Clinical features, treatment, and outcome of nivolumab-induced cholangitis.

BACKGROUND: Cholangitis is an uncommon and severe adverse reaction of nivolumab with unclear clinical features. The purpose of this study was to investigate the clinicopathological features, imaging, and treatment of nivolumab-induced cholangitis. METHODS: Case reports, case series, and clinical studies of nivolumab-induced cholangitis were retrospectively analyzed by searching Chinese and English databases from January 1, 2017 to December 31, 2023. RESULTS: Thirty-eight patients entered the study. The median number of cycles of cholangitis onset was seven cycles after administration (range 1, 28) and the median time was 11 days (range 78, 390). Abdominal pain (42.1%) and fever (18.4%) were the most important initial symptoms. Some patients (15.8%) showed elevated liver enzymes without any clinical symptoms. The median alkaline phosphatase level was 1721 IU/L (range 126, 9118), and the median γ-glutamyltranspeptidase level was 829 IU/L (range 104, 3442). Anti-nuclear antibodies, anti-mitochondrial antibodies, and IgG4 typically show negative results. Imaging shows extrahepatic bile duct and intrahepatic bile duct dilation, hypertrophy, and stenosis. Liver biopsy and biliary tract biopsy mainly found CD8 inflammatory cell infiltration. Systemic steroids (84.2%) and ursodeoxycholic acid (UDCA) (34.2%) were administered, and 24 patients (63.2%) had poor to moderate response to steroids. Thirty-one patients (81.6%) improved and seven patients (18.4%) did not improve. CONCLUSIONS: Clinicians must remain vigilant for patients experiencing cholestasis while on nivolumab and should assess for cholangitis and carry out appropriate imaging tests. Considering the excellent efficacy of UCDA in cholangitis, steroids combined with UDCA may be a viable treatment option in cases where steroids are ineffective for cholangitis.

Clinical characteristics, treatment, and outcomes of nivolumab induced immune thrombocytopenia.

Immune thrombocytopenia (ITP) represents an uncommon hematological side effect associated with nivolumab, and its distinct clinical attributes remain poorly defined. This research aimed to explore the clinical manifestations and outcomes of ITP induced by nivolumab. Reports on nivolumab induced ITP up to April 30, 2024, were collected for retrospective analysis. The study involved 34 patients with a median age of 67 years (range 32, 82). The onset of ITP varied from 10 to 100 days post initial dosage, with a median onset at 70 days. The majority of patients exhibited no symptoms, with only 23.5% experiencing clinically significant bleeding and 11.8% facing non-clinically significant bleeding. The median platelet count was 12 × 109/L (range 0, 115), with 67.6% of patients having platelet levels below 25 × 109/L. Bone marrow biopsy revealed mainly elevated megakaryocytes. Platelet-associated IgG levels were elevated with a median of 210 ng/107 cells (range 73, 1130). Subsequent interventions, which included cessation of nivolumab, administration of systemic corticosteroids, intravenous immunoglobulin therapy, a thrombopoietin receptor agonist, platelet transfusion, and rituximab treatment, resulted in 82.4% of subjects achieving normalized platelet counts, whereas 5.9% passed away due to ITP. ITP is a rare life-threatening immune-related adverse event and necessitates close monitoring. Systemic steroids are the primary treatment for ITP, while intravenous immunoglobulin, thrombopoietin receptor agonist and rituximab are other options.

Clinical Features, Treatment, and Outcomes of Nivolumab-Induced Hemophagocytic Lymphohistiocytosis.

Haemophagocytic lymphohistiocytosis (HLH) is a rare and fatal immune-related event of nivolumab. The clinical features of nivolumab-induced HLH are unclear. The aim of this study was to investigate the clinical features, treatment, and outcome of nivolumab-induced HLH to provide information for prevention and treatment. We collected nivolumab-induced HLH-related case reports for retrospective analysis by searching the Chinese and English databases from inception to March 31, 2024. HLH developed in 24 patients, with a median age of 57 years (range: 26, 86). The onset of HLH symptoms ranged from 3 days to 68 weeks after administration, with a median time of 5.5 weeks. Fever (87.5%) was the most common symptom and could be accompanied by splenomegaly (66.7%) and hepatomegaly (20.8%). Laboratory tests revealed hemocytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, increased sCD25, and decreased natural killer cell activity. Bone marrow biopsy showed hemophagocytosis (62.5%). After discontinuing nivolumab, HLH patients receiving systemic steroids, tocilizumab, and anakinra showed positive results. As a rare adverse reaction of nivolumab, HLH requires rapid diagnosis and appropriate treatment based on clinical symptoms and laboratory tests. Tocilizumab and anakinra can be used as an effective treatment against the steroid HLH.

Clinical characteristics, treatment and outcome of pembrolizumab-induced acute pancreatitis.

Acute pancreatitis (AP) is a rare adverse event of pembrolizumab with unclear clinical features. This study investigated the clinical features of pembrolizumab-induced AP to provide a reference for prevention and treatment. Case reports, case series and clinical studies of pembrolizumab-induced AP were collected by searching Chinese and English databases up to January 31, 2024. Thirty-one patients were included, with a median age of 59 years (range 39, 82). The median time from administration to onset of AP was 5.05 months (range 0.5, 16) and the median cycle was 7 cycles (range 1, 35). Twenty-two (71.0%) patients had elevated pancreatic amylase with a median value of 860 IU/L (range 105-12562), and 16 (51.6%) patients had elevated lipase with a median value of 282 IU/L (range 153-1034). Pancreatic biopsy showed neutrophil infiltration (9.7%) and lymphocyte infiltration (6.5%). Immunohistochemical staining showed CD8 dominated inflammatory infiltration (6.5%). The computed tomography showed diffuse enlargement (51.6%) and focal enlargement (51.6%) of the pancreas. Endoscopic ultrasound showed enlarged hypoechoic pancreas(16.1%). PET/CT showed increased FDG uptake (16.1%). The magnetic resonance cholangial pancreatography showed narrowing of main pancreatic duct (12.9%). AP symptoms and pancreatic enzymes improved after discontinuation of pembrolizumab and administration of steroids and infliximab. Clinicians should be aware that AP is a rare adverse reaction to pembrolizumab. Pembrolizumab induced AP can be initiated with steroids for control, and infliximab can be initiated with steroid-refractory AP.

Clinical features, treatment, and outcomes of patients with carfilzomib induced thrombotic microangiopathy.

BACKGROUND: Thrombotic microangiopathy (TMA) is associated with carfilzomib, and knowledge of carfilzomib-induced TMA is based mainly on case reports. This study investigated the clinical characteristics of patients with carfilzomib-induced TMA and provided a reference for the rational use of carfilzomib. METHODS: Reports of carfilzomib-induced TMA were collected for retrospective analysis by searching the Chinese and English databases from inception to January 31, 2024. RESULTS: Sixty-six patients were included, with a median age of 63 years (range 39, 85). The median time to onset of TMA was 42 days (range 1, 1825) from initial administration, and the median number of cycles was 3 cycles (range 1, 15). Hemolytic anemia was recorded in 64 patients, with a median of 8.3 g/dL (range 4.6, 13). Sixty-three patients had thrombocytopenia with a median of 18 × 109/L (range 1, 139). The median value of increased LDH was 1192 IU/L (range 141, 5378). ADAMTS13 activity was normal in 41 (62.1 %) of the 42 patients. Mutations were found in 9 (13.6 %) of the 15 patients. Fifty-seven patients achieved a clinical response after discontinuing carfilzomib and receiving therapeutic plasma exchange (53.0 %), eculizumab (24.2 %), or hemodialysis (39.4 %). CONCLUSION: Carfilzomib-induced TMA is an important adverse event that should be considered in patients receiving carfilzomib for multiple myeloma with anemia, thrombocytopenia, and acute kidney injury. Withdrawal of carfilzomib and treatment with eculizumab have proven successful in some patients.

Clinical Characteristics and Outcomes of Pembrolizumab Induced Gastritis: A Systematic Review of the Literature.

BACKGROUND: Pembrolizumab is associated with the development of gastritis, but its clinical features have not been characterized. To explore the clinical features of pembrolizumab induced gastritis and provide reference for the prevention and treatment of gastritis. METHODS: Case reports and case series related to pembrolizumab induced gastritis were retrospectively analyzed by searching the database from inception to September 30, 2023. RESULTS: Thirty-nine patients with gastritis entered the study with a median age of 63 years (range 34, 81). The median time to gastritis was 11.1 months (range 0.3, 60) and 7 cycles (range 1, 27) after administration. Epigastric pain (24 cases, 61.5%), nausea (17 cases, 43.6%), and vomiting (16 cases, 41.0%) were the most frequently complained symptoms. Esophagogastroduodenoscopy mainly showed erythematous (16 cases, 41.0%), hemorrhage (14 cases, 35.9%) and erosions (11 cases, 28.2%). Gastric mucosal biopsy shows chronic active gastritis with lymphocytic infiltration. These patients' symptoms and gastric mucosa improved or recovered after receiving systemic steroid and proton pump inhibitor therapy regardless of whether pembrolizumab was discontinued. These patients' symptoms and gastric mucosa improved or recovered after treatment with systemic steroids, proton pump inhibitors, and biological agents. CONCLUSIONS: Gastritis is an extremely rare adverse effect of pembrolizumab. When patients receiving pembrolizumab complain of abdominal symptoms, endoscopy, tissue biopsy, and immunohistochemical staining should be actively performed for early identification and diagnosis of gastritis.

Clinical features, treatment, and outcome of pembrolizumab induced cholangitis.

Pembrolizumab induced hepatitis has received increasing attention, while pembrolizumab induced cholangitis is poorly understood. This study investigated the clinical features, treatment, and outcome of pembrolizumab induced cholangitis. Case reports, case series and clinical studies of pembrolizumab induced cholangitis were collected by retrieving English and Chinese database from inception until October 30, 2023. Fifty patients with cholecystitis entered our study with a median age of 68 years (range 48, 89). The median time to onset of cholecystitis was 1.1 months (range 0.3, 24), and the median number of cycles was 5 cycles (range 1, 27) after initial administration. Most of the patients had no clinical symptoms and only showed elevated biliary enzymes (24 cases, 48.0%), while some patients showed jaundice (12 cases, 24.0%), abdominal pain (10 cases, 20.0%) and fever (7 cases, 14.0%). The median alkaline phosphatase value was 1111 IU(range 130, 3515) and the median glutamyltransferase value was 649.5 IU(range 159, 3475). The imaging features of gallbladder were bile duct dilatation, stenosis and bile duct wall thickening and irregularity. Bile duct biopsy showed inflammatory infiltration, mainly CD8 + T cell infiltration. Immunosuppression treatment resulted in complete response in 4 cases (8.0%), partial response in 28 cases (56.0%), and poor response in 15 cases (30.0%). Cholangitis is a rare and serious adverse effect of pembrolizumab. Clinicians should be aware of the possibility of cholangitis when administering pembrolizumab. Steroids may not be effective in most patients with cholecystitis, and ursodeoxycholic acid may be an option.

Modular access to chiral bridged piperidine-γ-butyrolactones via catalytic asymmetric allylation/aza-Prins cyclization/lactonization sequences.

Chiral functionalized piperidine and lactone heterocycles are widely spread in natural products and drug candidates with promising pharmacological properties. However, there remains no general asymmetric methodologies that enable rapid assemble both critical biologically important units into one three-dimensional chiral molecule. Herein, we describe a straightforward relay strategy for the construction of enantioenriched bridged piperidine-γ-butyrolactone skeletons incorporating three skipped stereocenters via asymmetric allylic alkylation and aza-Prins cyclization/lactonization sequences. The excellent enantioselectivity control in asymmetric allylation with the simplest allylic precursor is enabled by the synergistic Cu/Ir-catalyzed protocol; the success of aza-Prins cyclization/lactonization can be attributed to the pivotal role of the ester substituent, which acts as a preferential intramolecular nucleophile to terminate the aza-Prins intermediacy of piperid-4-yl cation species. The resulting chiral piperidine-γ-butyrolactone bridged-heterocyclic products show impressive preliminary biological activities against a panel of cancer cell lines.

Clinical characteristics, diagnosis, treatment, and prognosis of nivolumab induced gastritis.

Gastritis has recently been reported to be associated with nivolumab, and the clinical characteristics of nivolumab induced gastritis remain unclear. To explore the clinical characteristics of nivolumab induced gastritis, and to provide reference for the classification and treatment guidelines of immune checkpoint inhibitors -related gastritis. Case reports, case series, and clinical studies of nivolumab induced gastritis were retrospectively analyzed by searching the database from the establishment of the database until September 30, 2023. Forty-seven were included, with a median age of 57 years (range 16, 93). The median time of symptom onset was 6 months (range 0.5,36) and 6.5 cycles (range 2, 62). Nausea (29 cases, 61.7%), vomiting (29 cases, 61.7%), and epigastric pain (28 cases, 59.6%) were the most common complaints. Esophagogastroduodenoscopy mainly showed erythema (28 cases, 59.6%). Gastric mucosa biopsy showed epithelial inflammatory cell infiltration (22 cases, 46.8%) and apoptosis (15 cases, 31.9%). Most patients' symptoms and gastric mucosa improved or recovered after receiving systemic steroid and proton pump inhibitor therapy regardless of whether nivolumab was discontinued. Two patients died from gastritis related events. Gastritis should be considered as the cause of unexplained epigastric symptoms in the administration of nivolumab. Understanding the clinical features of nivolumab induced gastritis is very important for accurate diagnosis and timely management of these patients.

Comparison of clinical outcomes among patients with isolated axial vs muscular calf vein thrombosis: A systematic review and meta-analysis.

OBJECTIVE: Thrombi in the axial calf veins have quite different anatomical and physiological characteristics from that in the muscular calf veins, but their treatment was usually addressed in the same manner. We performed a meta-analysis of randomized and cohort studies to compare clinical outcomes among patients with isolated axial vs muscular calf deep vein thrombosis (DVT). METHODS: Recurrent venous thromboembolism (VTE) was selected as the primary outcome. Resolution, proximal propagation of calf DVT, pulmonary embolism (PE), major bleeds, and clinically relevant non-major bleeds were separately analyzed as secondary outcomes. Data were pooled and compared with risk ratio (RR) and 95% confidence interval (CI). RESULTS: Thirteen studies, consisting of 4889 patients, met the inclusion criteria and were included for analysis. A greater rate of recurrent VTE (FE model: RR, 1.23; 95% CI, 1.00-1.53; I2 = 29%), resolution (FE model: RR, 1.32; 95% CI, 1.01-1.72; I2 = 31%), proximal propagation (FE model: RR, 1.63; 95% CI, 1.10-2.41; I2 = 40%), and PE (FE model: RR, 2.79; 95% CI, 1.31-5.95; I2 = 0%) in the axial group compared with the muscular group. There was no difference in the pooled estimates for major bleeds (FE model: RR, 1.09; 95% CI, 0.61-1.95; I2 = 0%), and clinically relevant non-major bleeds (FE model: RR, 1.80; 95% CI, 0.93-3.48) in the axial and muscular arms. CONCLUSIONS: Patients with calf DVT limited to muscular veins might have a lower rate of recurrent VTE, resolution, proximal propagation, and PE vs those with axial calf vein involvement and exhibited similar safety outcomes.

Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ-Hydroxy α-Amino Acids and Small Peptides.

An atom- and step-economical and redox-neutral cascade reaction enabled by asymmetric bimetallic relay catalysis by merging a ruthenium-catalyzed asymmetric borrowing-hydrogen reaction with copper-catalyzed asymmetric Michael addition has been realized. A variety of highly functionalized 2-amino-5-hydroxyvaleric acid esters or peptides bearing 1,4-non-adjacent stereogenic centers have been prepared in high yields with excellent enantio- and diastereoselectivity. Judicious selection and rational modification of the Ru catalysts with careful tuning of the reaction conditions played a pivotal role in stereoselectivity control as well as attenuating undesired α-epimerization, thus enabling a full complement of all four stereoisomers that were otherwise inaccessible in previous work. Concise asymmetric stereodivergent synthesis of the key intermediates for biologically important chiral molecules further showcases the synthetic utility of this methodology.

Organocatalytic atroposelective synthesis of axially chiral N,N'-pyrrolylindoles via de novo indole formation.

The first organocatalytic atroposelective synthesis of axially chiral N,N'-pyrrolylindoles based on o-alkynylanilines was successfully established via de novo indole formation catalyzed by chiral phosphoric acid (CPA). This new synthetic strategy introduced CPA-catalyzed asymmetric 5-endo-dig cyclization of new well-designed o-alkynylanilines containing a pyrrolyl unit, resulting in a wide range of axially chiral N,N'-pyrrolylindoles in high yields with exclusive regioselectivity and excellent enantioselectivity (up to 99% yield, >20 : 1 rr, 95 : 5 er). Considering the potential biological significance of N-N atropisomers, preliminary biological activity studies were performed and revealed that these structurally important N,N'-pyrrolylindoles had a low IC50 value with promising impressive cytotoxicity against several kinds of cancer cell lines. DFT studies reveal that the N-nucleophilic cyclization mediated by CPA is the rate- and stereo-determining step, in which ligand-substrate dispersion interactions facilitate the axial chirality of the target products.

Clinical characteristics, treatment, and management of pembrolizumab induced hemophagocytic lymphohistiocytosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare and fatal adverse reaction to pembrolizumab. The clinical characteristics of pembrolizumab induced HLH are unknown. Exploring the clinical features of pembrolizumab induced HLH is crucial for the treatment and prevention of immune checkpoint inhibitor-induced HLH. METHODS: The literature related to pembrolizumab induced HLH was collected for retrospective analysis by searching the Chinese and English databases from inception until August 31, 2023. RESULTS: A total of 24 patients were included, including 17 men (70.8%) with a median age of 61 years (41,80). The time between the last infusion and the start of HLH ranged from 2 to 46 days, with a median time of 14 days. Fever (100%) was the most common symptom, accompanied by splenomegaly (14 cases, 58.3%) and hepatomegaly (6 cases, 25.0%). Laboratory examination revealed revealed anemia (18 cases, 75.0%), leukopenia (12 cases, 50.0%), thrombocytopenia (20 cases, 83.3%), hypertriglyceridemia (11 cases, 45.8%), hypofibrinogenemia (11 cases, 45.8%). decreased natural killer cell function (7 cases, 29.2%), and elevated soluble CD25(15 cases, 62.5%). All patients developed hyperferriinemia, with a median of 30,808 ng/mL (range 1303 ~ 100,000). Bone marrow biopsy showed hemophagocytosis (15 cases, 62.5%). After discontinuation of pembrolizumab and treatment with steroids, etoposide, intravenous immunoglobulin, cytokine blocking, and immunosuppression, 17 patients recovered or improved, and 5 patients eventually died. CONCLUSION: HLH should be suspected when unexplained fever, cytopenia, splenomegaly, and elevated aminotransferase occur in patients using pembrolizumab. Screening for risk factors before treatment with pembrolizumab may be necessary to prevent HLH.

Clinical characterization, treatment, and outcome of nivolumab-induced bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is a serious and rare complication of nivolumab. This study aimed to explore the clinical characteristics of nivolumab-induced BP and provide a reference for prevention and treatment of BP. METHODS: Literature on nivolumab-induced BP was collected for retrospective analysis by searching both Chinese and English databases as of July 31, 2023. RESULTS: Sixty patients were included, with a median age of 71 years (range 30 to 85 years), and they were predominantly male (78.3%). The median time to onset of BP was 31 weeks (range 2.4, 216) after nivolumab administration. Tense bullae (93.3%), pruritus (55.0%), and urticarial plaques (31.7%) were the most common manifestations. Lesions were found on the limbs (50.0%), trunk (38.3%), palms and soles (15.0%). Skin biopsies mainly showed subepidermal bullous/blister (50.0%) and eosinophilic infiltration (46.7%). Direct immunofluorescence showed mainly linear deposition of C3 and IgG (46.7%) at the dermal-epidermal junction. The patients stopped taking nivolumab and received systemic steroids (73.3%), topical steroids (63.3%), monoclonal antibodies (21.7%), doxycycline/minocycline (30.0%) and other treatments. Symptoms improved or were relieved in 88.4% of patients but did not improve in 8.3% of patients. CONCLUSION: Clinicians should closely monitor symptoms of BP in those receiving and discontinuing nivolumab, especially in older men. Early diagnosis and timely initiation of treatment may improve patient outcomes.

Clinical characteristics, treatment and outcome of nivolumab-induced myasthenia gravis.

BACKGROUND: To investigate the clinical features of nivolumab-induced myasthenia gravis (MG) and provide evidence for the rational use of nivolumab in the clinic. METHODS: We collected case reports and case series of nivolumab-induced MG for retrospective analysis by searching Chinese and English databases from 2014 to October 31, 2022. RESULTS: Of the 67 patients included, the median age was 72.5 years (range 34-86), including 44 males (65.7%). MG occurred in the median 2nd treatment cycle (range, 1st-6th) after nivolumab treatment, being mild in 12 patients (17.9%) and moderate to severe in 44 patients (65.7%). Ptosis (n = 48,71.6%), diplopia (n = 34,50.7%), dyspnea (n = 30, 44.8%), limb muscle weakness (n = 30, 44.8%) and dysphagia (n = 27, 40.3%) were the most common symptoms. Fifty-six patients (83.6%) were classified as having generalized myasthenia gravis (GMG), the remaining 11 patients (16.4%) isolated ocular myasthenia gravis (OMG). Twenty-one patients (31.3%) had MG combined with myositis, 10 patients (14.9%) had myocarditis, and 9 patients (13.4%) had both myositis and myocarditis. Forty patients (59.7%) were positive for anti-acetylcholine receptor antibodies. The serum creatine kinase level was significantly increased in 37 patients (55.2%), with a median value of 4000 IU/L (219,14229). After discontinuation of nivolumab and immunosuppressive therapy, 46 patients (68.7%) finally recovered or improved their MG symptoms, while 15 patients (22.4%) did not recover. Eleven patients (16.4%) died of MG complications. CONCLUSION: MG is a serious and rare adverse reaction to nivolumab. Nivolumab-induced MG should be timely and correctly identified, and immunotherapy should be given.

Clinical features, diagnosis, and management of pembrolizumab-induced myasthenia gravis.

Myasthenia gravis (MG) is a rare but life-threatening adverse event with pembrolizumab. What is known about pembrolizumab-induced MG is largely based on case reports. This analysis collected pembrolizumab-induced MG cases from Chinese and English databases published from September 1, 2014, to June 30, 2022. Demographic and clinical information of the patients, management, and outcome data were collected and analyzed. Sixty-five patients with a median age of 73 years (range 30-86), including 43 male patients (66.2%), were included. Eight patients (12.3%) with prior MG experienced worsening symptoms after receiving pembrolizumab. The median time to the onset of MG was four weeks (range 0.7-27). The most common symptoms were ptosis (81.5%, 53 patients), diplopia (50.8%, 33 patients), dyspnea (44.6%, 29 patients), trunk or peripheral weakness (43.1%, 28 patients), and dysphagia (30.8%, 20 patients). Concurrent myositis and myocarditis occurred in 13 (20.0%) and 17 patients (26.2%). Pembrolizumab was discontinued in 63 patients (96.9%). Forty-four patients (67.7%) received combination therapies based on steroids (intravenous immune globulin, plasmapheresis, or immunosuppressants). Twenty-seven patients (41.5%) had symptoms completely recovered. Fourteen patients (21.5%) died from immunotoxicity or primary cancers. Clinicians should consider the possibility of pembrolizumab-induced MG, especially during the first eight weeks of therapy. Patients should be treated as early as possible, regardless of the severity of the initial symptoms.

Economic evaluation of FLOT and ECF/ECX perioperative chemotherapy in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma.

OBJECTIVE: The perioperative chemotherapy with fluorouracil, leucovorin, oxaliplatin plus docetaxel (FLOT) was recommended by the Chinese Society of Clinical Oncology Guidelines for gastric cancer (2018 edition) for patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (class IIA). However, the economic impact of FLOT chemotherapy in China remains unclear. The analysis aimed to compare the cost-effectiveness of FLOT versus epirubicin, cisplatin plus fluorouracil or capecitabine (ECF/ECX) in patients with locally advanced resectable tumours. DESIGN: We developed a Markov model to compare the healthcare and economic outcomes of FLOT and ECF/ECX in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma. Costs were estimated from the perspective of Chinese healthcare system. Clinical and utility inputs were derived from the FLOT4 phase II/III clinical trial and published literature. Sensitivity analyses were employed to assess the robustness of our result. The annual discount rate for costs and health outcomes was set at 5%. OUTCOME MEASURES: The primary outcome of incremental cost-effectiveness ratios (ICERs) was calculated as the cost per quality-adjusted life years (QALYs). RESULTS: The base-case analysis found that compared with ECF/ECX, the use of FLOT chemotherapy was associated with an additional 1.08 QALYs, resulting in an ICER of US$851/QALY. One-way sensitivity analysis results suggested that the HR of overall survival and progression-free survival had the greatest impact on the ICER. Probabilistic sensitivity analysis demonstrated that FLOT was more likely to be cost-effective compared with ECF/ECX at a willingness-to-pay threshold of US$31 513/QALY. CONCLUSIONS: For patients with locally advanced resectable tumours, the FLOT chemotherapy is a cost-effective treatment option compared with ECF/ECX in China. TRIAL REGISTRATION NUMBER: NCT01216644.

Diagnosis and Management of Fingolimod-Associated Macular Edema.

Objective: To investigate the clinical features, treatment, and prognosis of fingolimod-associated macular edema (FAME) and to provide a reference for its rational management. Methods: FAME-related case reports were included in a pooled analysis by searching Chinese and English databases from 2010 to November 31, 2021. Results: The median age of 41 patients was 50 years (range, 21, 67 years), of whom 32 were women. The median time to onset of FAME was 3 m (range.03, 120), and blurred vision (17 cases) and decreased vision (13 cases) were the most common complaints. A total of 55 eyes were involved in FAME, including the left eye (14 cases), right eye (10 cases), and both eyes (15 cases), of which 46 eyes had best-corrected visual acuity close to normal (20/12-20/60) and 8 eyes had moderate to severe visual impairment (20/80-20/500). Fundus examination in 23 patients showed macular edema (11 cases). Optical coherence tomography (OCT) in 39 patients mainly showed perifoveal cysts (24 cases), ME (23 cases), and foveal thickening (19 cases). Fundus fluorescein angiography (FFA) in 18 patients showed vascular leakage (11 cases). Complete resolution of ME occurred in 50 eyes and recovery of visual acuity occurred in 45 eyes at a median time of 2 m (range 0.25, 24) after discontinuation of fingolimod or administration of topical therapy. Conclusions: Macular edema is a known complication of fingolimod. All patients using fingolimod require regular eye exams, especially those with a history of diabetes and uveitis and those undergoing cataract surgery.

Clinical features, diagnosis, and management of dasatinib-induced nephrotic syndrome.

Knowledge of dasatinib-induced nephrotic syndrome is largely based on case reports. The clinical features of dasatinib-induced nephrotic syndrome are unknown. We collected case reports of 25 patients with nephrotic syndrome and analyzed their clinical characteristics. Overall, the onset of nephrotic syndrome ranged from 10 days to 5 years after dasatinib administration. Nine patients (36.0%) had clinical symptoms, mainly periorbital edema and lower-extremity edema. Serum albumin ranged from 1.2 g/dL to 3.7 g/dL in 10 patients (38.5%). The 24-h urine protein values ranged from 3.54 g/day to 118 g/day. Kidney biopsy of 13 patients (52.0%) mainly showed focal foot process effacement, mesangial hyperplasia, endothelial cell damage and focal segmental glomerulosclerosis. Proteinuria resolved or recovered after dasatinib discontinuation or dose reduction or switching to other tyrosine kinase inhibitors (TKIs).

Clinical characteristics and treatment of terlipressin-induced ischemic skin necrosis: A synthesis of 35 literature reported cases.

WHAT IS KNOWN AND OBJECTIVE: The clinical features of terlipressin-induced ischemic skin necrosis are unknown. The purpose of this study is to explore the clinical features of terlipressin-induced skin necrosis. METHODS: We searched Chinese and English databases to collect case reports of terlipressin-induced skin necrosis for retrospective analysis. RESULTS AND DISCUSSION: A total of 42 patients (31 males and 11 females) from 35 studies were included, with a median age of 54 years (range 0.17-84). The onset of skin ischemia ranged from a few hours to 21 days. The most common clinical manifestations were bulla (15 cases, 35.7%), cyanosis (12 cases, 28.6%), necrosis (11 cases, 26.2%), and purpura (10 cases, 23.8%). The following were often affected: the legs (26 cases), 61.9%), abdomen (13, 31.0%), scrotum (10 cases, 23.8%), feet (10 cases, 23.8%), upper extremities (8 cases, 19.0%), and hands (7 cases, 16.7%). Skin biopsy showed fibrin thrombus (7 cases, 38.9%), nonspecific inflammation (6 cases, 33.3%), and necrosis (10 cases, 55.6%). After discontinuation of terlipressin, skin symptoms improved in most patients. WHAT IS NEW AND CONCLUSION: Ischemic skin necrosis is a rare and serious adverse effect of terlipressin. Patients receiving terlipressin therapy should be monitored closely for terlipressin-related ischemic complications. Terlipressin should be discontinued immediately if ischemic complications occur.