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Summary Background The incidence of pilonidal disease is increasing. The choice of surgical approach differs between surgeons and countries. With better understanding of the etiology of the disease, there is a shift toward more successful concepts of treatment. In many cases, management can be challenging owing to the number of previous failed operations. Objective The aim of this retrospective single-center cohort study was to compare recurrence rates and postoperative wound complications between five treatment arms. Methods A total of 299 patients who underwent surgery for pilonidal disease between November 1994 and May 2019 were included. Primary endpoint was time to recurrence, secondary endpoint was wound care complication rate. Results Median follow-up was 85.8 months in 286 patients. An overall recurrence rate of 16.1% was observed at 24 months, 21.4% at 60 months, and 47.4% at 303 months; 24 months postoperatively, there was a range from 10.5% for excision with primary midline closure to 30.0% for the Bascom I procedure. Recurrence in excision with primary midline closure was 71.8% 268 months postoperatively. No statistically significant differences were observed between the five groups (p = 0.54). The highest prevalence of wound complications (46.3%) was in excision with midline closure. Cox regression showed that previous pilonidal operations are an independent prognostic factor for developing recurrence (p = 0.006). Multivariate logistic regression revealed that previous pilonidal operations have a significant predictive value for developing postoperative wound complications (odds ratio = 4.04, 95% confidence interval [1.61–10.18]; p = 0.003). Conclusion In order to improve surgical outcomes, emphasis should be given to adoption of techniques with high success rates.

Supplementary Figures S1-S2; Supplementary Table S1.

Purpose: Heat shock protein-90 (HSP-90), a molecular chaperone required by numerous oncogenic kinases [e.g., HER-2, epidermal growth factor receptor (EGFR), Raf-1, v-Src, and AKT] for conformational stability, has attracted wide interest as a novel target for cancer therapy. HSP-90 inhibition induces degradation of HSP-90 client proteins, leading to a combinatorial inhibition of multiple oncogenic signaling pathways with consecutive growth arrest and apoptosis. MET, a tyrosine kinase that is constitutively active in tumor cells with MET oncogene amplification, has recently been identified as another HSP-90 client.Experimental Design: The aim of our study was to assess the efficacy of SNX-2112, a synthetic HSP-90 inhibitor, in 3 different MET-amplified tumor cell lines (GTL-16, MKN-45, and EBC-1) as well as PR-GTL-16 cells, a GTL-16 subline selected for resistance to the highly selective MET kinase inhibitor PHA-665752.Results: In all cell lines, SNX-2112 led to degradation of MET, HER-2, EGFR, and AKT, as well as abrogation of Ras/Raf/MEK/MAPK and PI3K/AKT signaling, followed by complete cell cycle arrest. SNX-5542, an orally bioavailable prodrug of SNX-2112, displayed significant antitumor efficacy in vivo in nude mice bearing MET-amplified tumor xenografts. Importantly, HSP-90 inhibition maintained its antitumor efficacy in PR-GTL-16 cells both in vitro and in vivo, suggesting that HSP-90 inhibition could be a particularly valuable strategy in MET-amplified tumors that have acquired resistance to MET kinase inhibition.Conclusions: Our study provides evidence for the efficacy of HSP-90 inhibition in MET-amplified cancer cells, particularly when MET kinase inhibitor resistance has emerged. Clin Cancer Res; 17(1); 122–33. ©2011 AACR.

Summary Background Sacral neuromodulation (SNM) is a widely accepted treatment for pelvic floor disorders, including constipation and fecal incontinence (FI). In 2017, a standardized electrode placement method, the H technique, was introduced to minimize failure rates and improve clinical outcomes. We aimed to investigate the technical feasibility and functional outcome of the procedure. Methods In this prospective study, we evaluated the first 50 patients who underwent SNM according to the H technique between 2017 and 2020 at a tertiary care hospital. Patient demographic and clinical data were collected, and the impact of various factors on patients’ postoperative quality of life (QoL) was assessed after a follow-up of 40 months. Functional outcome was monitored prospectively using a standardized questionnaire. Results Of 50 patients, 36 (72%) reported greater than 50% symptom relief and received a permanent implant (95% CI: 58.3–82.5). We observed 75% success in relieving FI (95% CI: 58.9–86.3) and 64% in constipation (95% CI: 38.8–83.7). Complication occurred in five (10%) patients. Preoperative vs. postoperative physical and psychological QoL, Vaizey score, and obstructed defecation syndrome (ODS) scores revealed significant improvements (all p p = 0.035). Conclusion We provide evidence for the technical feasibility and efficacy of the SNM implantation using the H technique. The medium-term results are promising for patients with FI and constipation. Male patients and those with a BMI > 25 are more prone to perioperative complications.

Simple Summary Today, the presence of well-organized functional structures of immune cells at tumor sites, known as ectopic lymphoid structures, and their strong association with patient survival have been reported in more than ten different cancer types. We aimed to investigate whether there is a link between the patient-specific characteristics of pre-formed isolated lymphoid structures in non-tumorous colon tissue and the disease pathobiology for patients with metastatic colorectal cancer. The study employed a powerful approach of quantitative tissue image cytometry to compare lymphoid structures of different anatomical locations within the same patients. We showed that the properties of isolated lymphoid structures in non-tumorous colon tissue predefine the immune phenotype of ectopic lymphoid structures at primary and metastatic sites. We discovered that B-cell-enriched and highly proliferative lymphoid structures are prognostic towards an improved clinical outcome. The knowledge gained from this study expands our understanding of tumor-immune interactions and draws particular attention to the anti-tumor immune response guided by isolated lymphoid structures outside of tumor tissue. Abstract The gut-associated lymphoid tissue represents an integral part of the immune system. Among the powerful players of the mucosa-associated lymphoid tissue are isolated lymphoid structures (ILSs), which as information centers, drive the local (and systemic) adaptive immune responses. Germinal center reactions, taking place within ILSs, involve the coordinated action of various immune cell types with a central role given to B cells. In the current study, we aimed at dissecting the impact of ILSs within non-tumorous colon tissue (NT) on the pathobiology of colorectal cancer (CRC) with metastasis in the liver (CRCLM). In particular, we focused on the immune phenotypes of ILSs and ectopic lymphoid structures (ELSs), built up at matching primary and metastatic tumor sites. We implemented an integrative analysis strategy on the basis of tissue image cytometry and clonality assessment to explore the immune phenotype of ILS/ELS at three tissue entities: NT, CRC, and CRCLM (69 specimens in total). Applying a panel of lineage markers used for immunostaining, we characterized and compared the anatomical features, the cellular composition, the activation, and proliferation status of ILSs and ELSs, and assessed the clinical relevance of staining-derived data sets. Our major discovery was that ILS characteristics at the NT site predefine the immune phenotype of ELSs at CRC and CRCLM. Thereby, B-cell-enriched (CD20) and highly proliferative (Ki67) ILSs and ELSs were found to be associated with improved clinical outcome in terms of survival and enabled patient stratification into risk groups. Moreover, the data revealed a linkage between B-cell clonality at the NT site and the metastatic characteristics of the tumor in the distant liver tissue. Consolidation of immunostaining-based findings with the results of compendium-wide transcriptomic analysis furthermore proposed CD27 as a novel marker of T follicular helper cells within lymphoid structures. Overall, the study nominates the ILS immune phenotype as a novel prognostic marker for patients with metastatic CRC.

Background Taxane-based checkpoint inhibitor combination therapy might improve the outcome in recurrent/metastatic (R/M) head and neck cancer (HNSCC) patients. Thus, we investigated the efficacy and safety of docetaxel (DTX) plus pembrolizumab (P) in a prospective phase I/II trial. Methods Platinum-resistant R/M HNSCC patients received DTX 75 mg/m^2 plus P 200 mg for up to six cycles followed by P maintenance therapy. The primary endpoint was overall response rate (ORR) and safety. Secondary endpoints comprised disease control rate (DCR), overall survival (OS) and progression free survival (PFS). Results Twenty-two patients were enrolled. Nine patients (40.9%) had a primary tumor in the oropharynx, 8 (36.4%) in the oral cavity, 3 (13.6%) in the hypopharynx and 2 (9.1%) in the larynx. The ORR was 22.7% (95% CI 10.1%-43.4%) and one (4.5%) complete response was achieved. The DCR was 54.6% (95% 34.7%-73.1%). The median PFS was 5.8 months (95% CI 2.7–11.6) and the median OS 21.3 months (95% CI 6.3–31.1). The 1-year PFS and OS rates were 27.3% and 68.2%, respectively. While the most frequent adverse event (AE) was myelosuppression, which was reported in all 22 patients, 3 (13.6%) patients experienced grade 3 febrile neutropenia. The most common immune-related AEs were grade skin rash (40.9%) and hypothyroidism (40.9%). One patient (4.5%) experienced grade 5 immune thrombocytopenia. Conclusion DXT in combination with P shows promising activity accompanied with a manageable side effect profile in pre-treated R/M HNSCC patients.

Summary Background After publishing promising results for the treatment of patients with human papilloma virus (HPV) positive oropharyngeal cancer with radiochemotherapy regarding 2‑year survival, we present an update of the disease-specific and disease-free survival after 5 years. Patients and methods A total of 29 patients of which 18 were HPV negative and 11 HPV positive with squamous cell carcinoma of the oropharynx received radiation therapy with or without chemotherapy (cisplatin) or immunotherapy (cetuximab) between 2007 and 2009. At time of the present analysis, six patients are still alive including four with HPV positive and two with HPV negative oropharyngeal carcinoma, while 15 out of 16 patients with HPV negative tumors died and 1 died of another cause with evidence of disease. Results Since the 2‑year disease-specific survival of patients with HPV positive cancer of the oropharynx was published with 100% versus 30.4% in HPV negative tumors, we now present the 5‑year disease-specific survival after treatment, which was 85.7% in HPV positive versus 11.1% in HPV negative patients. Conclusion We present the results of patients receiving radiochemo(immuno)therapy for oropharyngeal cancer regarding the HPV status, which is still promising.

An empirical distribution function estimator for the difference of order statistics from two independent populations can be used for inference between quantiles from these populations. The inferential properties of the approach are evaluated in a simulation study where different sample sizes, theoretical distributions, and quantiles are studied. Small to moderate sample sizes, tail quantiles, and quantiles which do not coincide with the expectation of an order statistic are identified as problematic for appropriate Type I error control.

Objective/Background Matrix metalloproteinases (MMPs) play a pivotal role in the development and progression of abdominal aortic aneurysms (AAAs). The action of MMPs depends on a balance between tissue inhibitors of MMPs (TIMPs) and compounds that may prolong protease activity, such as neutrophil gelatinase-associated lipocalin (NGAL). Methods The study was designed to analyse gene expression and protein concentration of MMPs, TIMPs, and NGAL in AAA walls and intraluminal thrombi (ILTs) of patients on simvastatin (n = 10) and not on statins (n = 10). The patients were matched by age, sex, and AAA diameter. Expression of MMP2, MMP9, TIMP1, TIMP2, and NGAL was investigated by real time polymerase chain reaction, and MMP2, MMP9, MMP9/TIMP1, MMP9/TIMP2, and MMP9/NGAL protein levels by enzyme-linked immunosorbent assay. Results MMP2 and MMP9 protein and mRNA levels were comparable in the simvastatin and non-statin groups (p > .05); however, there was a significant decrease in TIMP1 mRNA in AAA tissue (p = .04). Moreover, a significant increase in MMP9/TIMP2 complex concentration in ILTs of patients on simvastatin was noted (median 94.71 ng/mL in the simvastatin group vs. 36.80 ng/mL in the non-statin group; p = .01). No significant difference was observed for NGAL mRNA or protein content in AAA and ILT. Conclusion Simvastatin treatment in patients with AAAs may influence the concentration of proteases and their inhibitors (TIMPs) in aneurysmal wall tissue and ILTs. Thus, further studies should be undertaken to understand the different influence of statin therapy on the components of the MMP/TIMP system in AAAs and ILTs.

The objective was primarily to identify risk factors for bloodstream infections (BSI) caused by different pathogens.A retrospective single-center cohort study was performed on 472 burn patients with an abbreviated burn severity index (ABSI)≥3, a total burn surface area (TBSA)≥10%, and an ICU stay of at least 24h. Risk factors for different BSI pathogens were analyzed by competing risks regression model of Fine and Gray.A total of 114 burn patients developed 171 episodes of BSIs caused by gram-negative bacteria (n=78;46%), gram-positive bacteria (n=69;40%), and fungi (n=24;14%) median after 14days (range, 1-164), 16days (range, 1-170), and 16days (range, 0-89), respectively. A total of 24/114 patients (21%) had fatal outcomes. Isolation of the most common bloodstream isolates Enterococcus sp. (n=26), followed by Candida sp. and Pseudomonas sp. (n=22 for both) was significantly associated with increased TBSA (p≤0.006) and ABSI (p0.0001) and need for fasciotomy (p0.01). The death risk of patients with MDR gram-negative bacteremia was significantly increased by a hazard ratio of 12.6 (95% CI:4.8-32.8; p0.0001).A greater TBSA and ABSI were associated with a significantly higher incidence of BSIs caused by Pseudomonas sp., Enterococcus sp. and Candida sp.

Reliable determination of Ki67 labeling index (Ki67 LI) on core needle biopsy specimens (CNB) is essential for determining breast cancer intrinsic subtype (IST), preoperative treatment decisions and short-term treatment response during neoadjuvant therapy. However, analyses investigating robustness of Ki67 LI assessment upon repeated tumor biopsies are scarce and results of studies investigating agreement of KI67 LI between CNB and surgical resection (SR) specimens are conflicting. In the present study, we analysed the role of clinical and pathological factors in influencing concordance of Ki67 LI between CNB and SR specimens. 502 matched pairs of CNB and SR specimens of patients with invasive ER-positive, HER2-negative breast cancer were included in our study. Ki67 LI was determined according to recent recommendations. Luminal B disease was defined by Ki67 LI > 20% according to SR. Ki67 LI values were considered concordant by a divergence of 10% points. Agreement was calculated by Cohen's kappa. Associations with clinicopathological factors were analyzed by Chi square test and logistic regression. Factors investigated included age, menopausal status, CNB method, BIRADS assessment category of imaging abnormality, time between CNB and SR, extent of surgery, histological grade (including individual grading score components according to Elston and Ellis), tumor size, lymph node stage, estrogen- (ER), progesterone- (PR) and HER2-receptor status. A cutoff value of 20% for KI67 LI in SR demonstrated a sensitivity of 90% and a specificity of 60% for identifying luminal B breast cancer in CNB. Upon investigating measurement agreement, we found substantial agreement of Ki67 LI between CNB and SR specimens with a weighted kappa value of 0.837. IST assesment in CNB and SR showed only moderate concordance with a kappa value of 0.587. Concordant diagnosis of IST in CNB and SR was significantly associated with PR expression and histological grade (p>0.05). Agreement of Ki67 LI was higher in tumors expressing low and high levels of PR compared to tumors with intermediate PR score. 27% and 22% of low and intermediate grade breast cancers showed discordant IST in CNB and SR, respectively. In contrast, only 3% of high grade breast cancers differed regarding IST upon repeated measurements. Interestingly, concordance of IST was significantly associated with all separate grading score components in CNB samples such as extent of glandular differentiation (p=0.015), nuclear polymorphism (p=0.005) and number of mitotic figures (p>0.001). We conclude that agreement of breast cancer IST according to Ki67 LI between CNB and SR specimens is significantly influenced by histological tumor grade and PR status. These factors, including all three grading score components are likely to mirror tumor heterogeneity that might compromise obtaining a CNB sample representative of the entire tumor. Our results cast a doubt upon robustness of single CNB-driven measurements of prognostic indicators and outcome predictors in estrogen-receptor positive breast cancer of low or intermediate histological grade. Whether molecular testing of CNB specimens improves classification of luminal breast cancer and helps resolve diagnostic disparities remains to be determined. Citation Format: Zsuzsanna Bago-Horvath, Fabian Roessler, Philipp Wimmer, Martina Mittlboeck, Nicolas Kozakowski, Katja Pinker-Domenig, Rupert Bartsch, Peter Dubsky, Martin Filipits, Margaretha Rudas. Factors influencing agreement of Ki67 labeling index between core needle biopsy and surgical resection specimens [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-02-10.