Associations with Organ Involvement and Autoantibodies in Systemic Sclerosis: Results from the Canadian Scleroderma Research Group (CSRG)

Objective: Serum from SSc patients was analyzed centrally to determine ANA patterns and extractable nuclear antigens (ENAs) between lcSSc and dcSSc and associations with organ involvement. Methods: 1145 SSc patients had ANA and ENA analyzed by indirect immunofluorescence on HEp-2 substrate at a screening serum dilution of 1/160. Most ENA antibodies [Sm. U1-RNP, Ro52, SS-A/Ro60, topoisomeraseI (Topo1), SS-B/La, chromatin, ribosomal P and Jo1] were measured by laser bead immunoassay;and RNA polymerase III (RNAP) by ELISA. Results: ANA was positive in 95% (same in lcSSc, and dcSSc). Centromere pattern was present in 34%, speckled 22%, nucleolar 18%, homogeneous and speckled (H&S) 16%, multiple nuclear dots 6%. Anti-centromere Ab (ACA) occurred in 46% of lcSSc and 11% of dcSSc (P = 0.0001). ENAs that differed between lcSSc and dcSSc subsets were Topo1 (OR 2.4, P = 0.0001) and RNAP (OR 5.6, P 0.0001) more common in dcSSc. Overall, 15% had positive Topo1;usually with a H&S pattern (67%);Topo1 was associated with ILD on CXR (OR 2.3;95% CI 1.5 - 3.5) and HRCT (OR 3.8;95% CI 1.8 - 8.2). RNAP occurred in 18.5% (35.4% in dcSSc vs. 8.9% in lcSSc). Scleroderma renal crisis (SRC) was 13 times more likely if RNAP positive;P = 0.0001. ACA was only weakly associated with sPAP > 50 mmHg (OR 1.8;95%CI 1.1 - 3.0). Conclusion: ANA homogeneous pattern alone is rare in SSc;ACA was significantly more common in lcSSc. Many ENAs are equal in lcSSc and dcSSc except RNAP and Topo1. RNAP has the highest OR of SRC. Topo1 is less strongly associated with ILD. Abstract word count: 249, Body word count 1246, Figures 2, Tables 2. Key Messages: 1) 95% of SSc has a positive ANA and ANA patterns in SSc include centromere, nucleolar, and homogeneous and speckled together;2) Most ENAs are equal in both dcSSc and lcSSc except anti RNA polymerase III and topoisomerase I;3) RNA polymerase III has the highest association (odds ratio) with scleroderma renal crisis, topoisomerase I is associated with interstitial lung disease;whereas anticentromere was not associated with elevated pulmonary arterial pressures on echocardiogram.

Predictors of a Cerebrovascular Accident in a Population of Systemic Sclerosis Patients Followed at a Large Academic Center with a Dedicated Scleroderma Center

Aim: The aim of this study is to describe the clinical characteristics of patients with a diagnosis of systemic sclerosis who later suffer a stroke and to identify associations for this relationship. Background: Prior studies have showed an increased risk of cardiovascular disease among patients with chronic inflammatory disorders, with chronic inflammation leading to atherosclerosis believed to be the culprit. Systemic sclerosis (SSc) is a chronic inflammatory disease characterized by diffuse fibrosis of the skin and internal organs. Previous studies have suggested a possible link between systemic sclerosis and macrovascular complications such as stroke. Methods: This is a retrospective chart review of patients treated within the University of Pennsylvania Health System from October 2015 to April 2019 with a diagnosis of SSc. Using ICD10 codes, we identified a cohort of SSc patients who suffered a stroke. Information regarding demographics and stroke risk factors were gathered from the charts of patients with a diagnosis of both SSc plus stroke and compared to a control group of randomly selected patients with SSc who never suffered a stroke. Continuous variables were conveyed using a mean plus a standard deviation. A two-sample t-test was used to compare the two groups of patients. Qualitative variables were compared using a two-tailed Fisher’s exact test. Results: Based on a large cohort of SSc patients (n = 2080) followed between October 2015 and April 2019, we identified 36 SSc patients who developed a subsequent stroke (1.7% of cohort). When looking at risk factors for stroke in SSc patients, we identified hypertension and atrial fibrillation to be associated with the diagnosis of stroke in such patients. Specifically, 28 of the 36 patients with both SSc and stroke also had a diagnosis of hypertension while in the control group, only 17 of 36 patients had hypertension. Atrial fibrillation was seen in 9 of 36 patients with both SSc and CVA while it was seen in only 2 of 36 patients in the control group. Conclusions: This case control study demonstrated that the presence of hypertension and atrial fibrillation had a statistically significant association with the diagnosis of CVA in patients with SSc.

Systemic Scleroderma at University Teaching Hospital (UTH) of Cocody (Abidjan—Cote d’Ivoire): A 19 Cases Report

Objective: The aim of this study was to describe the epidemiological, clinical and therapeutic features of systemic scleroderma at Cocody UTH. Methodology: We conducted a retrospective and descriptive study over a period of 10 years (September 15, 2008 to April 15, 2019) on the files of patients hospitalized for systemic scleroderma in the rheumatology unit of the UTH of Cocody. We used the classification criteria of the American Society of Rheumatology (1980) to retain the diagnosis. Results: Nineteen patients’ files had been collected, representing a hospital frequency of 0.32%. The average age was 37.25 ± 13.82 years old. There were 15 women and 4 men. The average consultation time was 26.44 months. The mode of revelation of the disease was mostly cutaneous and articular. All patients had cutaneous sclerosis (average Rodnan score = 27.63/11.61 (min = 4, max = 49).) Scleroderma was diffuse in 70.59% of cases;a Raynaud’s phenomenon was seen in 47.37%. The main clinical manifestations were: cutaneous (100%), articular (89.47%), pulmonary (57.89%) and digestive (63.16%). No renal damage was found. Pulmonary fibrosis (5 cases), pulmonary arterial hypertension (3 cases) and pericardial effusion (2 cases) were sometimes founded in explorations. The positivity of antinuclear antibodies (ANA) was seen in 72% of patients and anti scl70 antibodies in 42.85%. The treatment included corticosteroids and immunosuppressants, respectively used in 84.2% and 63.16% of cases. The outcome was marked by 5 cases of death attributed to respiratory distress. Conclusion: Systemic scleroderma seems to be a very rare condition in Ivorian rheumatology milieu. The main systemic manifestations were digestive and pulmonary. Treatment was very often symptomatic sometimes associated with D-penicillamine.

Present and future of new systemic therapies for early and intermediate stages of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a high mortality neoplasm which usually appears on a cirrhotic liver.The therapeutic arsenal and subsequent prognostic outlook are intrinsically linked to the HCC stage at diagnosis.Notwithstanding the current deployment of treatments with curative intent(liver resection/local ablation and liver transplantation)in early and intermediate stages,a high rate of HCC recurrence persists,underscoring a pivotal clinical challenge.Emergent systemic therapies(ST),particularly immunotherapy,have demonstrate promising outcomes in terms of increase overall survival,but they are currently bound to the advanced stage of HCC.This review provides a comprehensive analysis of the literature,encompassing studies up to March 10,2024,evaluating the impact of novel ST in the early and intermediate HCC stages,specially focusing on the findings of neoadjuvant and adjuvant regimens,aimed at increasing significantly overall survival and recurrence-free survival after a treatment with curative intent.We also investigate the potential role of ST in enhancing the downstaging rate for the intermediate-stage HCC initially deemed ineligible for treatment with curative intent.Finally,we critically discuss about the current relevance of the results of these studies and the encouraging future implications of ST in the treatment schedules of early and intermediate HCC stages.

Systemic oncological therapy in breast cancer patients on dialysis

The advancement of renal replacement therapy has significantly enhanced the survival rates of patients with end-stage renal disease(ESRD)over time.How-ever,this prolonged survival has also been associated with a higher likelihood of cancer diagnoses among these patients including breast cancer.Breast cancer treatment typically involves surgery,radiation,and systemic therapies,with ap-proaches tailored to cancer type,stage,and patient preferences.However,renal replacement therapy complicates systemic therapy due to altered drug clearance and the necessity for dialysis sessions.This review emphasizes the need for opti-mized dosing and administration strategies for systemic breast cancer treatments in dialysis patients,aiming to ensure both efficacy and safety.Additionally,ch-allenges in breast cancer screening and diagnosis in this population,including soft-tissue calcifications,are highlighted.

Systemic therapy in gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are the most common type of soft tissue sarcoma in the gastrointestinal tract.Most GISTs have been attributed to activated gain-of-function mutations in either KIT or platelet-derived growth factor receptorα,making these molecular features essential targets for therapeutic interventions.Although surgery is the standard treatment for localized GISTs,patients often experience relapse and disease progression even after surgery.In recent years,targeted therapy has significantly improved the prognosis of patients with advanced GISTs.Imatinib mesylate,a KIT inhibitor,is the first-line treatment for advanced GISTs and has revolutionized the treatment of this disease.However,drug resistance remains a major issue with imatinib treatment,as a significant majority of patients become resistant to imatinib either after initiation or after 2–3 years of treatment.Consequently,novel tyrosine kinase inhibitors such as sunitinib,regorafenib,ripretinib,and avapritinib have been introduced to address drug resistance.Immunotherapy has emerged as a potential approach for the treatment of advanced GISTs.This review comprehensively summarizes the pathogenesis of GISTs and the development of targeted therapies and immunotherapies,provides an overview of the emergence of drug resistance in advanced GISTs,and discusses the challenges and prospects associated with the treatment of GISTs.

Re-evaluating the role of pelvic radiation in the age of modern precision medicine and systemic therapy

The efficacy of pelvic radiation in the management of locally advanced stage rectal cancer has come under scrutiny in the context of modern precision medicine and systemic therapy as evidenced by recent clinical trials such as FOWARC(J Clin Oncol 2019;37:3223-3233),NCT04165772(N Engl J Med 2022;386:2363-2376),and PROSPECT(N Engl J Med 2023;389:322-334).In this review,we comprehensively assess these pivotal trials and offer additional insights into the evolving role of pelvic radiation in contemporary oncology.

Juvenile Systemic Sclerosis: About 9 Cases

Scleroderma is a rare disease with two primary forms: localized scleroderma (LS) and systemic sclerosis (SSc). Both are chronic conditions that can manifest in various patterns (subtypes) and are linked to extracutaneous involvement in pediatric patients. Juvenile SSc poses a higher risk of morbidity and mortality, with patients facing life-threatening complications such as lung, heart, and visceral organ fibrosis, and vasculopathy. In contrast, mortality is extremely rare in juvenile LS, but patients are susceptible to significant morbidity, leading to severe disfigurement and functional impairment. Treatment for scleroderma aims to control inflammation and address specific issues. An early diagnosis significantly enhances the overall outcome. This study conducts a retrospective descriptive analysis aiming to document the clinical manifestations, management approaches, and outcomes of systemic sclerosis in a cohort of nine children receiving treatment for juvenile systemic sclerosis at Pediatric B department of Mohammed VI University, Hospital Center in Marrakech, Morocco.

Iatrogenic scleroderma renal crisis:A case report and mini literature review for renal crisis

Background:Systemic sclerosis is a connective tissue disease characterized by fibrosis of the skin and organs,marked changes in microvascular structure,cellular and humoral immune disorders.Renal involvement is more frequent and mainly characterized by moderate proteinuria,elevated serum creatinine levels,and hypertension.The most common kidney involvement in SSc is scleroderma renal crisis(SRC)that is fatal without prompt intervention.Case report:A 52-year-old Caucasian male with known diffuse cutaneous systemic sclerosis was hospitalized with communityacquired pneumonia.On the fifth day after appropriate antibiotic therapy and 60 mg/day methylprednisolone,decreased urine output,arterial hypertension,decreased renal function and pulmonary edema developed.The patient was diagnosed with a scleroderma renal crisis.Emergency hemodialysis was applied to the patient,and captopril 6×25 mg/day and nifedipine 2*60 mg/day treatment were given.He received a routine hemodialysis program for about three months.The hemodialysis program was terminated when the patient’s urine quality and quantity increased.Conclusions:SRC,characterized by malignant hypertension,azotemia,microangiopathic hemolytic anemia,and kidney failure,is one of the most important complications of systemic sclerosis with a poor prognosis without prompt intervention.Steroid use is one of the important risk factors that precipitate SRC development.With angiotensin-converting enzyme inhibitors,survival increased after SRC,the need for dialysis decreased,and usually allowed the discontinuation of dialysis treatment within about 6-18 months.Suspicion of SRC in the presence of the above-mentioned findings in patients with a diagnosis or suspected systemic sclerosis can be considered the most important treatment step.

Systemic treatment of hepatocellular carcinoma secondary to nonalcoholic fatty liver disease

Hepatocellular carcinoma(HCC)is the third leading cause of cancer death globally,with 15%of cases arising on a background of non-alcoholic fatty liver disease(NAFLD).NAFLD is a heterogenous condition ranging from fatty liver to cirrhosis and is itself a growing global problem,with estimated worldwide prevalence of 50%in 2040.Pathophysiology of NAFLD-HCC is not well understood,there are no dedicated screening programs,and there have been no clinical studies of anticancer treatments in this population specifically.However,the NAFLD-HCC population appears different than other aetiologies-patients tend to be older,diagnosed at more advanced stages,have more comorbidities,and overall worse prognosis.Understanding of best treatment options for this group of patients is an urgent unmet clinical need.This narrative review discusses NAFLD-HCC pathophysiology and systemic treatment,and offers suggestions for future directions in this therapy area.

BCD020 rituximab bioanalog compared to standard treatment in juvenile systemic lupus erythematosus: The data of 12 months casecontrol study

BACKGROUND Systemic lupus erythematosus(SLE)is the most frequent and serious systemic connective tissue disease.Nowadays there is no clear guidance on its treatment in childhood.There are a lot of negative effects of standard-of-care treatment(SOCT),including steroid toxicity.Rituximab(RTX)is the biological B-lymphocyte-depleting agent suggested as a basic therapy in pediatric SLE.AIM To compare the benefits of RTX above SOCT.METHODS The data from case histories of 79 children from the Saint-Petersburg State Pediatric Medical University from 2012 to 2022 years,were analyzed.The diagnosis of SLE was established with SLICC criteria.We compared the outcomes of treatment of SLE in children treated with and without RTX.Laboratory data,doses of glucocorticosteroids,disease activity measured with SELENA-SLEDAI,RESULTS Patients,treated with RTX initially had a higher degree of disease activity with prevalence of central nervous system and kidney involvement,compared to patients with SOCT.One year later the disease characteristics became similar between groups with a more marked reduction of disease activity(SELENA-SLEDAI activity index)in the children who received RTX[-19 points(17;23)since baseline]compared to children with SOCT[-10(5;15.5)points since baseline,P=0.001],the number of patients with active lupus nephritis,and daily proteinuria.During RTX therapy,infectious diseases had three patients;one patient developed a bi-cytopenia.CONCLUSION RTX can be considered as the option in the treatment of severe forms of SLE,due to its ability to arrest disease activity compared to SOCT.

B cell depletion in scleroderma lung disease: A promising new treatment?

Evidence suggests that B cells may participate in the fibrotic process Based on this experimental evidence, treatment with rituximab(RTX) has been tried in systemic sclerosis(SSc) with promising results. In a randomized controlled study from our research group it was shown that treatment with 2 courses of RTX leads to a significant improvement of lung function at 1 year compared to baseline. All relevant studies have so far reported clinical and/or histologic improvement of skin fibrosis something that adds further evidence in favor of a disease modifying role of RTX in SSc. It is more than obvious that novel therapies for SSc-associated lung disease are needed. A large scale, randomized, controlled study assessing the efficacy of RTX in SSc associated interstitial lung disease is warranted. If RTX turns out to be effective it would be a major therapeutic advance in SSc since it can be administered on a long term basis due to its acceptable safety profile.

Journey of a patient with scleroderma from renal failure up to kidney transplantation

The increased awareness of systemic sclerosis(SS)and its pathogenetic background made the management of this disease more amenable than previously thought.However,scleroderma renal crisis(SRC)is a rarely seen as an associated disorder that may involve 2%-15%of SS patients.Patients presented with earlier,rapidly progressing,diffuse cutaneous SS disease,mostly in the first 3-5 years after non-Raynaud clinical manifestations,are more vulnerable to develop SRC.SRC comprises a collection of acute,mostly symptomatic rise in blood pressure,elevation in serum creatinine concentrations,oliguria and thrombotic microangiopathy in almost 50%of cases.The advent of the antihypertensive angiotensin converting enzyme inhibitors in 1980 was associated with significant improvement in SRC prognosis.In a scleroderma patient maintained on regular dialysis;every effort should be exerted to declare any possible evidence of renal recovery.A given period of almost two years has been suggested prior to proceeding in a kidney transplant(KTx).Of note,SS patients on dialysis have the highest opportunity of renal recovery and withdrawal from dialysis as compared to other causes of end-stage renal disease(ESRD).KTx that is the best well-known therapeutic option for ESRD patients can also be offered to SS patients.Compared to other primary renal diseases,SS-related ESRD was considered for a long period of poor patient and allograft survivals.Pulmonary involvement in an SS patient is considered a strong post-transplant independent risk factor of death.Recurrence of SRC after transplantation has been observed in some patients.However,an excellent post-transplant patient and graft outcome have been recently reported.Consequently,the absence of extrarenal manifestations in an SS-induced ESRD patient can be accepted as a robust indicator for a successful KTx.

Combining local regional therapy and systemic therapy:Expected changes in the treatment landscape of recurrent hepatocellular carcinoma

Improvements in early screening,new diagnostic techniques,and surgical treatment have led to continuous downward trends in hepatocellular carcinoma(HCC)morbidity and mortality rates.However,high recurrence and refractory cancer after hepatectomy remain important factors affecting the long-term prognosis of HCC.The clinical characteristics and prognosis of recurrent HCC are heterogeneous,and guidelines on treatment strategies for recurrent HCC are lacking.Therapies such as surgical resection,radiofrequency ablation,and transhepatic arterial chemoembolization are effective for tumors confined to the liver,and targeted therapy is a very important treatment for unresectable recurrent HCC with systemic metastasis.With the deepening of the understanding of the immune microenvironment of HCC,blocking immune checkpoints to enhance the antitumor immune response has become a new direction for the treatment of HCC.In addition,improvements in the tumor immune microenvironment caused by local treatment may provide an opportunity to improve the therapeutic effect of HCC treatment.Ongoing and future clinical trial data of combined therapy may develop the new treatment scheme for recurrent HCC.This paper reviews the pattern of recurrent HCC and the characteristics of the immune microenvironment,demonstrates the basis for combining local treatment and systemic treatment,and reports current evidence to better understand current progress and future approaches in the treatment of recurrent HCC.

Pembrolizumab induced scleroderma

Systemic sclerosis(SSc)is a rare connective tissue disorder.It is a chronic multisystem disease characterized by vascular dysfunction and progressive fibrosis of tissue,with skin hardening and thickening(known as scleroderma)being the hallmark of the disease.It tends to affect females more than males and has a higher prevalence in African American population with earlier onset and more severe disease.While scleroderma can be a manifestation of conditions other than SSC,the presence of skin thickening of the fingers,extending proximally to metacarpophalangeal joints is sufficient to classify a patient as having SSc.SSc treatment is challenging given the heterogeneity of the disease,multiple organ involvement,different subtypes and poorly understood etiology and pathogenesis.Yet,systemic immunosuppressive therapy is often the treatment of choice.Here we present a 60-year-old white female who developed skin thickening of her fingers extending to the forearms and of her proximal thighs after being treated with pembrolizumab for metastatic non-small cell lung cancer.It was difficult to determine internal organ involvement given her history of metastatic lung cancer,but scleroderma specific autoantibodies were negative.Her symptoms improved after treatment with methotrexate and stopping pembrolizumab.This is one of the first case reports of scleroderma secondary to pembrolizumab.

Systemic treatment for metastatic colorectal cancer

Significant progress has been achieved in the treatment of metastatic colorectal cancer(mCRC)patients during the last 20 years.There are currently numerous treatments available for the first-line treatment of mCRC.Sophisticated molecular technologies have been developed to reveal novel prognostic and predictive biomarkers for CRC.The development of next-generation sequencing and wholeexome sequencing,which are strong new tools for the discovery of predictive molecular biomarkers to facilitate the delivery of customized treatment,has resulted in tremendous breakthroughs in DNA sequencing technology in recent years.The appropriate adjuvant treatments for mCRC patients are determined by the tumor stage,presence of high-risk pathologic characteristics,microsatellite instability status,patient age,and performance status.Chemotherapy,targeted therapy,and immunotherapy are the main systemic treatments for patients with mCRC.Despite the fact that these novel treatment choices have increased overall survival for mCRC,survival remains optimal for individuals with non-metastatic disease.The molecular technologies currently being used to support our ability to practice personalized medicine;the practical aspects of applying molecular biomarkers to regular clinical practice;and the evolution of chemotherapy,targeted therapy,and immunotherapy strategies for the treatment of mCRC in the front-line setting are all reviewed here.

Application of Nano-Delivery Systems in Lymph Nodes for Tumor Immunotherapy

Immunotherapy has become a promising research“hotspot”in cancer treatment.“Soldier”immune cells are not uniform throughout the body;they accumulate mostly in the immune organs such as the spleen and lymph nodes(LNs),etc.The unique structure of LNs provides the microenvironment suitable for the survival,activation,and proliferation of multiple types of immune cells.LNs play an important role in both the initiation of adaptive immunity and the generation of durable anti-tumor responses.Antigens taken up by antigen-presenting cells in peripheral tissues need to migrate with lymphatic fluid to LNs to activate the lymphocytes therein.Meanwhile,the accumulation and retaining of many immune functional compounds in LNs enhance their efficacy significantly.Therefore,LNs have become a key target for tumor immunotherapy.Unfortunately,the nonspecific distribution of the immune drugs in vivo greatly limits the activation and proliferation of immune cells,which leads to unsatisfactory anti-tumor effects.The efficient nano-delivery system to LNs is an effective strategy to maximize the efficacy of immune drugs.Nano-delivery systems have shown beneficial in improving biodistribution and enhancing accumulation in lymphoid tissues,exhibiting powerful and promising prospects for achieving effective delivery to LNs.Herein,the physiological structure and the delivery barriers of LNs were summarized and the factors affecting LNs accumulation were discussed thoroughly.Moreover,developments in nano-delivery systems were reviewed and the transformation prospects of LNs targeting nanocarriers were summarized and discussed.

Ionizable drug delivery systems for efficient and selective gene therapy

Gene therapy has shown great potential to treat various diseases by repairing the abnormal gene function.However,a great challenge in bringing the nucleic acid formulations to the market is the safe and effective delivery to the specific tissues and cells.To be excited,the development of ionizable drug delivery systems(IDDSs)has promoted a great breakthrough as evidenced by the approval of the BNT162b2 vaccine for prevention of coronavirus disease 2019(COVID-19)in 2021.Compared with conventional cationic gene vectors,IDDSs can decrease the toxicity of carriers to cell membranes,and increase cellular uptake and endosomal escape of nucleic acids by their unique pH-responsive structures.Despite the progress,there remain necessary requirements for designing more efficient IDDSs for precise gene therapy.Herein,we systematically classify the IDDSs and summarize the characteristics and advantages of IDDSs in order to explore the underlying design mechanisms.The delivery mechanisms and therapeutic applications of IDDSs are comprehensively reviewed for the delivery of plasmid DNA(pDNA)and four kinds of RNA.In particular,organ selecting considerations and high-throughput screening are highlighted to explore efficiently multifunctional ionizable nanomaterials with superior gene delivery capacity.We anticipate providing references for researchers to rationally design more efficient and accurate targeted gene delivery systems in the future,and indicate ideas for developing next generation gene vectors.

Systemic treatment for advanced pancreatic cancer

Pancreatic cancer is a deadly disease with an extremely poor 5-year survival rate due to treatment resistance and late-stage detection.Despite numerous years of research and pharmaceutical development,these figures have not changed.Treatment options for advanced pancreatic cancer are still limited.This illness is typically detected at a late stage,making curative surgical resection impossible.Chemotherapy is the most commonly utilized technique for treating advanced pancreatic cancer but has poor efficacy.Targeted therapy and immunotherapy have made significant progress in many other cancer types and have been proven to have extremely promising possibilities;these therapies also hold promise for pancreatic cancer.There is an urgent need for research into targeted treatment,immunotherapy,and cancer vaccines.In this review,we emphasize the founda-tional findings that have fueled the therapeutic strategy for advanced pancreatic cancer.We also address current advancements in targeted therapy,immuno-therapy,and cancer vaccines,all of which continue to improve the clinical outcome of advanced pancreatic cancer.We believe that clinical translation of these novel treatments will improve the low survival rate of this deadly disease.

Systematic sequential therapy for ex vivo liver resection and autotransplantation: A case report and review of literature

BACKGROUND Perihilar cholangiocarcinoma(pCCA)is a highly malignant tumor arising from the biliary tree.Radical surgery is the only treatment offering a chance of long-term survival.However,limited by the tumor’s anatomic location and peri-vascular invasion,most patients lose the chance for curative treatment.Therefore,more methods to increase the resectability of tumors as well as to improve outcomes are needed.CASE SUMMARY A 68-year-old female patient had a hepatic hilar mass without obvious symptoms.Laboratory results showed hepatitis B positivity.Magnetic resonance imaging indicated that the mass(maximum diameter:41 mm)invaded the left and right branches of the main portal vein,as well as the middle,left and right hepatic veins;enlarged lymph nodes were also detected in the hilum.The patient was diagnosed with pCCA,and the clinical stage was determined to be T4N1M0(stage IIIC).Considering the tumor’s anatomic location and vascular invasion,systematic conversion therapy followed by ex vivo liver resection and autotrans-plantation(ELRA)was determined as personalized treatment for this patient.Our original systemic sequential therapeutic strategy(lenvatinib and tislelizumab in combination with gemcitabine and cisplatin)was successfully adopted as conversion therapy because she achieved partial response after three cycles of treatment,without severe toxicity.ELRA,anastomotic reconstruction of the middle hepatic vein,right hepatic vein,root of portal vein,inferior vena cava and right hepatic artery,and lymph node dissection were performed at one month after systemic therapy.Pathological and immunohistochemical examination confirmed the diagnosis of pCCA with lymph node metastasis.Although the middle hepatic vein was partially obstructed four months later,hepatic vein stent implantation successfully addressed this problem.The patient has survived for 22 mo after the diagnosis,with no evidence of recurrence or metastasis.CONCLUSION An effective therapeutic strategy for conversion therapy greatly increases the feasibility and efficiency of ELRA.