Progressive changes in platelet counts and Fib-4 scores precede the diagnosis of advanced fibrosis in NASH patients

BACKGROUND Cirrhosis and its complications develop in a subgroup of patients with nonalcoholic fatty liver disease(NASH).Early detection of liver fibrosis represents an important goal of clinical care.AIM To test the hypothesis that the development of cirrhosis in nonalcoholic fatty liver disease patients is preceded by the long-term trends of platelet counts and Fib-4 scores.METHODS We identified all patients in our healthcare system who had undergone fibrosis staging by liver biopsy or magnetic resonance elastography(MRE)for nonalcoholic fatty liver disease during the past decade(n=310).Platelet counts,serum glutamic-pyruvic transaminase and serum glutamic oxalacetic transaminase values preceding the staging tests were extracted from the electronic medical record system,and Fib-4 scores were calculated.Potential predictors of advanced fibrosis were evaluated using multivariate regression analysis.RESULTS Significant decreases in platelet counts and increases in Fib-4 scores were observed in all fibrosis stages,particularly in patients with cirrhosis.In the liver biopsy group,the presence of cirrhosis was best predicted by the combination of the Fib-4 score at the time closest to staging(P<0.0001),the presence of diabetes(P=0.0001),and the correlation coefficient of the preceding timedependent drop in platelet count(P=0.044).In the MRE group,Fib4 score(P=0.0025)and platelet drop(P=0.0373)were significant predictors.In comparison,the time-dependent rise of the Fib-4 score did not contribute in a statistically significant way.CONCLUSION Time-dependent changes in platelet counts and Fib-4 scores contribute to the prediction of cirrhosis in NASH patients with biopsy-or MRE-staged fibrosis.Their incorporation into predictive algorithms may assist in the earlier identification of high-risk patients.

Neoadjuvant treatment of esophageal cancer

The management of esophageal cancer has been evolving over the past 30 years. In the United States, multimodality treatment combining chemotherapy and radiotherapy (RT) prior to surgical resection has come to be accepted by many as the standard of care, although debate about its overall effect on survival still exists, and rightfully so. Despite recent improvements in detection and treatment, the overall survival of patients with esophageal cancer remains lower than most solid tumors, which highlights why further advances are so desperately needed. The aim of this article is to provide a complete review of the history of esophageal cancer treatment with the addition of chemotherapy, RT, and more recently, targeted agents to the surgical management of resectable disease.

Endoscopic treatment of Barrett's esophagus:From metaplasia to intramucosal carcinoma

The annual incidence of adenocarcinoma arising from Barrett’s esophagus (BE) is approximately 0.5%. Through a process of gradual transformation from lowgrade dysplasia to high-grade dysplasia (HGD), adenocarcinoma can develop in the setting of BE. The clinical importance of appropriate identifi cation and treatment of BE in its various stages, from intestinal metaplasia to intramucosal carcinoma (IMC) hinges on the dramatically different prognostic status between early neoplasia and more advanced stages. Once a patient has symptoms of adenocarcinoma, there is usually locally advanced disease with an approximate 5-year survival rate of about 20%. Esophagectomy has been the gold standard treatment for BE with HGD, due to the suspected risk of harboring occult invasive carcinoma, which was traditionally estimated to be as high as 40%. In recent years, the paradigm of BE early neoplasia management has recently evolved, and endoscopic therapies (endoscopic mucosal resection, radiofrequency ablation, and cryotherapy) have entered the clinical forefront as acceptable non-surgical alternatives for HGD and IMC. The goal of endoscopic therapy for HGD or IMC is to ablateall BE epithelium (both dysplastic and non-dysplastic) due to risk of synchronous/metachronous lesion development in the remaining BE segment.

Impact of minimally invasive surgery on the treatment of benign esophageal disorders

Thanks to the development of minimally invasive surgery, the last 20 years have witnessed a change in the treatment algorithm of benign esophageal disorders. Today a laparoscopic operation is the treatment of choice for esophageal achalasia and for most patients with gastroesophageal reflux disease. Because the pathogenesis of achalasia is unknown, treatment is palliative and aims to improve esophageal emptying by decreasing the functional obstruction at the level of the gastro-esophageal junction. The refinement of minimally invasive techniques accompanied by large, multiple randomized control trials with long-term outcome has allowed the laparoscopic Heller myotomy and partial fundoplication to become the treatment of choice for achalasia compared to endoscopic procedures, including endoscopic botulinum toxin injection and pneumatic dilatation. Patients with suspected gastroesophageal reflux need to undergo a thorough preoperative workup. After establishing diagnosis, treatment for gastroesophageal reflux should be individualized to patient characteristics and a decision about an operation made jointly between surgeon and patient. The indications for surgery have changed in the last twenty years. In the past, surgery was often considered for patients who did not respond well to acid reducing medications. Today, the best candidate for surgery is the patient who has excellent control of symptoms with proton pump inhibitors. The minimally invasive approach to antireflux surgery has allowed surgeons to control reflux in a safe manner, with excellent long term outcomes. Like achalasia and gastroesophageal reflux, the treatment of patients with paraesophageal hernias has also seen a major evolution. The laparoscopic approach has been shown to be safe, and durable, with good relief of symptoms over the long-term. The most significant controversy with laparoscopic paraesophageal hernia repair is the optimal crural repair. This manuscript reviews the evolution of these techniques.

Molecular pathogenesis and therapeutic strategies of human osteosarcoma

Osteosarcoma（OS）is a devastating illness with rapid rates of dissemination and a poor overall prognosis,despite aggressive standard-of-care surgical techniques and combination chemotherapy regimens.Identifying the molecular mechanisms involved in disease pathogenesis and progression may offer insight into new therapeutic targets.Defects in mesenchymal stem cell differentiation,abnormal expression of oncogenes and tumor suppressors,and dysregulation within various important signaling pathways have all been implicated in development of various disease phenotypes.As such,a variety of basic science and translational studies have shown promise in identifying novel markers and modulators of these disease-specific aberrancies.Born out of these and similar investigations,a variety of emerging therapies are now undergoing various phases of OS clinical testing.They broadly include angiogenesis inhibitors,drugs that act on the bone microenvironment,receptor tyrosine kinase inhibitors,immune system modulators,and other radio-or chemo-sensitizing agents.As new forms of drug delivery are being developed simultaneously,the possibility of targeting tumors locally while minimizing systemic toxicityis is seemingly more achievable now than ever.In this review,we not only summarize our current understanding of OS disease processes,but also shed light on the multitude of potential therapeutic strategies the scientific community can use to make long-term improvements in patient prognosis.

Management of granulomatous lobular mastitis: an international multidisciplinary consensus(2021 edition)

Granulomatous lobular mastitis(GLM) is a rare and chronic benign inflammatory disease of the breast. Difficulties exist in the management of GLM for many front-line surgeons and medical specialists who care for patients with inflammatory disorders of the breast. This consensus is summarized to establish evidence-based recommendations for the management of GLM. Literature was reviewed using PubMed from January 1, 1971 to July 31, 2020. Sixty-six international experienced multidisciplinary experts from 11 countries or regions were invited to review the evidence.Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus. Experts discussed and concluded 30 recommendations on historical definitions,etiology and predisposing factors, diagnosis criteria, treatment, clinical stages, relapse and recurrence of GLM. GLM was recommended as a widely accepted definition. In addition, this consensus introduced a new clinical stages and management algorithm for GLM to provide individual treatment strategies. In conclusion, diagnosis of GLM depends on a combination of history, clinical manifestations, imaging examinations, laboratory examinations and pathology.The approach to treatment of GLM should be applied according to the different clinical stage of GLM. This evidencebased consensus would be valuable to assist front-line surgeons and medical specialists in the optimal management of GLM.

Lineage structure of the human antibody repertoire in response to influenza vaccination

The adaptive immune system produces a large and diverse set of antibodies,each with an individual evolutionary and clonal history.This so called"antibody repertoire"protects each individual against insults such as infection and cancer,and responds to vaccination with B cell proliferation in response to the antigenic stimulation.Hybridomas and antigen-specific FACSbased analysis have given us much insight on how the immune system generates the complex and diverse immune response required to protect the body from the wide variety of potential pathogens.However,these methods have not been sufficient to make global and unbiased characterizations of the clonal structure of the immune system of a particular individual。

X-ray detection of ingested non-metallic foreign bodies

AIM: To determine the utility of X-ray in identifying non-metallic foreign body(FB) and assess inter-radiologist agreement in identifying non-metal FB. METHODS: Focus groups of nurses, fellows, and attending physicians were conducted to determine commonly ingested objects suitable for inclusion. Twelve potentially ingested objects(clay, plastic bead, crayon, plastic ring, plastic army figure, glass bead, paperclip, drywall anchor, eraser, Lego?, plastic triangle toy, and barrette) were embedded in a gelatin slab placed on top of a water-equivalent phantom to simulate density of a child's abdomen. The items were selected due to wide availability and appropriate size for accidental pediatric ingestion. Plain radiography of the embedded FBs was obtained. Five experienced radiologists blinded to number and types of objects were asked to identify the FBs. The radiologist was first asked to count thenumber of items that were visible then to identify the shape of each item and describe it to a study investigator who recorded all responses. Overall inter-rater reliability was analyzed using percent agreement and κ coefficient. We calculated P value to assess the probability of error involved in accepting the κ value.RESULTS: Fourteen objects were radiographed including 12 original objects and 2 duplicates. The model's validity was supported by clear identification of a radiolucent paperclip as a positive control, and lack of identification of plastic beads(negative control) despite repeated inclusion. Each radiologist identified 7-9 of the 14 objects(mean 8, 67%). Six unique objects(50%) were identified by all radiologists and four unique objects(33%) were not identified by any radiologist(plastic bead, LegoTM, plastic triangle toy, and barrette). Identification of objects that were not present, false-positives, occurred 1-2 times per radiologist(mean 1.4). An additional 17% of unique objects were identified by less than half of the radiologists. Agreement between radiologists was considered almost perfect(kappa 0.86 ± 0.08, P < 0.0001).CONCLUSION: We demonstrate potential non-identification of commonly ingested non-metal FBs in children. A registry for radiographic visibility of ingested objects should be created to improve clinical decision-making.

Minimally invasive approaches for the treatment of inflammatory bowel disease

Despite significant improvements in medical management of inflammatory bowel disease, many of these patients still require surgery at some point in the course of their disease. Their young age and poor general conditions, worsened by the aggressive medical treatments, make minimally invasive approaches particularly enticing to this patient population. However, the typical inflammatory changes that characterize these diseases have hindered wide diffusion of laparoscopy in this setting, currently mostly pursued in high-volume referral centers, despite accumulating evidences in the literature supporting the benefits of minimally invasive surgery. The largest body of evidence currently available for terminal ileal Crohn's disease shows improved short term outcomes after laparoscopic surgery, with prolonged operative times. For Crohn's colitis, high quality evidence supporting laparoscopic surgery is lacking.Encouraging preliminary results have been obtained with the adoption of laparoscopic restorative total proctocolectomy for the treatment of ulcerative colitis. A consensus about patients' selection and the need for staging has not been reached yet. Despite the lack of conclusive evidence, a wave of enthusiasm is pushing towards less invasive strategies, to further minimize surgical trauma, with single incision laparoscopic surgery being the most realistic future development.

Impact of gender-affirming hormone therapy on the development of COVID-19 infections and associated complications:A systematic review

BACKGROUND Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)can produce a wide range of clinical manifestations from asymptomatic to life-threatening.Various researchers have worked to elucidate the pathogenic mechanisms underlying these variable presentations.Differences in individual responses to systemic inflammation and coagulopathy appear to be modulated by several factors,including sex steroid hormones.Transgender men or non-binary individuals who undergo gender-affirming hormone therapy(GAHT)are a unique population of interest for exploring the androgen-mediated coronavirus disease 2019(COVID-19)hypothesis.As the search for reliable and effective COVID-19 treatments continues,understanding the risks and benefits of GAHT may mitigate COVID-19 related morbidity and mortality in this patient population.AIM To investigate the potential role of GAHT in the development of COVID-19 infections and complications.METHODS This systematic review implemented an algorithmic approach using PRISMA guidelines.PubMed,Scopus,Google Scholar top 100 results,and archives of Plastic and Reconstructive Surgery was on January 12,2022 using the key words“gender”AND“hormone”AND“therapy”AND“COVID-19”as well as associated terms.Non-English articles,articles published prior to 2019(prior to COVID-19),and manuscripts in the form of reviews,commentaries,or letters were excluded.References of the selected publications were screened as well.RESULTS The database search resulted in the final inclusion of 14 studies related to GAHT COVID-19.Of the included studies,only two studies directly involved and reported on COVID-19 in transgender patients.Several clinical trials looked at the relationship between testosterone,estrogen,and progesterone in COVID-19 infected cis-gender men and women.It has been proposed that androgens may facilitate initial COVID-19 infection,however,once this occurs,testosterone may have a protective effect.Multiple clinical studies have shown that low baseline testosterone levels in men with COVID-19 are associated with worsening outcomes.The role of female sex hormones,including estrogen and progesterone have also been proposed as potential protective factors in COVID-19 infection.This was exemplified in multiple studies investigating different outcomes in pre-and post-menopausal women as well as those taking hormone replacement therapy.Two studies related specifically to transgender patients and GAHT found that estrogen and progesterone could help protect men against COVID-19,and that testosterone hormone therapy may increase the risk of contracting COVID-19.CONCLUSION Few studies were found related to the role of GAHT in COVID-19 infections.Additional research is necessary to enhance our understanding of this relationship and provide better care for transgender patients.

Adenovirus-mediated gene delivery:Potential applications for gene and cell-based therapies in the new era of personalized medicine

With rapid advances in understanding molecular pathogenesis of human diseases in the era of genome sciences and systems biology,it is anticipated that increasing numbers of therapeutic genes or targets will become available for targeted therapies.Despite numerous setbacks,efficacious gene and/or cell-based therapies still hold the great promise to revolutionize the clinical management of human diseases.It is wildly recognized that poor gene delivery is the limiting factor for most in vivo gene therapies.There has been a long-lasting interest in using viral vectors,especially adenoviral vectors,to deliver therapeutic genes for the past two decades.Among all currently available viral vectors,adenovirus is the most efficient gene delivery system in a broad range of cell and tissue types.The applications of adenoviral vectors in gene delivery have greatly increased in number and efficiency since their initial development.In fact,among over 2000 gene therapy clinical trials approved worldwide since 1989,a significant portion of the trials have utilized adenoviral vectors.This review aims to provide a comprehensive overview on the characteristics of adenoviral vectors,including adenoviral biology,approaches to engineering adenoviral vectors,and their applications in clinical and preclinical studies with an emphasis in the areas of cancer treatment,vaccination and regenerative medicine.Current challenges and future directions regarding the use of adenoviral vectors are also discussed.It is expected that the continued improvements in adenoviral vectors should provide great opportunities for cell and gene therapies to live up to its enormous potential in personalized medicine.

The wonders of BMP9:From mesenchymal stem cell differentiation,angiogenesis,neurogenesis,tumorigenesis,and metabolism to regenerative medicine

Although bone morphogenetic proteins(BMPs)initially showed effective induction of ectopic bone growth in muscle,it has since been determined that these proteins,as members of the TGF-b superfamily,play a diverse and critical array of biological roles.These roles include regulating skeletal and bone formation,angiogenesis,and development and homeostasis of multiple organ systems.Disruptions of the members of the TGF-b/BMP superfamily result in severe skeletal and extra-skeletal irregularities,suggesting high therapeutic potential from understanding this family of BMP proteins.Although it was once one of the least characterized BMPs,BMP9 has revealed itself to have the highest osteogenic potential across numerous experiments both in vitro and in vivo,with recent studies suggesting that the exceptional potency of BMP9 may result from unique signaling pathways that differentiate it from other BMPs.The effectiveness of BMP9 in inducing bone formation was recently revealed in promising experiments that demonstrated efficacy in the repair of critical sized cranial defects as well as compatibility with bone-inducing bio-implants,revealing the great translational promise of BMP9.Furthermore,emerging evidence indicates that,besides its osteogenic activity,BMP9 exerts a broad range of biological functions,including stem cell differentiation,angiogenesis,neurogenesis,tumorigenesis,and metabolism.This review aims to summarize our current understanding of BMP9 across biology and the body.

Stem cell therapy for chronic skin wounds in the era of personalized medicine:From bench to bedside

With the significant financial burden of chronic cutaneous wounds on the healthcare system,not to the personal burden mention on those individuals afflicted,it has become increasingly essential to improve our clinical treatments.This requires the translation of the most recent benchtop approaches to clinical wound repair as our current treatment modalities have proven insufficient.The most promising potential treatment options rely on stem cellbased therapies.Stem cell proliferation and signaling play crucial roles in every phase of the wound healing process and chronic wounds are often associated with impaired stem cell function.Clinical approaches involving stem cells could thus be utilized in some cases to improve a body’s inhibited healing capacity.We aim to present the laboratory research behind the mechanisms and effects of this technology as well as current clinical trials which showcase their therapeutic potential.Given the current problems and complications presented by chronic wounds,we hope to show that developing the clinical applications of stem cell therapies is the rational next step in improving wound care.

Stem cells, growth factors and scaffolds in craniofacial regenerative medicine

Current reconstructive approaches to large craniofacial skeletal defects are often complicated and challenging.Critical-sized defects are unable to heal via natural regenerative processes and require surgical intervention,traditionally involving autologous bone(mainly in the form of nonvascularized grafts)or alloplasts.Autologous bone grafts remain the gold standard of care in spite of the associated risk of donor site morbidity.Tissue engineering approaches represent a promising alternative that would serve to facilitate bone regeneration even in large craniofacial skeletal defects.This strategy has been tested in a myriad of iterations by utilizing a variety of osteoconductive scaffold materials,osteoblastic stem cells,as well as osteoinductive growth factors and small molecules.One of the major challenges facing tissue engineers is creating a scaffold fulfilling the properties necessary for controlled bone regeneration.These properties include osteoconduction,osteoinduction,biocompatibility,biodegradability,vascularization,and progenitor cell retention.This review will provide an overview of how optimization of the aforementioned scaffold parameters facilitates bone regenerative capabilities as well as a discussion of common osteoconductive scaffold materials.

Gastroesophageal reflux disease:From pathophysiology to treatment

This review focuses on the pathophysiology of gastroesophageal reflux disease (GERD) and its implications for treatment. The role of the natural anti-reflux mechanism (lower esophageal sphincter, esophageal peristalsis, diaphragm, and trans-diaphragmatic pressure gradient), mucosal damage, type of refluxate, presence and size of hiatal hernia, Helicobacter pylori infection, and Barrett’s esophagus are reviewed. The conclusions drawn from this review are: (1) the pathophysiology of GERD is multifactorial; (2) because of the pathophysiology of the disease, surgical therapy for GERD is the most appropriate treatment; and (3) the genesis of esophageal adenocarcinoma is associated with GERD.

Minimally invasive esophagectomy

Esophageal resection is associated with a high morbidity and mortality rate. Minimally invasive esophagectomy (MIE) might theoretically decrease this rate. We reviewed the current literature on MIE, with a focus on the available techniques, outcomes and comparison with open surgery. This review shows that the available literature on MIE is still crowded with heterogeneous studies with different techniques. There are no controlled and randomized trials, and the few retrospective comparative cohort studies are limited by small numbers of patients and biased by historical controls of open surgery. Based on the available literature, there is no evidence that MIE brings clear benef its compared to conventional esophagectomy. Increasing experience and the report of larger series might change this scenario.

Gastroesophageal reflux disease and severe obesity:Fundoplication or bariatric surgery?

Increases in the prevalence of obesity and gastroesophageal reflux disease (GERD) have paralleled one another over the past decade, which suggests the possibility of a linkage between these two processes. In both instances, surgical therapy is recognized as the most effective treatment for severe, refractory disease. Current surgical therapies for severe obesity include (in descending frequency) Roux-en-Y gastric bypass, adjustable gastric banding, sleeve gastrectomy, and biliopancreatic diversion with duodenal switch, while fundoplication remains the mainstay for the treatment of severe GERD. In several large series, however, the outcomes and durability of fundoplication in the setting of severe obesity are not as good as those in patients who are not severely obese. As such, bariatric surgery has been suggested as a potential alternative treatment for these patients. This article reviews current concepts in the putative pathophysiological mechanisms by which obesity contributes to gastroesophageal reflux and their implications with regards to surgical therapy for GERD in the setting of severe obesity.

Transhiatal versus transthoracic esophagectomy for esophageal cancer

Esophageal cancer continues to represent a formidable challenge for both patients and clinicians. Relative 5-year survival rates for patients have improved over the past three decades, probably linked to a combination of improved surgical outcomes, progress in systemic chemotherapy and radiotherapy, and the increasing acceptance of multimodality treatment. Surgical treatment remains a fundamental component of the treatment of localized esophageal adenocarcinoma. Multiple approaches have been described for esophagectomy, which can be thematically grouped under two major categories: either transthoracic or transhiatal. The main controversy rests on whether a more extended resection through thoracotomy provides superior oncological outcomes as opposed to resection with relatively limited morbidity and mortality through a transhiatal approach. After numerous trials have addressed these issues, neither approach has consistently proven to be superior to the other one, and both can provide excellent short-term results in the hands of experienced surgeons. Moreover, the available literature suggests that experience of the surgeonand hospital in the surgical management of esophageal cancer is an important factor for operative morbidity and mortality rates, which could supersede the type of approach selected. Oncological outcomes appear to be similar after both procedures.

Insulin-like growth factor(IGF)signaling in tumorigenesis and the development of cancer drug resistance

One of the greatest obstacles to current cancer treatment efforts is the development of drug resistance by tumors.Despite recent advances in diagnostic practices and surgical interventions,many neoplasms demonstrate poor response to adjuvant or neoadjuvant radiation and chemotherapy.As a result,the prognosis for many patients afflicted with these aggressive cancers remains bleak.The insulin-like growth factor(IGF)signaling axis has been shown to play critical role in the development and progression of various tumors.Many basic science and translational studies have shown that IGF pathway modulators can have promising effects when used to treat various malignancies.There also exists a substantial body of recent evidence implicating IGF signaling dysregulation in the dwindling response of tumors to current standard-of-care therapy.By better understanding both the IGF-dependent and-independent mechanisms by which pathway members can influence drug sensitivity,we can eventually aim to use modulators of IGF signaling to augment the effects of current therapy.This review summarizes and synthesizes numerous recent investigations looking at the role of the IGF pathway in drug resistance.We offer a brief overview of IGF signaling and its general role in neoplasia,and then delve into detail about the many types of human cancer that have been shown to have IGF pathway involvement in resistance and/or sensitization to therapy.Ultimately,our hope is that such a compilation of evidence will compel investigators to carry out much needed studies looking at combination treatment with IGF signaling modulators to overcome current therapy resistance.

Multifaceted signaling regulators of chondrogenesis:Implications in cartilage regeneration and tissue engineering

Defects of articular cartilage present a unique clinical challenge due to its poor self-healing capacity and avascular nature.Current surgical treatment options do not ensure consistent regeneration of hyaline cartilage in favor of fibrous tissue.Here,we review the current understanding of the most important biological regulators of chondrogenesis and their interactions,to provide insight into potential applications for cartilage tissue engineering.These include various signaling pathways,including fibroblast growth factors(FGFs),transforming growth factor b(TGF-b)/bone morphogenic proteins(BMPs),Wnt/b-catenin,Hedgehog,Notch,hypoxia,and angiogenic signaling pathways.Transcriptional and epigenetic regulation of chondrogenesis will also be discussed.Advances in our understanding of these signaling pathways have led to promising advances in cartilage regeneration and tissue engineering.