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Calcific tendinitis is a relatively rare condition in which calcium is inappropriately deposited in tendons, resulting in a local inflammatory reaction that can cause severe symptoms in certain cases. The cause of this disease process is not completely understood, although repetitive microtrauma likely plays a role in its development. Although the disorder most often involves the rotator cuff, it can affect other structures throughout the body, such as the tendons about the ankle and hip—including the rectus femoris and gluteus maximus. Nonoperative management typically involves using an anti-inflammatory medication and activity modification and can be augmented with formal physical therapy and modalities. Although nonoperative management provides adequate relief for many patients, sometimes operative debridement of the calcific deposit with or without repair of the involved tendon is required. The authors report an unusual case of calcific tendinitis of the gluteus maximus insertion in a golfer. The patient had tried nonoperative treatment for approximately 2 years with no real relief, and a recent exacerbation of the pain was significantly delaying his return to sport. Although plain radiographs did not show abnormalities, magnetic resonance imaging showed a calcific deposit in the insertion of the gluteus maximus tendon. After discussing further treatment options with the patient, the decision was made to remove the deposit and repair the insertion. He recovered completely and was able to return to play. The frequency, pathogenesis, and treatment of this condition are discussed in this case report, as well as the possible link to golf in this patient. [ Orthopedics. 2016; 39(5):e997–e1000.]

As an effective and noninvasive treatment of various diseases, photodynamic therapy (PTD) relies on the combination of light, a photosensitizer, and oxygen to generate cytotoxic reactive oxygen species that can damage malignant tissue. Much attention has been paid to covalent modifications of the photosensitizers to improve their photophysical properties and to optimize the pathway of the photosensitizers interacting with cells within the target tissue. Herein we report the design and synthesis of a supramolecular heterometallic Ru–Pt metallacycle via coordination-driven self-assembly. While inheriting the excellent photostability and two-photon absorption characteristics of the Ru(II) polypyridyl precursor, the metallacycle also exhibits red-shifted luminescence to the near-infrared region, a larger two-photon absorption cross-section, and higher singlet oxygen generation efficiency, making it an excellent candidate as a photosensitizer for PTD. Cellular studies reveal that the metallacycle selectively accumulates in mitochondria and nuclei upon internalization. As a result, singlet oxygen generated by photoexcitation of the metallacycle can efficiently trigger cell death via the simultaneous damage to mitochondrial function and intranuclear DNA. In vivo studies on tumor-bearing mice show that the metallacycle can efficiently inhibit tumor growth under a low light dose with minimal side effects. The supramolecular approach presented in this work provides a paradigm for the development of PDT agents with high efficacy.

Photodynamic therapy (PDT) is a treatment procedure that relies on cytotoxic reactive oxygen species (ROS) generated by the light activation of a photosensitizer. The photophysical and biological properties of photosensitizers are vital for the therapeutic outcome of PDT. In this work a 2D rhomboidal metallacycle and a 3D octahedral metallacage were designed and synthesized via the coordination-driven self-assembly of a Ru(II)-based photosensitizer and complementary Pt(II)-based building blocks. The metallacage showed deep-red luminescence, a large 2-photon absorption cross-section, and highly efficient ROS generation. The metallacage was encapsulated into an amphiphilic block copolymer to form nanoparticles to encourage cell uptake and localization. Upon internalization into cells, the nanoparticles selectively accumulate in the lysosomes, a favorable location for PDT. The nanoparticles are almost nontoxic in the dark, and can efficiently destroy tumor cells via the generation of ROS in the lysosomes under 2-photon near-infrared light irradiation. The superb PDT efficacy of the metallacage-containing nanoparticles was further validated by studies on 3D multicellular spheroids (MCS) and in vivo studies on A549 tumor-bearing mice.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms. The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Here, Alcala and colleagues present a multi-omics analysis of these tumours, revealing distinct molecular and prognostic subgroups.

Ancillary studies facilitate accurate diagnosis of morphologically challenging mesothelial proliferations. The current diagnostic algorithm proceeds from BAP1 immunohistochemistry to CDKN2A fluorescence in situ hybridization. While MTAP immunohistochemistry has recently shown promise as a surrogate for CDKN2A fluorescence in situ hybridization, it has been examined in only a few single-institution studies. Furthermore, there are no published reports on interobserver agreement or interlaboratory reproducibility for MTAP immunohistochemistry. We performed MTAP immunohistochemistry on 20 benign mesothelial lesions and 99 malignant mesotheliomas from five mesothelioma centers in four countries, and each MTAP stain was independently interpreted by four pathologists. CDKN2A fluorescence in situ hybridization data were available for a subset of cases, and a subset of cases was subjected in MTAP immunohistochemistry in multiple laboratories to assess interlaboratory reproducibility. Interobserver agreement in MTAP immunostain interpretation was excellent for all mesothelial lesions (kappa: 0.85) and for malignant mesothelioma cases only (kappa: 0.82). Interlaboratory reproducibility was also excellent (kappa values for paired protocols: 0.77–0.89). MTAP loss by immunohistochemistry was 78% sensitive and 96% specific for CDKN2A homozygous deletion. MTAP immunohistochemistry is a reliable surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant mesothelioma. Interobserver agreement is excellent for interpretation of MTAP staining, and protocols performed in different laboratories yield concordant MTAP staining results. Rare cases with immunohistochemical MTAP loss may retain normal CDKN2A copy number, and the MTAP staining results should be correlated with clinicopathologic findings and other ancillary studies.

Malignant mesothelioma (MM) is an aggressive cancer primarily diagnosed on the basis of histological criteria 1 . The 2015 World Health Organization classification subdivides mesothelioma tumors into three histological types: epithelioid, biphasic and sarcomatoid MM. MM is a highly complex and heterogeneous disease, rendering its diagnosis and histological typing difficult and leading to suboptimal patient care and decisions regarding treatment modalities 2 . Here we have developed a new approach—based on deep convolutional neural networks—called MesoNet to accurately predict the overall survival of mesothelioma patients from whole-slide digitized images, without any pathologist-provided locally annotated regions. We validated MesoNet on both an internal validation cohort from the French MESOBANK and an independent cohort from The Cancer Genome Atlas (TCGA). We also demonstrated that the model was more accurate in predicting patient survival than using current pathology practices. Furthermore, unlike classical black-box deep learning methods, MesoNet identified regions contributing to patient outcome prediction. Strikingly, we found that these regions are mainly located in the stroma and are histological features associated with inflammation, cellular diversity and vacuolization. These findings suggest that deep learning models can identify new features predictive of patient survival and potentially lead to new biomarker discoveries. Deep convolutional neural networks predict survival of mesothelioma patients and identify histological features associated with outcome that transcend current histological classifications.

Although diabetes results in part from a deficiency of normal pancreatic beta cells, inducing human beta cells to regenerate is difficult. Reasoning that insulinomas hold the “genomic recipe” for beta cell expansion, we surveyed 38 human insulinomas to obtain insights into therapeutic pathways for beta cell regeneration. An integrative analysis of whole-exome and RNA-sequencing data was employed to extensively characterize the genomic and molecular landscape of insulinomas relative to normal beta cells. Here, we show at the pathway level that the majority of the insulinomas display mutations, copy number variants and/or dysregulation of epigenetic modifying genes, most prominently in the polycomb and trithorax families. Importantly, these processes are coupled to co-expression network modules associated with cell proliferation, revealing candidates for inducing beta cell regeneration. Validation of key computational predictions supports the concept that understanding the molecular complexity of insulinoma may be a valuable approach to diabetes drug discovery. Diabetes results in part from a deficiency of functional pancreatic beta cells. Here, the authors study the genomic and epigenetic landscapes of human insulinomas to gain insight into possible pathways for therapeutic beta cell regeneration, highlighting epigenetic genes and pathways.

Introduction To identify potential risk factors for the development of jaw osteoradionecrosis (ORN) after 3D-conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) among patients with newly diagnosed head and neck cancer. Material and methods This study included 776 patients who underwent 3D-CRT or IMRT for head and neck cancer at the Department of Radiotherapy at the University Hospital Halle-Wittenberg between 2003 and 2013. Sex, dental status prior to radiotherapy, tumor site, bone surgery during tumor resection, concomitant chemotherapy, and the development of advanced ORN were documented for each patient. ORN was classified as grade 3, 4, or 5 according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer classification or grade 3 or 4 according to the late effects in normal tissues/subjective, objective, management, and analytic scale. The cumulative incidence of ORN was estimated. Cox regression analysis was used to identify prognostic risk factors for the development of ORN. Results Fifty-one patients developed advanced ORN (relative frequency 6.6 %, cumulative incidence 12.4 %). The highest risk was found in patients who had undergone primary bone surgery during tumor resection (hazard ratio [HR] = 5.87; 95 % confidence interval [CI]: 3.09–11.19) and in patients with tumors located in the oral cavity (HR = 4.69; 95 % CI: 1.33–16.52). Sex, dentition (dentulous vs. edentulous), and chemotherapy had no clinically relevant influence. Discussion and conclusion In contrast to most previous studies, we noted a low cumulative incidence of advanced ORN. Patients with tumors located in the oral cavity and those who undergo bone surgery during tumor resection prior to RT may be considered a high-risk group for the development of ORN.

Abstract The incidence of germ-cell testicular cancer (TC) has increased in recent decades. Current evidence does not indicate a unanimous association between occupational exposure to welding fumes and TC risk. However, most publications do not provide information on exposure levels to welding fumes. We investigated the association between occupational exposure to welding fumes and the risk of TC in a German case–control study (268 cases and 797 control subjects). A measurement-based welding-exposure matrix was used to estimate year-specific exposure values which were linked to job-task descriptions. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated via logistic regression, conditional on study area and 5-year age groups. ORs were adjusted for a history of cryptorchidism, a family history of TC, and ever exposure to metal-working fluids (MWF). Regular welding was associated with an elevated TC risk (OR: 2.26, CI: 0.92–5.53) compared to occasional welding (OR: 1.14, CI: 0.78–1.69). For non-seminoma, there was an indication of a strong association among regular welders (OR: 3.71, CI: 1.08–12.80) and for non-welders using MWFs (OR: 3.39, CI: 1.21–9.53). However, these estimates were based on few exposed cases. We did not observe dose–effect relationships with increasing lifetime exposure to welding fumes, duration, or average intensity. We found an association between regular welding and TC risk based on standardized job-task descriptions, but not when using the year-specific exposure values.

Studies comparing endocrine-specific outcomes following parathyroidectomy (PTx) versus concurrent parathyroidectomy and thyroidectomy (PTx + Tx) are few. 10,019 patients were selected from the Collaborative Endocrine Surgery Quality Improvement Program (2014–2019). Baseline characteristics and short-term (≤30 days) outcomes for PTx + Tx vs PTx patients were compared using bivariate and multivariable methods. PTx + Tx patients were more likely to experience clinical hypoparathyroidism (6.7% vs 0.5%, p < 0.001), recurrent laryngeal nerve transection, (0.4% vs 0.1%, p = 0.002) and hematoma requiring evacuation (1.0% vs 0.2%, p < 0.001). Readmissions and ED visits for hypocalcemia were more frequent after PTx + Tx vs PTx. Concurrent surgery was associated with an 8-fold increase in risk of short-term complications (Odds Ratio (OR): 8.0, 95% Confidence Interval (CI): 5.7–11.1, p < 0.001). Patients undergoing PTx + Tx have increased rates of postoperative complications, ED visits, and readmissions compared to patients undergoing parathyroidectomy alone. These findings could help guide surgeon-patient discussions on the risks of concurrent surgery. •Concurrent parathyroid surgery with thyroidectomy carries an 8-fold increased risk of complications compared with parathyroidectomy alone.•Hypoparathyroidism, recurrent laryngeal nerve injury, and hematoma are significantly more likely following concurrent surgery.•Hypocalcemia is the largest driver of endocrine-related ED visits and hospital admissions in the post-op period.•These findings may help guide surgeon-patient discussions on the risks of concurrent parathyroid and thyroid surgery.