Eosinophilic Esophagitis in Children: Endoscopic Findings at Diagnosis and Post-intervention.

PURPOSE OF REVIEW: The goal of this review is to present and summarize studies on endoscopic findings in eosinophilic esophagitis (EoE), at diagnosis and in response to treatment, utilizing rigorous peer-reviewed literature in children wherever possible and to introduce a recently proposed standardized endoscopic evaluation system. RECENT FINDINGS: Gold standard of diagnosis and assessment of response to therapy in EoE requires multiple endoscopies with biopsies for histology, which allows for observation of the esophageal mucosa. Typical endoscopic findings in patients with EoE include edema, exudate, furrowing, concentric rings, and strictures. Endoscopic findings have been broadly characterized into inflammatory features (edema, exudate, furrowing) and fibro-stenotic features (rings, stricture), in order to better reflect their underlying pathophysiology. Recent studies suggest strong correlations between endoscopic findings, through composite scoring systems, and histology, and therefore may be helpful as part of disease surveillance. The EoE Endoscopic Reference Score (EREFS) classification system was proposed in 2013 as an outcome metric for standardization in reporting endoscopic signs of EoE. Subsequent studies support utility of composite scoring, which utility has similarly been seen in pediatric treatment trials. Endoscopy in children provides insight into the natural history of EoE, with progressively more fibro-stenotic features occurring over time, giving an additional perspective into esophageal remodeling and response to treatment. Recognition of typical endoscopic findings at diagnosis and upon repeat endoscopy has allowed a clinician to monitor visual changes in esophageal mucosal health. Further studies to assess the role of composite scoring in disease management are needed.

Association of the postoperative white blood cells (WBC) count in peripheral blood after radical surgical treatment of left upper lobe non-small cell lung cancer (NSCLC) with overall survival - single center results.

INTRODUCTION: The individual patient prognosis after radical surgery for Non-small cell lung cancer (NSCLC) of left upper lobe remains still unclear. The purpose of this study is to evaluate the predictive value of elevated white blood cell count in peripheral blood as early indicator of postoperative NSCLC prognosis. METHODS: A retrospective statistical analysis was performed studying patients subject to radical treatment of left upper lobe NSCLC in period of five years with subsequent one to three-year monitoring of morbidity and mortality of the patient population. The statistical ROC (Receiver Operating Characteristic) analysis of the WBC count in peripheral blood third day after the operation was used to evaluate the relationship with overall survival, with respect to patients surviving for at least 24 months. RESULTS: Based on the results of the ROC analysis with a total area under the curve (AUC) of 0.67, it is possible to confirm that the WBC count established third day after the operation allows us to classify patients into groups according to the 24-month overall survival. CONCLUSION: Our findings confirm the potential of using WBC count to improve current protocols to establish postoperative prognosis for NSCLC of the upper left lobe (Tab. 2, Fig. 1, Ref. 11).

IgE-associated food allergy alters the presentation of paediatric eosinophilic esophagitis.

BACKGROUND: Links between food allergens and eosinophilic esophagitis (EoE) have been established, but the interplay between EoE- and IgE-associated immediate hypersensitivity to foods remains unclear. OBJECTIVE: We sought to determine the prevalence of IgE-associated food allergy at the time of diagnosis of EoE in children and to determine whether differences existed in presentation and disease compared to subjects with EoE alone. METHODS: Eosinophilic esophagitis patients were stratified based on the diagnosis of IgE-associated immediate hypersensitivity (EoE + IH vs. EoE-IH). Clinical, histologic, pathologic, and endoscopic differences were investigated using a retrospective database. RESULTS: We found that 29% of the 198 EoE patients in our cohort had EoE + IH. These subjects presented at a younger age than those without IH (6.05 vs. 8.09 years, P = 0.013) and were more likely to have comorbid allergic disease. Surprisingly, the EoE + IH group presented with significantly different clinical symptoms, with increased dysphagia, gagging, cough, and poor appetite compared to their counterparts in the EoE-IH group. Male gender, allergic rhinitis, the presence of dysphagia, and younger age were independently associated with having EoE + IH. Specific IgE levels to common EoE-associated foods were higher in EoE + IH, regardless of eliciting immediate hypersensitivity symptoms. In contrast, IgE levels for specific foods triggering EoE were relatively lower in both the groups than IgE levels for immediate reactions. CONCLUSIONS AND CLINICAL RELEVANCE: Immediate hypersensitivity is common in children with EoE and identifies a population of EoE patients with distinct clinical characteristics. Our study describes a subtype of EoE in which IgE-mediated food allergy may impact the presentation of paediatric EoE.

Histopathology of drug rash with eosinophilia and systemic symptoms syndrome: a morphological and phenotypical study.

BACKGROUND: The histopathological features of drug rash with eosinophilia and systemic symptoms (DRESS) syndrome remain poorly characterized. OBJECTIVES: To better characterize the histopathological features of DRESS syndrome, and define the phenotype of the effector cells in the skin and compare it with maculopapular rash (MPR). METHODS: We conducted a retrospective study on 50 skin biopsies from patients with DRESS syndrome (n = 36). Histopathological and immunophenotypical features were studied and compared with a series of MPRs (n = 20). RESULTS: Foci of interface dermatitis, involving cutaneous adnexae, were frequently seen in cases of DRESS. Eosinophils were seen in only 20% of cases and neutrophils in 42%. Eczematous (40%), interface dermatitis (74%), acute generalized exanthematic pustulosis-like (20%) and erythema multiforme-like (24%) patterns were observed. The association of two or three of these patterns in a single biopsy was significantly more frequent in cases of DRESS than in a series of nondrug-induced dermatoses (P < 0.01), and appeared to be more marked in DRESS syndrome with severe cutaneous lesions (P = 0.01) than in less severe cases of DRESS and MPR. A higher proportion of CD8(+) and granzyme B(+) lymphocytes was observed in cases of DRESS with severe cutaneous eruptions (erythroderma and/or bullae). Atypical lymphocytes were found in 28% of biopsies, and expressed CD8 in most cases; a cutaneous T-cell clone was rarely found (6%). CONCLUSIONS: The histopathology of DRESS syndrome highlights various associated inflammatory patterns in a single biopsy. Cutaneous effector lymphocytes comprise a high proportion of polyclonal CD8(+) granzyme B(+) T lymphocytes.

Frequency and prognostic value of cutaneous molecular residual disease in mycosis fungoides: a prospective multicentre trial of the Cutaneous Lymphoma French Study Group.

BACKGROUND: Monoclonal T-cell receptor (TCR) rearrangement is detected in 57-75% of early-stage mycosis fungoides (MF) at diagnosis. A retrospective study showed molecular residual disease (MRD) in 31% of patients in complete clinical remission (CR) after 1 year of treatment. OBJECTIVES: To confirm the frequency of MRD at 1 year and to determine its prognostic value for further relapse. METHODS: Patients with T1-, T2- or T4-stage MF were prospectively included in this multicentre study. At diagnosis, clinical lesions and healthy skin were biopsied. After 1 year of topical treatment, previously involved skin of patients in CR was biopsied for histology and analysis of TCR-γ gene rearrangement. The results were compared with the clinical status each year for 4 years. RESULTS: We included 214 patients, 133 at T1, 78 at T2 and three at T4 stage. At diagnosis, 126 of 204 cases (61·8%) showed TCR clonality in lesional skin. After 1 year, 83 of 178 patients (46·6%) still being followed up were in CR and 13 of 63 (21%) showed MRD. At 4 years, 55 of 109 patients (50·5%) still being followed up were in CR and 44 of 109 (40·4%) were in T1 stage. MRD did not affect clinical status at 4 years (CR vs. T1/T2, P = 1·0; positive predictive value 36·4%; negative predictive value 67·6%). CONCLUSIONS: T-cell clonality at diagnosis and MRD at 1 year are not prognostic factors of clinical status at 4 years.

[Metachronous lung metastases of mammary carcinoma, or dual malignancy? a surgeons and oncologists point of view case report]. / Metachronní plicní metastázy mamárního karcinomu nebo duplexní malignita? Pohled chirurga a onkologa kazuistika.

Synchronous and metachronous metastases significantly diminish the possibility of remission from cancer. Therefore, therapy needs to be highly effective and strictly individualised. The authors present a case report of a female patient after radical mastectomy due to breast cancer with incidental detection of peripheral lung carcinoid. The aim of the case report is to inform about current trends in primary lung carcinoid therapy through a surgeons and oncologists point of view.

Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients.

BACKGROUND: BRAF inhibitors are being developed for the treatment of metastatic melanoma harboring a V600E mutation. The use of vemurafenib significantly increases progression-free survival (PFS) and overall survival (OS) in this population of patients, but is associated with numerous adverse skin reactions. PATIENTS AND METHODS: We carried out a systematic dermatologic study of 42 patients treated with vemurafenib. We collected detailed dermatologic symptoms, photos and biopsy specimens of the skin lesions which enabled us to classify the side-effects. The management and evolution of the skin symptoms are also reported. RESULTS: All patients presented with at least one adverse skin reaction. The most common cutaneous side-effects consisted in verrucous papillomas (79%) and hand-foot skin reaction (60%). Other common cutaneous toxic effects were a diffuse hyperkeratotic perifollicular rash (55%), photosensitivity (52%) and alopecia (45%). Epidermoid cysts (33%) and eruptive nevi (10%) were also observed. Keratoacanthomas (KA) and squamous cell carcinoma (SCC) occurred in 14% and 26% of the patients, respectively. CONCLUSIONS: These cutaneous side-effects are cause of concern due to their intrinsic potential for malignancy or because of their impact on patients' quality of life. Management of this skin toxicity relies on symptomatic measures and sun photoprotection.

Anaphylactic responses to histamine in mice utilize both histamine receptors 1 and 2.

BACKGROUND: Anaphylaxis is a severe, potentially life-threatening reaction that can occur in response to common triggers, including food allergens (e.g., peanut), insect stings, and several medications. Activation of mast cells and basophils to release preformed mediators, such as histamine, is thought to be an important process that underlies reactions. Histamine can exert effects through four different receptors, termed H1R-H4R. Despite clinical use of both H1R and H2R blockers in the therapy for acute allergic reactions, there is little mechanistic evidence to support the necessity for blocking H2R, a receptor best characterized for its role in stomach acid production. METHODS: Here, we sought to define the necessity for histamine receptors in the pathology of anaphylaxis using H1R and H2R knockout (KO) mice, as well as a H1R/H2R double KO strain. RESULTS: In response to IgE-mediated systemic anaphylaxis, the symptoms and decreases in core body temperature observed in wild-type mice were reduced but not ablated in either H1R or H2R KO. In contrast, H1R/H2R KO were significantly protected and were indistinguishable from histamine-deficient mice. Intravenous injection of histamine was sufficient to elicit these responses, and similar to IgE-mediated anaphylaxis, loss of both H1R and H2R was necessary for complete protection. CONCLUSION: Our data demonstrate definitively that both H1R and H2R participate in the immediate systemic responses during histamine-associated pathophysiology and mechanistically support the utility of H2R-blocking therapeutics in alleviating symptoms of anaphylaxis.

A homozygous insertion-deletion in the type VII collagen gene (COL7A1) in Hallopeau-Siemens dystrophic epidermolysis bullosa.

The Hallopeau-Siemens type of recessive dystrophic epidermolysis bullosa (HS-RDEB) is a life-threatening autosomal disease characterized by loss of dermal-epidermal adherence with abnormal anchoring fibrils (AF). We recently linked HS-RDEB to the type VII collagen gene (COL7A1) which encodes the major component of AF. We describe a patient who is homozygous for an insertion-deletion in the FN-4A domain of the COL7A1 gene. This defect causes a frameshift mutation which leads to a premature stop codon in the FN-5A domain, resulting in a marked diminution in mutated mRNA levels, with no detectable type VII collagen polypeptide in the patient. Our data suggest strongly that this null allele prevents normal anchoring fibril formation in homozygotes and is the underlying cause of HS-RDEB in this patient.

[Polydipsia, increasing fatigue and a huge mediastinal tumor in a 49-year-old woman]. / Polydipsie, zunehmende Müdigkeit und große mediastinale Raumforderung bei einer 49-jährigen Patientin.

A 49-year-old woman presented with unspecific symptoms including polydipsia, increasing fatigue for several weeks, and vague abdominal pain. Serum calcium (5.30 mmol/l; normal range 2.00-2.60) and parathyroid hormone levels (> 2500.0 ng/l; normal range 15.0-68.0) were extremely elevated. Imaging studies showed a huge mediastinal tumor. Based on these findings a hypercalcemic crisis caused by primary hyperparathyroidism was diagnosed. After intensive care treatment and further diagnostic procedures, the patient's parathyroid adenoma was removed by parathyroidectomy. The postoperative course was uneventful.

Multicenter evaluation of an interdisciplinary 52-week weight loss program for obesity with regard to body weight, comorbidities and quality of life--a prospective study.

OBJECTIVES: To determine the effectiveness of a structured multidisciplinary non-surgical obesity therapy program on the basis of a temporary low-calorie-diet for 12 weeks, and additional intervention modules to enhance nutritional education, to increase physical activity and to modify eating behavior. DESIGN: Prospective multicenter observational study in obese individuals undergoing a medically supervised outpatient-based 52-week treatment in 37 centers in Germany. SUBJECTS: A total of 8296 participants with a body mass index (BMI) of >30 kg m(-2) included within 8.5 years. MEASUREMENTS: Main outcome measures were body weight loss, waist circumference (WC), blood pressure, quality of life and adverse events. RESULTS: In females, initial body weight was reduced after the 1-year-intervention by 19.6 kg (95% confidence intervals 19.2-19.9 kg) and in males by 26.0 kg (25.2-26.8) according to per protocol analysis of 4850 individuals. Intention-to-treat (ITT) analysis revealed a weight reduction of 15.2 kg (14.9-15.6) in females and 19.4 kg (18.7-20.1) in males. Overall, the intervention resulted in mean reduction in WC of 11 cm; it reduced the prevalence of the metabolic syndrome by 50% and the frequency of hypertension from 47 to 29% of all participants (ITT, all P<0.001). The beneficial effects could be documented for up to 3 years and comprised significant improvement of health-related quality of life. The incidence of adverse effects was low; the only event repeatedly observed and possibly related to either the intervention or the underlying disease was biliary disorders. CONCLUSION: The present non-surgical intervention program is a highly effective treatment of obesity grades I-III and obesity-related diseases, and therefore, could be a valuable basis for future weight maintenance strategies required for sustained success.

[Wound microbial sampling methods in surgical practice, imprint techniques]. / Metody odberu vzorku na kultivacní vysetrení v chirurgické praxi, otiskové metody.

The wound is a damage of tissue. The process of healing is influenced by many systemic and local factors. The most crucial and the most discussed local factor of wound healing is infection. Surgical site infection in the wound is caused by micro-organisms. This information is known for many years, however the conditions leading to an infection occurrence have not been sufficiently described yet. Correct sampling technique, correct storage, transportation, evaluation, and valid interpretation of these data are very important in clinical practice. There are many methods for microbiological sampling, but the best one has not been yet identified and validated. We aim to discuss the problem with the focus on the imprint technique.

[Severe necrotizing myopathy subsequent to Merkel cell carcinoma]. / Myopathie nécrosante sévère consécutive à un carcinome à cellules de Merkel.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare tumour with a poor prognosis. Rare cases of paraneoplastic neurological syndrome have been associated with this type of tumour, namely myasthenic syndrome of Lambert-Eaton and encephalomyelitis. We report the first case of severe necrotizing myopathy with anti-Hu antibodies complicating MCC. CASE REPORT: We describe the case of a 58-year-old woman with Merkel cell carcinoma (MCC) of the forearm complicated by severe necrotizing myopathy associated with the presence of anti-Hu antibodies. This myopathy occurred 3 months after complete remission of MCC. The patient was treated with high-dose corticosteroids combined with two intravenous infusions of immunoglobulins. Her neurological status deteriorated despite this treatment. Pararaneoplastic syndrome (anti-Hu antibodies, necrotizing myopathy) complicating MCC was suspected. There was no visible tumour relapse. After multidisciplinary discussion, it was decided to supplement treatment with chemotherapy (carboplatin and VP-16). The patient died 20 days after the first course of chemotherapy. DISCUSSION: Severe necrotizing myopathy with anti-Hu antibodies may be added to the list of possible paraneoplastic syndromes associated with Merkel cell carcinoma.

The spectrum of histopathological features in acute generalized exanthematous pustulosis: a study of 102 cases.

BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is a rare severe pustular reaction pattern with a typical clinical picture. OBJECTIVES: To characterize the histopathological features of AGEP in a large series of cases with a validated diagnosis. METHODS; A multinational retrospective histopathological study was conducted. It included 102 hospitalized patients (recruited within the EuroSCAR and RegiSCAR studies) with a validated diagnosis of probable or definite AGEP. A systematic description of the histopathological features in AGEP was done based on a standardized grading system. RESULTS: Sub/intracorneal pustules (41%), intraepidermal pustules (20%) or combinations of them (38%) were observed in 102 cases. The pustules were usually large (> 15 keratinocytes) (82% and 89%, respectively) and regularly contained eosinophils (36% and 32%, respectively). Spongiform features were less prominent in the sub/intracorneal pustules compared with the intraepidermal pustules (44% and 95%, respectively). The main epidermal features were necrotic keratinocytes (67%), including incidental segmental necrosis (7%), and spongiosis (80%) with neutrophil exocytosis (77%). The main dermal features were papillary oedema (88%) and mixed superficial (100%), interstitial (93%), and mid/deep-dermal infiltrates (95%) containing neutrophils (100%) and eosinophils (81%). Follicular pustules were also seen (23%), but vasculitis generally was absent. Classical features of plaque-type psoriasis were infrequent and usually mild. No significant differences were observed between a subgroup of 16 cases with and 86 cases without psoriasis. CONCLUSIONS: The present histopathological study concerns a large series of cases with a validated diagnosis of AGEP. It provides diagnostic clues in favour of AGEP in patients with a pustular eruption.

[Rare tumors of the gallbladder and bile ducts. A case review]. / Vzácné tumory zlucníku a zlucových cest. Kazuistika.

The authors deal with the problem of benigh tumours of the bile duct which might occur as a very suprising intraoperative finding instead of preoperatively diagnosed "gallstones". This situation can happen because of possible mistakes that might accompany today's modern practical investigative techniques. The presented report is an example of the pre-operatirely assumed choledocholithiasis which was not confirmed during the operation. Instead a rare bile duct tumour was found.

[Wells' cellulitis and bacterial necrotizing cellulitis induced by anakinra]. / Cellulite de Wells et dermohypodermite bactérienne nécrosante induites par l'anakinra.

BACKGROUND: Anakinra is a recombinant form of the naturally occurring human interleukin-1 receptor antagonist. It is used in the treatment of rheumatoid arthritis. The most frequent side effects are injection site reactions, which seem to have a toxic mechanism. PATIENTS AND METHODS: We report two unusual cases of injection site reactions with anakinra: a woman presented Wells' cellulitis of the thigh and a man developed serious bacterial cellulitis distinguished by deep necrosis at the site of the latest anakinra subcutaneous injection. DISCUSSION: The cases are examples of serious side effects that can occur during treatment with anakinra and underline the need for careful use of this new biological agent.

[Robotic procedures in the colorectal surgery]. / Robotické výkony v kolorektální chirurgii.

PURPOSE: The da Vinci surgical system (Intuitive Surgical, Sunnyvale, CA, USA) was developed specifically to compensate the technical limitations of laparoscopic instruments, such as two-dimensional vision, misalignment of hands and instruments, limited dexterity of instruments inside the patient, and fixed instrument tips. The da Vinci system provides a stable camera platform, three-dimensional imaging, excellent ergonomics, tremor elimination, ambidextrous capability, motion scaling, and instruments with multiple degrees of freedom. METHODS: These advantages can be applied in the field of colorectal surgery, and that's why we are reporting 45 cases that underwent robotic colorectal surgery. We concluded that the da Vinci system may be useful in surgical procedures, such as splenic flexure takedown, dissection of the inferior mesenteric artery with identification of the nervous plexus, and dissection of a narrow pelvis. The major drawbacks of robotic systems are high cost, and a lack of tactile sensation and tensile feedback to the surgeon, who must depend on visual cues to estimate the tension exerted on tissue by the robotic arms. RESULTS: In conclusion, robotic colorectal surgery can be performed safely and effectively, using the da Vinci surgical system, because this system has more dexterity and flexibility than conventional laparoscopic instruments. However, prospective randomized studies are necessary to evaluate the preservation of sexual and voiding function, as well as the oncological and functional (pelvic floor disorders) outcomes of this approach.

[The liquid biopsies: What is their contribution to the management of cancer?] / Les biopsies liquides : quel est leur apport en oncologie ?

The « liquid biopsies ¼ are samples of liquids such as blood, urine, spinal fluid that can contain tumor material. Clinical assays have been mainly focused on the peripheral blood containing circulating tumor cells and circulating tumor DNA. The circulating tumor cells are cancer cells released from the primary tumor or recurrences or metastases. They enter into the bloodstream after passing through the vessel wall. It is possible to analyze the circulating tumor cells by means of all cytologic and biomolecular techniques. The free circulating tumor DNA is made of fragments of DNA released by living or necrotic tumor cells proceeded from any place of the organism. The free circulating tumor DNA and DNA from circulating tumor cells show structural rearrangements among which some are therapeutic targets. Many studies showed that circulating tumor cells and circulating tumor DNA analyses are useful in revealing recurrences and tracking therapeutic targets.

Histamine drives severity of innate inflammation via histamine 4 receptor in murine experimental colitis.

Ulcerative colitis (UC) patients exhibit elevated histamine, but how histamine exacerbates disease is unclear as targeting histamine 1 receptor (H1R) or H2R is clinically ineffective. We hypothesized that histamine functioned instead through the other colon-expressed histamine receptor, H4R. In humans, UC patient biopsies exhibited increased H4R RNA and protein expression over control tissue, and immunohistochemistry showed that H4R was in proximity to immunopathogenic myeloperoxidase-positive neutrophils. To characterize this association further, we employed both the oxazolone (Ox)- and dextran sulfate sodium (DSS)-induced experimental colitis mouse models and also found upregulated H4R expression. Mast cell (MC)-derived histamine and H4R drove experimental colitis, as H4R-/- mice had lower symptom scores, neutrophil-recruitment mediators (colonic interleukin-6 (IL-6), CXCL1, CXCL2), and mucosal neutrophil infiltration than wild-type (WT) mice, as did MC-deficient KitW-sh/W-sh mice reconstituted with histidine decarboxylase-deficient (HDC-/-) bone marrow-derived MCs compared with WT-reconstituted mice; adaptive responses remained intact. Furthermore, Rag2-/- × H4R-/- mice had reduced survival, exacerbated colitis, and increased bacterial translocation than Rag2-/- mice, revealing an innate protective antibacterial role for H4R. Taken together, colonic MC-derived histamine initiates granulocyte infiltration into the colonic mucosa through H4R, suggesting alternative therapeutic targets beyond adaptive immunity for UC.