IgE blockade with omalizumab reduces pruritus related to immune checkpoint inhibitors and anti-HER2 therapies.

BACKGROUND: Immunoglobulin E (IgE) blockade with omalizumab has demonstrated clinical benefit in pruritus-associated dermatoses (e.g. atopic dermatitis, bullous pemphigoid, urticaria). In oncology, pruritus-associated cutaneous adverse events (paCAEs) are frequent with immune checkpoint inhibitors (CPIs) and targeted anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we sought to evaluate the efficacy and safety of IgE blockade with omalizumab in cancer patients with refractory paCAEs related to CPIs and anti-HER2 agents. PATIENTS AND METHODS: Patients included in this multicenter retrospective analysis received monthly subcutaneous injections of omalizumab for CPI or anti-HER2 therapy-related grade 2/3 pruritus that was refractory to topical corticosteroids plus at least one additional systemic intervention. To assess clinical response to omalizumab, we used the Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was defined as reduction in the severity of paCAEs to grade 1/0. RESULTS: A total of 34 patients (50% female, median age 67.5 years) received omalizumab for cancer therapy-related paCAEs (71% CPIs; 29% anti-HER2). All had solid tumors (29% breast, 29% genitourinary, 15% lung, 26% other), and most (n = 18, 64%) presented with an urticarial phenotype. In total 28 of 34 (82%) patients responded to omalizumab. The proportion of patients receiving oral corticosteroids as supportive treatment for management of paCAEs decreased with IgE blockade, from 50% to 9% (P < 0.001). Ten of 32 (31%) patients had interruption of oncologic therapy due to skin toxicity; four of six (67%) were successfully rechallenged following omalizumab. There were no reports of anaphylaxis or hypersensitivity reactions related to omalizumab. CONCLUSIONS: IgE blockade with omalizumab demonstrated clinical efficacy and was well tolerated in cancer patients with pruritus related to CPIs and anti-HER2 therapies.

The Use Of Dermal Regeneration Templates For Primary Burns Surgery In A UK Regional Burns Centre.

The gold standard of treatment for major burns is early burn excision and autografting. In major burns this is complicated by a lack of donor site availability. Another challenge after burn injury is achieving optimal cosmetic and functional outcomes. Dermal regeneration templates (DRT) are biomatrices that help to address these problems. Within our centre the most commonly used are two-stage Integra® and single-stage Matriderm®. We review the use and outcomes of DRT in primary burns reconstruction within our regional burns centre. All patients undergoing primary burn reconstruction using Integra® (n=59) or Matriderm® (n=35) over a 13-year period were included. Integra® was used in patients with significantly larger burns (20.4% TBSA vs 1.7% TBSA). Comparable levels of graft take were seen in both groups. Major infections were significantly higher in the Integra® group (11/35 compared to 3/59). There was no significant difference in haematoma development, hypertrophic scarring or the need for secondary reconstructive surgery. Burn contractures developed in 15 patients treated with Matriderm® and 21 with Integra®. DRT have been used safely and effectively and have played an increasingly important role in our service over the last 13 years. Integra® is used primarily in large burns with limited donor sites and Matriderm® in smaller burns in cosmetically sensitive areas.

Le traitement de référence des brûlures graves est l'excision précoce et la greffe autologue. Dans ces brûlures graves, ce traitement peut s'avérer difficile par le manque de disponibilité de sites donneurs. De plus, l'obtention de résultats satisfaisants tant sur le plan cosmétique que fonctionnel est un véritable challenge dans les suites de brûlures. Les matrices dermiques (DRT) sont des biomatériaux qui peuvent aider à résoudre ces problèmes. Dans notre centre, les matrices le plus souvent utilisées sont Integra® double couche et Matriderm ®. Nous avons étudié l'utilisation des matrices dermiques et leurs résultats dans la chirurgie primaire des brûlures dans notre centre de traitement des brûlures de province. Tous les patients ayant bénéficié d'une chirurgie primaire pour brûlure par Integra® (n=59) et par Matriderm® (n=35) dans les 13 dernières années ont été inclus. Integra® a été utilisé pour des patients présentant des brûlures significativement plus étendues (20,4% TBSA vs 1,7% TBSA). Le taux de prise des greffes est comparable dans les deux groupes. Les infections sévères sont plus élevées de façon significative dans le groupe traité par Integra® (11/59 contre 3/35). Il n'y a pas de différence significative en ce qui concerne les hématomes, l'évolution hypertrophique des cicatrices ou la nécessité de chirurgie secondaire. Des rétractions cicatricielles sont apparues chez 15 patients traités par Matriderm® et chez 21 patients traités par Integra®. L'utilisation des matrices dermiques nous semble sûre et utile et a été largement développée ces 13 dernières années dans notre centre. Integra® est utilisé en chirurgie primaire pour les brûlures très étendues où les sites donneurs font défaut alors que Matriderm® est utilisé pour les brûlures de petite surface à enjeu fonctionnel et cosmétique.

Outpatient dermatology consultations for oncology patients with acute dermatologic adverse events impact anticancer therapy interruption: a retrospective study.

BACKGROUND: Dermatologic adverse events (dAEs) of anticancer therapies may negatively impact dosing and quality of life. While therapy interruption patterns due to dAEs have been studied in hospitalized cancer patients, similar outcomes in outpatient oncodermatology are lacking. OBJECTIVES: To analyse the therapy interruption patterns, clinico-histopathologic characteristics and management outcomes of outpatient dermatology consultations for acute dAEs attributed to the most frequently interrupted class of oncologic agents. METHODS: We performed a retrospective cohort study of all cancer patients who received a same-day outpatient dermatology consultation for acute dAEs at our institution from 1 January to 30 June 2015. Relevant data were abstracted from electronic medical records, including demographics, oncologic history and explicit recommendations by both the referring clinician and consulting dermatologist on anticancer therapy interruption. Consultations with the most frequently interrupted class of oncologic treatment were characterized according to clinico-histopathologic features, dermatologic management and clinical outcomes. RESULTS: There were 426 same-day outpatient dermatology consultations (median age 59, 60% female, 30% breast cancer), of which 295 (69%) had systemic anticancer therapy administered within 30 days prior. There was weak inter-rater agreement between referring clinicians and consulting dermatologists on interruption of anticancer treatment (n = 150, κ = 0.096; 95% CI -0.02 to 0.21). Seventy-three (25%) consultations involved interruption by the referring clinician, most commonly targeted therapy (24, 33%). Maculopapular rash was commonly observed in 23 consultations with 25 dAEs attributed to targeted agents (48%), and topical corticosteroids were most frequently utilized for management (22, 38%). The majority (83%) of consultations with targeted therapy-induced dAEs responded to dermatologic treatment and 84% resumed oncologic therapy, although three (19%) at a reduced dose. Rash recurred only in two instances (13%). CONCLUSIONS: A high frequency of positive outcomes in the management of targeted therapy-induced dAEs by outpatient consulting dermatologists and low recurrence of skin toxicity suggests impactful reductions in interruption of anticancer therapy.

Urethral Sphincter Mechanism Incompetence in 163 Neutered Female Dogs: Diagnosis, Treatment, and Relationship of Weight and Age at Neuter to Development of Disease.

BACKGROUND: Urethral sphincter mechanism incompetence (USMI) is the most common cause of urinary incontinence in neutered bitches and is most common in dogs weighing >20 kg. OBJECTIVES: To describe a population of neutered bitches with USMI and investigate their initial presentation, the relationship between weight and age at neuter, and treatment. ANIMALS: One hundred and sixty-three female dogs with USMI (UI) diagnosed between January 2009 and December 2012, and 193 continent neutered control (C) bitches. METHODS: Retrospective data were collected from neutered female dogs with USMI and healthy, continent neutered females presented between January 2009 and December 2012. RESULTS: Urinary incontinent dogs weighed more than C dogs (P = .003), and there was no difference in age at neuter. The relationship between weight at diagnosis and age at neuter was found to impact the hazard of USMI. A decrease in the hazard of USMI was found in dogs weighing >25 kg for every month delay of neuter in the first year. The hazard did not change for dogs <15 kg. Median time from neuter to development of incontinence was 3.73 years. Phenylpropanolamine was prescribed in 75.5%, diethylstilbestrol in 21.5%, and both in 3.1% of dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Neutering bitches expected to be >25 kg adult weight later in their first year may decrease the hazard of developing USMI, whereas age at neutering of bitches <25 kg may not impact continence. Heavier dogs have increased risk of USMI, and onset occurs within a few years of neuter.

Health-related quality of life in patients who develop bronchiolitis obliterans syndrome following allo-SCT.

Bronchiolitis obliterans syndrome (BOS) remains an important complication following allo-SCT. The development of this condition portends a higher morbidity and mortality but the effect on heath-related quality of life (HRQL) is unknown. The aim of this study was to determine whether the development of BOS impacted HRQL compared with patients without BOS. This Institutional Review Board-approved prospective study analyzed 126 patients who underwent allo-SCT at our institution. Patients were administered three HRQL survey tools (SF-36, European Organization for Research and Treatment of Cancer QLQ-c30 and St George Respiratory Questionnaire (SGRQ)) before transplant and then again at 6 months, 1 year and 2 years after transplant. Patients were analyzed in three groups determined by highest chronic GVHD (cGVHD) severity and BOS status. Overall, our study group had improving HRQL after transplant when measured over time, measured by the SF-36 with stable HRQL, when measured by the SGRQ total score and QLQ-c30. Patients that developed BOS had significantly worse HRQL scores measured by the SGRQ and the SF-36 physical composite score. This difference was not explained by the severity of cGVHD that patients with BOS developed.

Outcomes following percutaneous upper gastrointestinal decompressive tube placement for malignant bowel obstruction in ovarian cancer.

OBJECTIVE: The objective of this study was to evaluate peri-operative and survival outcomes of ovarian cancer patients undergoing percutaneous upper gastrointestinal decompression for malignant bowel obstruction (MBO). METHODS: Retrospective chart review was used to identify patients with ovarian, peritoneal, or fallopian tube cancer who underwent palliative decompressive treatment for MBO from 1/2002 to 12/2010. Kaplan-Meier methods were used to estimate the median survival (MS) and multivariate analysis used to determine if any variables were associated with the hazard of death. RESULTS: Fifty-three patients met inclusion criteria. Median length of diagnosis prior to intervention was 21 months. Fifteen (28.3%) patients experienced complications and 9 required revision. Forty-nine (92.5%) experienced relief of symptoms after placement, and 91% tolerated some form of oral intake. Following placement, 19 (36%) patients received additional chemotherapy and 21(41%) patients received total parental nutrition (TPN). Thirty-five patients were discharged home/outpatient facility, 16 to hospice care, and 2 died prior to discharge. MS for all patients was 46 days. Patients who received chemotherapy had a MS of 169 days compared to 33 days (p<0.001). We failed to find an association between survival and TPN or performance status. CONCLUSIONS: Malignant bowel obstruction is a common complication of ovarian cancer. Management is palliative; risks and benefits of any therapy must be considered. Percutaneous decompressive therapy provides relief from associated symptoms, and allows patients to be discharged home. Median survival in this group is limited, and decisions regarding aggressive therapy should be individualized.

Polymerase chain reaction-based microsatellite polymorphism analysis of follicular and Hürthle cell neoplasms of the thyroid.

Follicular and Hürthle cell carcinomas of the thyroid cannot be differentiated from adenomas by either preoperative fine needle aspiration or intraoperative frozen section examination, and yet there exist potentially significant differences in the recommended surgical management. We examined, by PCR-based microsatellite polymorphism analysis, DNA obtained from 83 thyroid neoplasms [22 follicular adenomas, 29 follicular carcinomas, 20 Hürthle cell adenomas (HA), and 12 Hürthle cell carcinomas (HC)] to determine whether a pattern of allelic alteration exists that could help distinguish benign from malignant lesions. Alterations were found in only 7.5% of informative PCR reactions from follicular neoplasms, whereas they were found in 23.3% of reactions from Hürthle cell neoplasms. Although there were no significant differences between follicular adenoma and follicular carcinoma, HC demonstrated a significantly greater percentage of allelic alteration than HA on chromosomal arms 1q (P < 0.001) and 2p (P < 0.05) by Fisher's exact test. The documentation of an alteration on either 1q or 2p was 100% sensitive and 65% specific in the detection of HC (P < 0.0005, by McNemar's test). In conclusion, PCR-based microsatellite polymorphism analysis may be a useful technique in distinguishing HC from HA. Potentially, the application of this technique to aspirated material may allow this distinction preoperatively and thus facilitate more optimal surgical management. Consistent regions of allelic alteration may also indicate the locations of critical genes, such as tumor suppressor genes or oncogenes, that are important in the progression from adenoma to carcinoma. Finally, this study demonstrates that Hürthle cell neoplasms, now considered variants of follicular neoplasms, differ significantly from follicular neoplasms on a molecular level.

Splenic abscess: another look at an old disease.

OBJECTIVE: To study the changes in the incidence, causes, bacteriologic profile, and management of a splenic abscess. DESIGN: Retrospective case study. SETTING: Tertiary, university referral center. PATIENTS: Thirty-nine patients with a splenic abscess. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Demographics, signs and symptoms, causes, risk factors, diagnostic methods, bacteriologic profile, treatment, and outcome. RESULTS: Patients presented at a mean age of 43 years (range, 2-83 years), after a mean symptomatic period of 16 days, with fever (69%), abdominal pain (56%), nausea and vomiting (38%), and splenomegaly (31%). The majority of abscesses represented metastatic infection (n=19), and 11 were secondary to immunosuppression. Twelve patients had human immunodeficiency virus disease and 9 used intravenous drugs. In patients who underwent computed tomography, all had abnormal scans (n=33), with a well-defined abscess(es) in 28. Nine abscesses were polymicrobial; monomicrobial isolates included gram-positive organisms (23%), gram-negative organisms (31%), fungi (23%), and mycobacteria (23%). Patients presenting before 1989 (1981-1988) (n=15) and those presenting after 1989 (1989-1996) (n=24) differed in risk factors (intravenous drug abuse, 0% vs 47% [P=.02]; hematologic malignancy, 43% vs 9% [P=.04]) and gram-positive isolates (18% vs 64%; P=.06). Patients underwent splenectomy (n=18), open drainage (n=4), medical therapy (n=10), or percutaneous drainage (n=5) with respective survival rates of 94%, 50%, 70%, and 100%. CONCLUSIONS: In 1996, splenic abscesses are increasingly common. Intravenous drug abuse and human immunodeficiency virus disease are significant risk factors, and the diagnosis should be considered in a patient with fever and abdominal pain who uses intravenous drugs. Antimicrobial agents should be broad since 36% of abscesses were polymicrobial, and should include coverage of gram-positive organisms.

Polymerase chain reaction-based microsatellite analysis of fine-needle aspirations from Hürthle cell neoplasms.

Fine-needle aspiration (FNA) of the thyroid is the sine qua non in the preoperative evaluation of thyroid nodules. Despite this, cytological examination of FNA cannot differentiate malignant from benign Hürthle cell neoplasms. We have previously shown that Hürthle cell carcinomas harbor more genetic alterations on chromosomal arms 1q and 2p than Hürthle cell adenomas, and that all Hürthle cell neoplasms have a significantly higher frequency of alterations on chromosomal arm 1p compared with normal thyroid. To determine if these genetic alterations could be detected in FNA samples, we examined DNA from FNAs that were available from eight Hürthle cell neoplasms. Polymerase chain reaction (PCR) amplification of DNA demonstrated either direct correlation with alterations seen in the tumor samples or in some instances, additional chromosomal alterations. We conclude that PCR-based microsatellite DNA analysis of preoperative FNA samples from Hürthle cell neoplasms can potentially distinguish Hürthle cell carcinomas from adenomas and that with further validation and perfection, this technique may allow more optimal surgical management of patients with these lesions.

A comparison of the reliability of repeat cervical smears and colposcopy in patients with abnormal cervical cytology.

BACKGROUND: To determine the reliability of repeat cervical smears (Papanicolaou smears) in patients who have had an abnormal initial smear, prospective data were collected on patients being followed up for a previously abnormal cervical smear. METHODS: All 428 patients who were referred for colposcopy because of abnormal cervical smears underwent simultaneous cervical smears and coloposcopy with directed biopsy. Patients with colposcopic evidence of invasive carcinoma or a history of prior colposcopy were excluded. Cervical smear results were compared with the histologic findings on colposcopically directed biopsy. The ability of cervical smears to identify cervical intraepithelial neoplasia (CIN) and high-grade lesions (CIN 2 and 3) were also calculated for the repeat cervical smear. RESULTS: The sensitivity of repeat Papanicolau screening for CIN was 48%. When differentiating high-grade lesions from low-grade and benign biopsies, the sensitivity of the repeat cervical smear was only 25%. Of 110 patients with biopsy-proven high-grade lesions, 68% had low-grade initial cervical smears and 73% had low-grade or benign repeat cervical smear cytology. CONCLUSIONS: This study demonstrates that repeated Pap smears often fail to identify high-grade lesions and that the sensitivity of a repeat cervical smear is very low in patients with low-grade abnormalities found on routine screening examinations. Using follow-up cervical smears to monitor patients who have low-grade squamous intraepithelial lesions (LGSIL) carries unacceptable risks. A more reliable diagnostic test such as colposcopy is indicated.

Neuromodulation of guinea pig intestinal electrolyte transport by cholecystokinin octapeptide.

We examined the effect of cholecystokinin octapeptide on electrolyte transport across isolated guinea pig mucosa. Segments of distal ileum stripped of longitudinal muscle and bathed on both sides with a Krebs'-bicarbonate buffer responded to cholecystokinin octapeptide when studied under short-circuited conditions. Cholecystokinin octapeptide (0.5-50 nmol/L) evoked a transient (4-10-minute) increase in transepithelial potential difference and short-circuit current upon application to the serosal side. Maximal increases in short-circuit current, achieved at 50-500 nmol/L, were 67 +/- 11 microA/cm2, whereas half-maximal effects occurred at a concentration of 0.7 +/- 0.2 nmol/L. Pretreatment of the tissues with 0.5 mumol/L atropine reduced the maximal short-circuit response to cholecystokinin octapeptide by 53%. The change in short-circuit current due to cholecystokinin octapeptide was nearly abolished by pretreatment with 0.5 mumol/L tetrodotoxin, suggesting neuronal involvement. Cholecystokinin octapeptide-induced increases in short-circuit current were halved by removal of serosal buffer Ca2+ and were abolished in Cl(-)- and HCO3(-)-free buffer. The cholecystokin-receptor antagonists proglumide and lorglumide shifted the concentration-response curve for cholecystokinin octapeptide competitively to the right, having antagonists potencies of 130 and 0.03 mumol/L, respectively. Cerulein (0.1-500 nmol/L) also increased short-circuit current, whereas nonsulfated cholecystokinin octapeptide was ineffective. In conclusion, cholecystokinin octapeptide seems to act at neuronal cholecystokinin receptors to stimulate mucosal anion secretion, in part, by releasing acetylcholine.