Management of non-tubal ectopic pregnancies analysis of a large tertiary center case series.

PURPOSE: Ectopic pregnancies include cesarean scar (CSP), cornual and cervical pregnancies. Various treatment modalities have been- described, but no standardized procedure has been defined so far. The aim of our analysis was to evaluate the diagnostics and treatment at the Department of Obstetrics and Gynecology, LMU University Hospital, Munich. METHODS: In this retrospective, single-center analysis, 24 patients treated between 2015 and 2020 were analyzed. After verification of the diagnosis by imaging and HCG-analysis, the treatment was individually determined: therapy with methotrexate (MTX) locally with or without simultaneous systemic treatment, surgical treatment via curettage, excision with uterine reconstruction even hemi hysterectomy. RESULTS: Ten patients presented with CSP, six with cervical and eight with cornual pregnancies. Median age was 34.6 years. CSP was treated with local MTX in six cases; five required additional treatment with systemic MTX or curettage. Primary curettage or surgery was performed in four cases. In cervical pregnancies the primary therapy with local MTX injection and systemic treatment was performed in 50%. One patient was treated with MTX and insertion of a Bakri balloon. Trachelectomy was required in one case. 50% of cornual pregnancies were treated with MTX locally and intramuscularly and 50% received surgery. CONCLUSION: Treatment strategies were based on the patient's individual risk parameters. The results of this study show, that simultaneous treatment with local and systemic MTX had good outcomes and could avoid surgeries.

Risk of target non-attainment in obese compared to non-obese patients in calculated linezolid therapy.

OBJECTIVES: The aim was to characterize linezolid population pharmacokinetics in plasma and interstitial space fluid of subcutaneous adipose tissue (target site) of obese compared with non-obese patients and to determine dosing regimens enabling adequate therapy using Monte Carlo simulations. METHODS: In this prospective, parallel group, open-label, controlled, single-centre trial, 30 surgery patients (15 obese, 15 non-obese) received 600 mg of intravenous linezolid. A population pharmacokinetic analysis characterizing plasma and microdialysis-derived target site pharmacokinetics was followed by Monte Carlo simulations using twice/thrice daily 600-1200 mg short-term and extended infusions of linezolid. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic target attainment for time and exposure-related indices. RESULTS: In the model, lean body weight and obesity status largely explained between-patient variability in linezolid PK parameters (12.0-44.9%). Both factors caused lower area under the concentration-time curve in typical obese patients in plasma (-20.4%, 95% CI -22.0% to -15.9%) and at target-site (-37.7%, 95% CI -47.1% to -24.2%) compared with non-obese patients. Probability of target attainment showed improvement with increasing linezolid doses. Depending on lean body weight, adequate therapy was partially attained for 900- and 1200-mg linezolid doses and minimum inhibitory concentrations (MICs) ≤2 mg/L (probability of target attainment 62.5-100%) but could not be reached for MIC = 4 mg/L (probability of target attainment ≤82.3%). Additionally, lower linezolid distribution into the target site in obese patients as described above might compromise the plasma-based probability of target attainment analysis. DISCUSSION: This analysis revealed risks of linezolid underdosing in empirical antibiotic therapy of most resistant bacteria for obese and non-obese patients. Doubling the standard dose is associated with adequate probability of target attainment throughout most body masses for MIC ≤2 mg/L. Further clinical studies with adjusted dosing regimens in for example intensive care patients are needed.

Measurement of soft tissue drug concentrations in morbidly obese and non-obese patients - A prospective, parallel group, open-labeled, controlled, phase IV, single center clinical trial.

BACKGROUND: Pharmacokinetic (PK) and pharmacodynamic (PD) data on perioperative antibiotic prophylaxis or antibiotic therapy are rare in patients suffering from morbid obesity. Furthermore, dosing regimens should be based on PK/PD models that ensure effective antibiotic exposure not in plasma, but primarily at the site of infection, mostly in the interstitial fluid (ISF). The aim of this trial is to investigate whether current dosing regimens of various antibiotics lead to effective concentrations in the ISF of morbidly obese patients. METHODS: We designed a prospective, parallel group, open-labeled, controlled single center trial to investigate the plasma and tissue pharmacokinetics of the antibiotics linezolid, meropenem, tigecycline, piperacillin/tazobactam, fosfomcyine, cefazolin, metronidazole and as secondary aim the analgesics metamizole and acetaminophen. Inclusion criteria comprise body mass index ≥35 kg/m2 for obese or between 18.5 and 30 kg/m2 for non-obese patients scheduled for elective abdominal surgery. For PK analysis, blood and microdialysate samples of subcutaneous tissue were collected 0-8 h after study drug administration. The primary endpoint is to investigate a possible dependency of the area-under-the-curve (AUC0-8) in the interstitial fluid on body weight and obesity with population based pharmacokinetic analysis. DISCUSSION: Inadequate dosing regimes of antibiotics may be a relevant factor for morbidity and mortality of patients, as well as for the development of bacterial antibiotic resistance. The measurement of plasma and tissue concentrations will provide information necessary for PK/PD-modelling. These data about antibiotic PK/PDcharacteristics in soft tissue and their dependence on weight should help to develop weight-dependent models for calculation of patient's individual doses of different antibiotics. TRIAL REGISTRATION: EU clinical trials register (EudraCT-No. 2012-004383-22) and German Clinical trials Register (DRKS00004776).

Elimination of Doripenem during Dialysis and Pharmacokinetic Evaluation of Posthemodialysis Dosing for Patients Undergoing Intermittent Renal Replacement Therapy.

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa and Enterobacteriaceae Current dosing regimens recommend the administration of 0.25 to 0.5 g once daily in patients undergoing intermittent renal replacement therapy. As patients are usually dialyzed thrice weekly, we aimed to investigate a 1-g posthemodialysis regimen, thus reducing treatment costs and enhancing patient compliance. A second objective of this trial was to describe the pharmacokinetics of intradialytic doripenem. Ten oliguric or anuric patients in need of intermittent renal replacement therapy were included in this trial. All patients suffered from a septic episode. The mean hemofilter clearance was 123.46 ± 42.03 ml/min, and the total body clearance between hemodialysis sessions was 16.79 ± 6.02 ml/min. The average prehemodialysis trough concentration was 2.4 ± 1.3 mg/liter, while the EUCAST resistance breakpoint for Enterobacteriaceae is set at 2 mg/liter. The interpatient variability was considerably higher than the intrapatient variability. Apart from one patient who suffered an allergic reaction, doripenem was tolerated well by all patients. Our data indicate that posthemodialysis administration of 1 g of doripenem results in sufficient plasma levels in anuric but not oliguric patients during the entire dosing interval. (This trial was registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.).

[Drug reactions caused by chemotherapy agents]. / Arzneimittelreaktionen bei antineoplastischen Substanzen.

In recent years, several new classes of compounds have successfully been established in the treatment of cancer. They selectively inhibit disturbed signaling pathways or induce anti-tumor immune responses. These novel targeted cancer drugs show a favorable safety profile compared to conventional chemotherapeutic agents. The most important side effects of these anticancer agents include cutaneous reactions and occur in a time-dependant manner and show class-specific patterns. In this review article, we compare the cutaneous side effects of epidermal growth factor inhibitors (EGFRI), multikinase inhibitors (MKI), BRAF inhibitors (BRAFI), mTor inhibitors (mTorI) and immune checkpoint inhibitors and discuss severity-adapted management strategies.

[Successful treatment of granulomatous rosacea with dapsone]. / Erfolgreiche Therapie einer granulomatösen Rosazea mit Dapson.

Granulomatous rosacea is an uncommon variant of rosacea. It is characterized by disseminated, red-brown papules and nodules especially in periocular and centrofacial locations. This form of rosacea causes considerable distress among patients because of the inflammatory facial lesions and represents a therapeutic challenge. A 62-year old man with granulomatous rosacea failed to improve with systemic doxycycline. Systemic isotretinoin and corticosteroids produced only a temporary reduction in cutaneous findings. Finally, systemic treatment with dapsone resulted in remission of the skin lesions and long-term stabilization.

[Paraneoplastic palmoplantar hyperkeratosis. Minor form of acrokeratosis neoplastica Bazex?]. / Paraneoplastische palmoplantare Hyperkeratose. Minorform der Acrokeratosis paraneoplastica Bazex?

Acrokeratosis paraneoplastica Bazex is a rare, obligate paraneoplasia initially presenting with palmoplantar hyperkeratosis. Later stages show acral psoriasiform lesions on other parts of the body. Common associated malignancies are laryngeal cancer and other tumors of the head or neck region or neck lymph node metastases. A 49-year-old woman presented with palmoplantar hyperkeratoses for 4 months; in addition she had a squamous cell carcinoma of the larynx. We diagnosed a minor form of acrokeratosis paraneoplastica Bazex. Some authors consider this as a separate entity, but the well- known course argues against this hypothesis. We report a case and review the literature.

[New tyrosine kinase and EGFR inhibitors in cancer therapy. Cardiac and skin toxicity as relevant side effects. Part B: Skin]. / Neue Tyrosinkinase- und EGFR-Inhibitoren in der Tumortherapie. Herz und Haut als wichtige Schädigungsorgane. Teil B: Haut.

Recently, inhibitors of the epidermal growth factor receptor (EGFR) and multikinase inhibitors have been successfully established in the therapy of various solid tumors. EGFR inhibitors and multikinase inhibitors are specific and selective agents that intervene with the dysfunctional regulatory processes of malignant cells. This results in a favorable safety profile and range of side effects, especially in comparison to conventional chemotherapy. The various cutaneous adverse drug reactions are considered substance class effects and are the most frequent side effects of these targeted therapies. Therapy with EGFR inhibitors is associated with acneiform rash, painful paronychia, xerosis cutis, acral fissures, hair changes, and pruritus. Treatment with tyrosin kinase inhibitors may cause hand-foot syndrome, various types of drug rash, hair loss, xerosis cutis, and pruritus. These side effects may be stigmatizing and place a huge burden on the patient's quality of life. Treatment is a challenge and best performed in interdisciplinary cooperation of dermatologists and oncologists.

[Multiple Sister Mary Joseph's nodules in a patient with gastric cancer]. / Multiple "Sister Mary Joseph's nodules" bei einem Patienten mit Magenkarzinom.

HISTORY AND CLINICAL FINDINGS: A 52-year-old patient presented with a 6-months history of painful, progressive erythematous periumbilical papules and nodules. Seven months previously, an advanced stage of an adenocarcinoma of the stomach with peritoneal carcinosis and malignant ascites had been diagnosed. INVESTIGATIONS: Clinical examination showed ten firm, painful, umbilicated, erythematous, polygonal papules and nodules (size up to 7 mm), partly covered with central hemorrhagic crusts or scales. The histological examination revealed epithelial cell clusters infiltrating the dermis and forming tubular structures. The prominent nuclei varied in size, some were vacuolated. Signet ring structures were visible in the tumor. Immunohistochemical staining revealed MNF116 expressing tumor cells, consistent with a moderately differentiated adenocarcinoma. DIAGNOSIS: Multiple Sister Mary Joseph's nodules - periumbilical skin metastases from gastric carcinoma. TREATMENT AND COURSE: The previous palliative chemotherapy with capecitabine will be expanded by irinotecan after completion of local iradiation of an esophageal stenosis. The patient declined additional local therapeutic options such as excision or electric chemotherapy. CONCLUSION: Sister Mary Joseph's nodule is a rare, umbilical cutaneous metastatic tumor originating from advanced metastatic intraabdominal or intrapelvic malignancies. Our case is remarkable because of the number of the umbilical and periumbilical, but otherwise characteristic nodules. Sister Mary Joseph's nodules are associated with a dismal prognosis. As they may precede cancer diagnosis, histological investigation of suspect umbilical nodules should be performed.

Cutaneous side-effects of EGFR inhibitors and their management.

Epidermal growth factor receptor (EGFR) inhibitors are an increasingly important treatment option for metastasized cancer in patients. In addition to the pivotal role of EGFR in the development and progression of malignant tumors, EGFR is also important for proliferation and differentiation of the human epidermis and hair follicles. As a consequence, cutaneous side-effects are frequently observed during cancer therapy with EGFR inhibitors. During the first few weeks of treatment, acneiform eruptions are the earliest common side-effect. Xerosis and fissures are complications appearing in later treatment phases. Paronychia and alterations in hair growth are less common and generally seen after a longer period of treatment. We present an overview of the various cutaneous side-effects associated with EGFR inhibition and discuss their respective therapeutic options.