Atypical capillary malformations with subsequent diplegia: A difficult case of capillary malformation-arteriovenous malformation syndrome.

Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is a rare condition associated with mutations in the genes RASA1 and EPHB4. We present a challenging case of CM-AVM in a 17-month-old boy with permanent diplegia from an undiagnosed arteriovenous malformation underlying a large atypical capillary malformation over the lower thoracic spine. This case demonstrates that clinicians should have a low threshold for neuroimaging in the context of new neurologic symptoms in patients with atypical capillary malformations.

Transgenic expression of the human MRP2 transporter reduces cisplatin accumulation and nephrotoxicity in Mrp2-null mice.

The chemotherapeutic drug cisplatin is actively transported into proximal tubules, leading to acute renal injury. Previous studies suggest that the multidrug resistance-associated protein 2 (Mrp2) transporter may efflux cisplatin conjugates from cells. We sought to determine whether the absence of Mrp2 alters the accumulation and toxicity of platinum in the kidneys of mice and whether transgenic expression of the human MRP2 gene could protect against cisplatin injury in vivo. Plasma, kidneys, and livers from vehicle- and cisplatin-treated wild-type and Mrp2-null mice were collected for quantification of platinum and toxicity. By 24 hours, twofold higher concentrations of platinum were detected in the kidneys and livers of Mrp2-null mice compared with wild types. Enhanced platinum concentrations in Mrp2-null mice were observed in DNA and cytosolic fractions of the kidneys. Four days after cisplatin treatment, more extensive proximal tubule injury was observed in Mrp2-null mice compared with wild-type mice. Kidneys from naive Mrp2-null mice had elevated glutathione S-transferase mRNA levels, which could increase the formation of cisplatin-glutathione conjugates that may be metabolized to toxic thiol intermediates. Transgenic expression of the human MRP2 gene in Mrp2-null mice reduced the accumulation and nephrotoxicity of cisplatin to levels observed in wild-type mice. These data suggest that deficiency in Mrp2 lowers platinum excretion and increases susceptibility to kidney injury, which can be rescued by the human MRP2 ortholog.

GNAQ/GNA11 Mosaicism Is Associated with Abnormal Serum Calcium Indices and Microvascular Neurocalcification.

Mosaic mutations in genes GNAQ or GNA11 lead to a spectrum of diseases including Sturge-Weber syndrome and phakomatosis pigmentovascularis with dermal melanocytosis. The pathognomonic finding of localized "tramlining" on plain skull radiography, representing medium-sized neurovascular calcification and associated with postnatal neurological deterioration, led us to study calcium metabolism in a cohort of 42 children. In this study, we find that 74% of patients had at least one abnormal measurement of calcium metabolism, the commonest being moderately low serum ionized calcium (41%) or high parathyroid hormone (17%). Lower levels of ionized calcium even within the normal range were significantly associated with seizures, and with specific antiepileptics despite normal vitamin D levels. Successive measurements documented substantial intrapersonal fluctuation in indices over time, and DEXA scans were normal in patients with hypocalcemia. Neurohistology from epilepsy surgery in five patients revealed not only intravascular, but perivascular and intraparenchymal mineral deposition and intraparenchymal microvascular disease in addition to previously reported findings. Neuroradiology review clearly demonstrated progressive calcium deposition in individuals over time. These findings and those of the adjoining paper suggest that calcium deposition in the brain of patients with GNAQ/GNA11 mosaicism may not be a nonspecific sign of damage as was previously thought, but may instead reflect the central postnatal pathological process in this disease spectrum.

RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation.

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal-dominant disorder, caused by heterozygous RASA1 mutations, and manifesting multifocal CMs and high risk for fast-flow lesions. A limited number of patients have been reported, raising the question of the phenotypic borders. We identified new patients with a clinical diagnosis of CM-AVM, and patients with overlapping phenotypes. RASA1 was screened in 261 index patients with: CM-AVM (n = 100), common CM(s) (port-wine stain; n = 100), Sturge-Weber syndrome (n = 37), or isolated AVM(s) (n = 24). Fifty-eight distinct RASA1 mutations (43 novel) were identified in 68 index patients with CM-AVM and none in patients with other phenotypes. A novel clinical feature was identified: cutaneous zones of numerous small white pale halos with a central red spot. An additional question addressed in this study was the "second-hit" hypothesis as a pathophysiological mechanism for CM-AVM. One tissue from a patient with a germline RASA1 mutation was available. The analysis of the tissue showed loss of the wild-type RASA1 allele. In conclusion, mutations in RASA1 underscore the specific CM-AVM phenotype and the clinical diagnosis is based on identifying the characteristic CMs. The high incidence of fast-flow lesions warrants careful clinical and radiologic examination, and regular follow-up.

The Utility of Breast Cancer Index (BCI) Over Clinical Prognostic Tools for Predicting the Need for Extended Endocrine Therapy: A Safety Net Hospital Experience.

INTRODUCTION: Extended endocrine therapy (EET) benefits select patients with early-stage hormone-receptor positive (HR+) breast cancer (BC) but also incurs side effects and cost. The Clinical Treatment Score at Five Years (CTS5) is a free tool that estimates risks of late relapse in estrogen-receptor positive (ER+) BC using clinicopathologic factors. The Breast Cancer Index (BCI) incorporates 2 genomic assays to estimate late relapse risk and likelihood of benefit from EET. This retrospective study assesses the utility of BCI in selecting EET candidates in a safety net hospital. MATERIALS AND METHODS: We performed a retrospective chart review on 69 women with early-stage HR+, HER2- BC diagnosed at our institution from December 2009 to February 2016 on whom BCI was submitted. The CTS5 score was also calculated to assess clinical risk of late relapse. RESULTS: Median age was 53 years. All patients included in our analysis had early ER+ HER2-negative BC. Roughly half of the patients (55%) were postmenopausal and 61% were of Hispanic origin. A total of 34 patients (49%) were deemed high-risk (>5%) for late relapse by CTS5, compared to 42 (61%) by BCI. BCI identified 31 (45%) patients that would benefit from EET and of those, 74%% were advised EET. 16 (47%) clinical high-risk patients were advised against EET due to low benefit predicted by BCI. In the clinical low risk group, 9 (26%) were recommended EET based on high benefit predicted by BCI. CONCLUSION: BCI is reasonable to consider in early-stage HR+ BC and offered clinically relevant information over clinical pathologic information alone.

Phase I, pharmacokinetic and biological correlative study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, and cisplatin in patients with solid tumors.

PURPOSE: To evaluate the safety and describe the pharmacokinetic profile of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, in combination with cisplatin (CDDP) in adults with advanced solid tumors. EXPERIMENTAL DESIGN: CDDP was administered as a 2-h intravenous infusion followed by OSI-7904L intravenously over 30 min, both given every 3 weeks. Doses of each drug were escalated in separate cohorts of patients. Five dose levels of CDDP/OSI-7904L were explored: 60/6, 60/9, 60/12, 60/7.5, and 75/7.5 mg/m2. Pharmacokinetic samples, baseline plasma homocysteine, and genotype polymorphisms were evaluated. RESULTS: Twenty-seven patients were treated with 101 total courses of CDDP/OSI-7904L. Dose-limiting toxicity was observed in 2 patients in the CDDP/OSI-7904L 60/12 mg/m2 cohort. One patient experienced rash, stomatitis, dehydration, renal failure, hyperbilirubinemia, and fatal neutropenic sepsis, whereas the other patient experienced grade 3 nausea, vomiting, and ileus. Therefore, the CDDP/OSI-7904L 60/9 mg/m2 cohort was expanded, with 2 of 6 patients reporting significant fatigue. Other toxicities were mild or moderate. Intermediate dose levels of 60/7.5 and 75/7.5 mg/m2 were evaluated, and the latter was identified as the recommended dose for phase II studies. No major pharmacokinetic interactions between CDDP and OSI-7904L were observed. Three patients had partial responses (gastric adenocarcinoma and heavily pretreated breast cancer). There was no significant relationship between baseline homocysteine and toxicity. CONCLUSIONS: The recommended doses for CDDP and OSI-7904L administered once every 3 weeks are 75 and 7.5 mg/m2, respectively. Pharmacokinetic interaction between the agents was not apparent. Preliminary clinical activity was observed in breast and gastric cancer.

Pulse Dye Laser Therapy Successful for Elastosis Perforans Serpiginosa.

BACKGROUND: We describe a case of elastosis perforans serpiginosa and its successful management with PDL laser. CASE PRESENTATION: A 15-year-old male presented with a history of itchy, raised, red and unsightly lesions on the back of his neck. He was diagnosed with Elastosis Perforans Serpiginosa on tissue biopsy and underwent pulse dye laser therapy over four years with excellent results. CONCLUSIONS: Our results show that pulse dye laser therapy is a safe and effective treatment for elastosis perforans serpiginosa.

Diagnosis and management of children with Blue Rubber Bleb Nevus Syndrome: A multi-center case series.

BACKGROUND: Blue Rubber Bleb Nevus Syndrome (BRBNS) is a rare, severe, sporadically occurring disorder characterized by multiple venous malformations. AIMS: To present and analyze a case series of pediatric patients with BRBNS and to describe diagnostic approaches and management options applied. PATIENTS AND METHODS: Multicenter, retrospective study, evaluating the diagnosis and management of children with BRBNS. RESULTS: Eighteen patients diagnosed with BRBNS were included. Cutaneous venous malformations were observed in 78% and gastrointestinal venous malformations in 89%. Lesions were also found in other organs including muscles, joints, central nervous system, eyes, parotid gland, spine, kidneys and lungs. Gastrointestinal lesions were more common in the small intestine than in stomach or colon. The management varied significantly among centers. Endoscopic therapy and surgical therapy alone failed to prevent recurrence of lesions. In younger children and in patients with musculoskeletal or other organ involvement, sirolimus was used with 100% success rate in our series (5 patients treated) although poor compliance with subtherapeutic sirolimus trough levels led to recurrence in a minority. CONCLUSIONS: Considering the multi-organ involvement in BRBNS, diagnosis and management requires a multidisciplinary approach. The treatment includes conservative, medical, endoscopic and surgical options. Prospective multicenter studies are needed to identify the optimal management of this rare condition.

A Phase I Clinical Trial of the Phosphatidylserine-targeting Antibody Bavituximab in Combination With Radiation Therapy and Capecitabine in the Preoperative Treatment of Rectal Adenocarcinoma.

OBJECTIVES: There is interest in improving the tumoricidal effects of preoperative radiotherapy for rectal carcinoma by studying new radiosensitizers. The safety and toxicity profile of these combination regimens needs rigorous clinical evaluation. The primary objective of this study was to evaluate the toxicity of combining bavituximab, an antibody that targets exposed phosphatidylserine, with capecitabine and radiation therapy. MATERIALS AND METHODS: Patients with stage II or III rectal adenocarcinoma were enrolled on a phase I study combining radiation therapy, capecitabine, and bavituximab. A standard 3+3 trial designed was used. RESULTS: In general, bavituximab was safe and well tolerated in combination with radiation therapy and capecitabine in the treatment of rectal adenocarcinoma. One patient at the highest dose level experienced a grade III infusion reaction related to the bavituximab. One tumor demonstrated a complete pathologic response to the combination treatment. CONCLUSIONS: Bavituximab is safe in combination with capecitabine and radiation therapy at the doses selected for the study. Further clinical investigation would be necessary to better define the efficacy of this combination.

Phase I and pharmacokinetic study of tasidotin hydrochloride (ILX651), a third-generation dolastatin-15 analogue, administered weekly for 3 weeks every 28 days in patients with advanced solid tumors.

PURPOSE: To determine the safety, tolerability, and pharmacokinetics and to seek preliminary evidence of anticancer activity of tasidotin (ILX651), a novel dolastatin analogue, when administered as a 30-minute i.v. infusion weekly for 3 weeks every 4 weeks. EXPERIMENTAL DESIGN: Thirty patients with advanced solid malignancies were treated with 82 courses at six dose levels ranging from 7.8 to 62.2 mg/m2 weekly, initially according to an accelerated dose-escalation scheme, which evolved into a Fibonacci scheme as a relevant degree of toxicity was observed. Plasma and urine were sampled to characterize the pharmacokinetic behavior of tasidotin. RESULTS: A high incidence of neutropenia complicated by fever (one patient), or precluding treatment on day 15 (three patients), was the principal toxicity of tasidotin, at doses above 46.8 mg/m2. At all dose levels, nonhematologic toxicities were generally mild to moderate and manageable. Grade 3 toxicities included diarrhea and vomiting (one patient each). Drug-induced neurosensory symptoms were mild and there was no evidence of cardiovascular toxicity, which has been previously associated with other dolastatins. Tasidotin pharmacokinetics were mildly nonlinear, whereas metabolite kinetics were linear. A patient with non-small cell lung carcinoma experienced a minor response, and a patient with hepatocellular carcinoma had stable disease lasting 11 months. CONCLUSIONS: The recommended dose for phase II studies of tasidotin administered on this schedule is 46.8 mg/m2. The mild myelosuppression and manageable nonhematologic toxicities at the recommended dose, the evidence of antitumor activity, and the unique mechanistic aspects of tasidotin warrant further disease-directed evaluations on this and alternative schedules.

Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.

Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.

Bilateral facial capillary malformation associated with eye and brain abnormalities.

OBJECTIVE: To establish whether the prognosis of bilateral facial capillary malformation (BFCM) is worse compared with that of unilateral facial port-wine stain. DESIGN: Retrospective study. SETTING: Paediatric Dermatology Department, Great Ormond Street Hospital for Children NHS Trust, a tertiary referral center for vascular anomalies. PATIENTS: A cohort of 350 children who presented with facial CM was seen between January 1, 1994, and June 30, 2004. Twenty-seven children with BFCM were identified. A control group of 27 children with unilateral CM was randomly selected from the total cohort. MAIN OUTCOME MEASURES: Demographic, clinical, and radiographic characteristics were recorded and compared between the 2 groups: age at presentation, sex, distribution, extension, extrafacial lesions, glaucoma, ipsilateral leptomeningeal angiomatosis, and epilepsy. The recorded information was collected from the database of the Paediatric Dermatology Department, the hospital records, and the patients' photographs. RESULTS: Compared with the 27 children with unilateral facial CM, the 27 with BFCM showed a higher frequency of association with extrafacial lesions (17 [63%] vs 6 [22%]), glaucoma (21 [78%] vs 2 [7%]), and ipsilateral leptomeningeal angiomatosis (14 [52%] vs 2 [7%]). All patients who had BFCM with bilateral and complete involvement of the ophthalmic area had ipsilateral leptomeningeal angiomatosis. CONCLUSION: Patients with BFCM must be considered as a group with a worse prognosis compared with patients with unilateral facial CM.