Anticancer innovative therapy: Highlights from the ninth annual meeting.

The Ninth Annual Conference of "Anticancer Innovative Therapy", organized by Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (Fondazione IRCCS INT) and hosted by Hotel Michelangelo, was held in Milan on 25 January 2019. Cutting-edge science was presented in two main scientific sessions: i) pre-clinical evidences and new targets, and ii) clinical translation. The Keynote lecture entitled "Cancer stem cells (CSCs): metabolic strategies for their identification and eradication" presented by M. Lisanti, was one of the highlights of the conference. One key concept of the meeting was how the continuous advances in our knowledge about molecular mechanisms in various fields of research (cancer metabolism reprogramming, epigenetic regulation, transformation/invasiveness, and immunology, among others) are driving cancer research towards more effective personalized antineoplastic strategies. Specifically, recent preclinical data on the following topics were discussed: 1. Polycomb group proteins in cancer; 2. A d16HER2 splice variant is a flag of HER2 addiction across HER2-positive cancers; 3. Studying chromatin as a nexus between translational and basic research; 4. Metabolomic analysis in cancer patients; 5. CDK4-6 cyclin inhibitors: clinical activity and future perspectives as immunotherapy adjuvant; and 6. Cancer stem cells (CSCs): metabolic strategies for their identification and eradication. In terms of clinical translation, several novel approaches were presented: 1. Developing CAR-T cell therapies: an update of preclinical and clinical development at University of North Carolina; 2. Vγ9Vδ2 T-cell activation and immune suppression in multiple myeloma; 3. Predictive biomarkers for real-world immunotherapy: the cancer immunogram model in the clinical arena; and 4. Mechanisms of resistance to immune checkpoint blockade in solid tumors. Overall, the pre-clinical and clinical findings presented could pave the way to identify novel actionable therapeutic targets to significantly enhance the care of persons with cancer.

Compressive Femoral Neuropathy Associated with Iliopsoas Hematoma Complicating Hip Hemiarthroplasty: A Case Report.

INTRODUCTION: Femoral nerve compression caused by iliopsoas hematoma is a rare complication after hip surgery. To the best of our knowledge, this is the first case after hemiarthroplasty. In this case, iliacus hematoma resulted from spontaneous bleeding favored by anticoagulant therapy. CASE REPORT: A 78-year-old female developed left groin pain associated with typical symptoms of femoral nerve palsy about 2weeks after left hip hemiarthroplasty[1, 2, 3]. Computed tomography revealed the presence of a left iliopsoas hematoma that was surgically drained. Inguinal pain was immediately relieved, while nerve palsy recovered only partially, but the quality of life drastically improved and she was able to walk using a walker without pain. CONCLUSION: Even if it is a rare condition, the formation of a hematoma of iliopsoas muscle should be considered in patients that present symptoms of femoral nerve palsy, especially if treated with heparin or other anticoagulant drugs. Surgical drainage of the hematoma is indicated when symptoms are severe and disabling, and in this way, surgery could improve quality of life.

ESPEN expert group recommendations for action against cancer-related malnutrition.

Patients with cancer are at particularly high risk for malnutrition because both the disease and its treatments threaten their nutritional status. Yet cancer-related nutritional risk is sometimes overlooked or under-treated by clinicians, patients, and their families. The European Society for Clinical Nutrition and Metabolism (ESPEN) recently published evidence-based guidelines for nutritional care in patients with cancer. In further support of these guidelines, an ESPEN oncology expert group met for a Cancer and Nutrition Workshop in Berlin on October 24 and 25, 2016. The group examined the causes and consequences of cancer-related malnutrition, reviewed treatment approaches currently available, and built the rationale and impetus for clinicians involved with care of patients with cancer to take actions that facilitate nutrition support in practice. The content of this position paper is based on presentations and discussions at the Berlin meeting. The expert group emphasized 3 key steps to update nutritional care for people with cancer: (1) screen all patients with cancer for nutritional risk early in the course of their care, regardless of body mass index and weight history; (2) expand nutrition-related assessment practices to include measures of anorexia, body composition, inflammatory biomarkers, resting energy expenditure, and physical function; (3) use multimodal nutritional interventions with individualized plans, including care focused on increasing nutritional intake, lessening inflammation and hypermetabolic stress, and increasing physical activity.

The correlation between preoperative levels of albumin and tlc and mortality in patients with femoral neck fracture.

A femoral neck fracture in an elderly patient often represents a major challenge for the orthopaedic surgeon who has to face not only the fracture, but also all the multiple issues related to age. Among others, malnutrition has been recognised as an important factor associated with severe aggravation in these patients. One-hundred-and-forty-seven patients were enrolled to investigate the use of two markers of patient nutritional status, i.e. serum albumin level and total leukocyte count (TLC), as predictors of mortality in the elderly patient suffering from proximal femur fracture. We found that low preoperative values of serum albumin and TLC proved to be directly related to worse outcomes. Therefore, these exams can be useful to identify patients with a femoral neck fracture that have higher risk of malnutrition and consequent higher mortality and that can benefit from some measures, such as albumin or protein nutritional supplement.

Short femoral stem and porous titanium: winning combination?

A lot of different implants are available in hip replacement arthroplasty (THA), stems differ mainly by type of fixation, material, length, diameter, shape, surface coating, modularity, etc. The main quality of a non-cemented stem is to pursuit primary and secondary stability, to preserve bone stock, to be adaptable and modular. The literature shows that the most popular non cemented stems used in THA are metaphyseal femoral stem in which the distal portion has only the action to avoid varus stem placement but can also be a source of complications such as stress shielding. The stability of a short stem is closely dependent on material that must allow a high "scratch fit" and facilitate osteointegration with a generous surface of bone-implant contact. From September 2010 we have performed 287 THA using a modular titanium porous short stem. The article shows the preliminary results, which are very encouraging, showing excellent primary and secondary osteointegration, also slightly undersized implants or in elderly porotic patients.

Comparison of the POSSUM score and P-POSSUM score in patients with femoral neck fracture.

PURPOSE: The ageing of the population in developed countries has led to an increased number of patients with hip fractures all over the world. POSSUM and P-POSSUM scores predict morbidity and mortality of patients who will be undergoing a surgical treatment. The aim of this study was to evaluate accuracy of these two scores in hip-fractured patients. MATERIALS AND METHODS: Between January and December 2012, in our department 144 patients were hospitalised for femoral neck fractures according to the grade III or IV of Garden's classification treated with total hip arthroplasty or endoprosthesis. POSSUM scores and P-POSSUM scores were calculated for each patient with complete clinical data. We then calculated the observed and the expected ratio. RESULTS: 134 patients were eligible: 110 females and 24 males. The mean age for women was 79 years, and the mean age for men was 84 years. We observed 13 deaths and 66 complications. The POSSUM scores predicted 16 deaths and 60 complications, while P-POSSUM scores predicted 6 deaths. The O/E ratio for POSSUM mortality was 0.81 and for P-POSSUM was 2.17, while POSSUM morbidity was 1.1. CONCLUSION: In our study, we have shown that on the one hand, the POSSUM score predicted accurately both the mortality and morbidity in patients undergoing surgery for the femoral neck fracture, while on the other hand, the P-POSSUM score underestimated them. For this reason, we believe that the POSSUM is indeed a good audit tool, which can accurately predict both mortality and morbidity in a cohort of patients.

An optimal design for patient-specific templates for pedicle spine screws placement.

BACKGROUND: Currently, pedicle screws are positioned using a free-hand technique or under fluoroscopic guidance, with error in the range 10-40%, depending on the skill of the surgeon. METHODS: After spine CT acquisition, each vertebra is segmented and the surgeon plans screw positioning in a virtual environment, then the template is designed around the chosen trajectories. This design is based on surgical and mechanical considerations to obtain an optimal solution to guarantee template stability, simple positioning and minimized intervention invasiveness. In vitro evaluation on synthetic spine models and ex vivo animal tests on porcine specimens were performed, with the insertion of 28 Kirschner wires. RESULTS: During the in vitro tests, all the surgeons rendered positive evaluations regarding the device and considered template placement to be easy. Ex vivo tests were evaluated by CT examination, which showed that 96.5% of the Kirschner wires had been correctly inserted. CONCLUSIONS: The proposed solution is a promising, simple, highly precise, low-cost solution to safely performing posterior stabilization. Such a solution would be of interest even in hospitals in which a few spine interventions are performed per year, and for which it is not reasonable to purchase the equipment required for robotic or navigated approaches.

Sex differences in expression and subcellular localization of heart rhythm determinant proteins.

To evaluate sex differences in protein expression in the heart, we performed Western blot studies on a subset of Heart Rhythm Determinant (HRD) proteins. We examined key components of a variety of types of mechanical and electrical junctions including, connexin43, plakophilin-2, N-cadherin and plakoglobin, ankyrin-2 and actin. We describe novel findings in sex differences in cardiac protein expression and membrane localization. For most proteins examined, sex differences were significantly more pronounced in the membrane compartment than in overall expression. These studies extend our previous findings in microarray studies to demonstrate that sex differences in gene expression are likely to confer distinct functional properties on male and female myocardium.

Postobstructive regeneration of kidney is derailed when surge in renal stem cells during course of unilateral ureteral obstruction is halted.

Unilateral ureteral obstruction (UUO), a model of tubulointerstitial scarring (TIS), has a propensity toward regeneration of renal parenchyma after release of obstruction (RUUO). No information exists on the contribution of stem cells to this process. We performed UUO in FVB/N mice, reversed it after 10 days, and examined kidneys 3 wk after RUUO. UUO resulted in attenuation of renal parenchyma. FACS analysis of endothelial progenitor (EPC), mesenchymal stem (MSC) and hematopoietic stem (HSC) cells obtained from UUO kidneys by collagenase-dispersed single-cell suspension showed significant increase in EPC, MSC, and HSC compared with control. After RUUO cortical parenchyma was nearly restored, and TIS score improved by 3 wk. This reversal process was associated with return of stem cells toward baseline level. When animals were chronically treated with nitric oxide synthase (NOS) inhibitor at a dose that did not induce hypertension but resulted in endothelial dysfunction, TIS scores were not different from control UUO, but EPC number in the kidney decreased significantly; however, parenchymal regeneration in these mice was similar to control. Blockade of CXCR4-mediated engraftment resulted in dramatic worsening of UUO and RUUO. Similar results were obtained in caveolin-1-deficient but not -overexpressing mice, reflecting the fact that activation of CXCR4 occurs in caveolae. The present data show increase in EPC, HSC, and MSC population during UUO and a tendency for these cells to decrease to control level during RUUO. These processes are minimally affected by chronic NOS inhibition. Blockade of CXCR4-stromal cell-derived factor-1 (SDF-1) interaction by AMD3100 or caveolin-1 deficiency significantly reduced the UUO-associated surge in stem cells and prevented parenchymal regeneration after RUUO. We conclude that the surge in stem cell accumulation during UUO is a prerequisite for regeneration of renal parenchyma.

Aquaporin-4 expression is severely reduced in human sarcoglycanopathies and dysferlinopathies.

Aquaporin-4 (AQP4) is the major water channel expressed in fast-twitch skeletal muscle fibers. AQP4 is reduced in Duchenne and Becker Muscular Dystrophies, but not in caveolinopathies, thus suggesting an interaction with dystrophin or with members of the dystrophin-glycoprotein complex (DGC) rather than a nonspecific effect due to muscle membrane damage. To establish the role of sarcoglycans in AQP4 decrease occurring in muscular dystrophy, AQP4 expression was analyzed in muscle biopsies from patients affected by Limb Girdle Muscular Dystrophies (LGMDs) 2C-F genetically confirmed. In all the LGMD 2C-F (2alpha-, 1beta-, 2gamma-, 1delta-deficiency), AQP4 was severely decreased. This effect was associated to a marked reduction in alpha1-syntrophin levels. In control muscle AQP4 did not show a direct interaction with any of the four sarcoglycans but, it co-immunoprecipitated with alpha1-syntrophin, indicating that this modular protein may link AQP4 levels with the DGC complex. To determine whether AQP4 expression could be affected in other LGMDs due to the defect of a membrane protein not associated to the dystrophin complex, we examined AQP4 expression in 6 patients affected by dysferlin deficiency genetically confirmed. All the patients displayed a reduction of the water channel, and AQP4 expression appeared to correlate with the severity of the muscle histopathological lesions. However, differently from what observed in the sarcoglycans, alpha1-syntrophin expression was normal or just slightly reduced. These results seem to indicate an additional mechanism of regulation of AQP4 levels in muscle cells. In accordance with a specific effect of membrane muscle disorders, AQP4 protein levels were not changed in 3 mitochondrial and 3 metabolic myopathies. In conclusion, AQP4 expression and membrane localization are markedly reduced in LGMD 2B-2F. The role of AQP4 in the degenerative mechanism occurring in these diseases will be the object of our future research.

Design of an advanced temporary hip prosthesis for an effective recovery of septic mobilizations: a preliminary study.

The purpose of this study was the design and preliminary feasibility study of an advanced temporary hip prosthesis acting as an in-site drug dispensing system. An interactive device was designed to improve the recovery of bone infections compared to the mechanical spacers currently used in septic mobilizations. A commercial device was chosen and modified specifically for the purpose. First of all, the device was provided with a hydraulic multi-channel system connected via catheter to a subcutaneous valve, refillable with a drug aqueous solution from the outside. Moreover, since it allows samples of biological fluids for analyses to be drawn directly from the implantation site, this chemical dispensing system was designed to allow the course of infections to be monitored and customized therapies to be dosed. The insertion of biocompatible membranes inside the channel ends was considered essential to prevent their occlusion by fibrous tissue growth, thereby preserving the device functionality. Moreover, a biodegradable spongy ring was designed to be fixed onto the stem in distal position both to give primary stability to the implant and to act simultaneously as a scaffold for bonelike cell growth.

Periosteal chondroma of the proximal radius: a case report.

When a chondroma is localized in the superficial region of the bone it is defined periosteal or juxtacortical chondroma. This is a rare and benign cartilaginous lesion that more frequently affects males, and is generally observed in the tubular bones of the hand; it may, however, affect the other major bones, particularly the proximal end of the humerus. Age of onset is the second or third decade of life. Symptoms include moderate local pain. The clinical case presented here has two special features: the first is the site; based on an analysis of the international literature it seems that an analogous lesion at the level of the radial neck has not as yet been described; the second is the symptomatology that brought the patient to our attention.

Compression of the lower branch of the suprascapular nerve by a cyst: description of a case and review of the literature.

Ganglion cysts responsible for compression syndrome of the lower branch of the suprascapular nerve are described, but they are rare. The authors describe a well-documented case that was treated in a traditional manner by exeresis conducted through posterior access. Pain was relieved immediately, while force in external rotation and electromyographic findings improved as early as two months after surgery. One year after surgery the patient does not complain of the recurrence of symptoms. The literature is analyzed and therapeutic options available are discussed.

Caveolinopathies: mutations in caveolin-3 cause four distinct autosomal dominant muscle diseases.

The caveolin-3 protein is expressed exclusively in muscle cells. Caveolin-3 expression is sufficient to form caveolae-sarcolemmal invaginations that are 50 to 100 nm in diameter. Monomers of caveolin-3 oligomerize to form high molecular mass scaffolding on the cytoplasmic surface of the sarcolemmal membrane. A mutation in one caveolin-3 allele produces an aberrant protein product capable of sequestering the normal caveolin-3 protein in the Golgi apparatus of skeletal muscle cells. Improper caveolin-3 oligomerization and membrane localization result in skeletal muscle T-tubule system derangement, sarcolemmal membrane alterations, and large subsarcolemmal vesicle formation. To date, there have been eight autosomal dominant caveolin-3 mutations identified in the human population. Caveolin-3 mutations can result in four distinct, sometimes overlapping, muscle disease phenotypes: limb girdle muscular dystrophy, rippling muscle disease, distal myopathy, and hyperCKemia. Thus, the caveolin-3 mutant genotype-to-phenotype relation represents a clear example of how genetic background can influence phenotypic outcome. This review examines in detail the reported cases of patients with caveolin-3 mutations and their corresponding muscle disease phenotypes.

Familial isolated hyperCKaemia associated with a new mutation in the caveolin-3 (CAV-3) gene.

An 18 year old man and his mother both presented with persistent, isolated raised serum creatine kinase (hyperCKaemia) without muscle symptoms. Analysis of caveolin-3 protein expression in muscle biopsy of the propositus showed a reduction in the protein. Genetic analysis revealed a new heterozygous mutation in the caveolin-3 (CAV-3) gene: a C-->T transition at nucleotide position 83 in exon 1 leading to a substitution of a proline for a leucine at amino acid position 28 (P28L). This is the first pathogenic mutation in the CAV-3 gene associated with isolated familial hyperCKaemia. It expands the genetic heterogeneity in patients with caveolin-3 deficiency and confirms that caveolin-3 deficiency should be considered in the differential diagnosis of isolated hyperCKaemia.

Ulnar nerve entrapment in Guyon's tunnel by an anomalous palmaris longus muscle with a persisting median artery.

A case of ulnar nerve entrapment in Guyon's tunnel caused by an aberrant palmaris muscle, associated with a patent median artery and duplication of the median nerve, is reported.

Caveolae-deficient endothelial cells show defects in the uptake and transport of albumin in vivo.

The role of endothelial cell caveolae in the uptake and transport of macromolecules from the blood-space to the tissue-space remains controversial. To address this issue directly, we employed caveolin-1 gene knock-out mice that lack caveolin-1 protein expression and caveolae organelles. Here, we show that endothelial cell caveolae are required for the efficient uptake and transport of a known caveolar ligand, i.e. albumin, in vivo. Caveolin-1-null mice were perfused with 5-nm gold-conjugated albumin, and its uptake was followed by transmission electron microscopy. Our results indicate that gold-conjugated albumin is not endocytosed by Cav-1-deficient lung endothelial cells and remains in the blood vessel lumen; in contrast, gold-conjugated albumin was concentrated and internalized by lung endothelial cell caveolae in wild-type mice, as expected. To quantitate this defect in uptake, we next studied the endocytosis of radioiodinated albumin using aortic ring segments from wild-type and Cav-1-null mice. Interestingly, little or no uptake of radioiodinated albumin was observed in the aortic segments from Cav-1-deficient mice, whereas aortic segments from wild-type mice showed robust uptake that was time- and temperature-dependent and competed by unlabeled albumin. We conclude that endothelial cell caveolae are required for the efficient uptake and transport of albumin from the blood to the interstitium.