Pretreatment and analysis techniques development of TKIs in biological samples for pharmacokinetic studies and therapeutic drug monitoring

Tyrosine kinase inhibitors(TKIs)have emerged as the first-line small molecule drugs in many cancer therapies,exerting their effects by impeding aberrant cell growth and proliferation through the modulation of tyrosine kinase-mediated signaling pathways.However,there exists a substantial inter-individual variability in the concentrations of certain TKIs and their metabolites,which may render patients with compromised immune function susceptible to diverse infections despite receiving theoretically efficacious anticancer treatments,alongside other potential side effects or adverse reactions.Therefore,an urgent need exists for an up-to-date review concerning the biological matrices relevant to bioanalysis and the sampling methods,clinical pharmacokinetics,and therapeutic drug monitoring of different TKIs.This paper provides a comprehensive overview of the advancements in pretreatment methods,such as protein precipitation(PPT),liquid-liquid extraction(LLE),solid-phase extraction(SPE),micro-SPE(μ-SPE),magnetic SPE(MSPE),and vortex-assisted dispersive SPE(VA-DSPE)achieved since 2017.It also highlights the latest analysis techniques such as newly developed high performance liquid chromatography(HPLC)and high-resolution mass spectrometry(HRMS)methods,capillary electrophoresis(CE),gas chromatography(GC),supercritical fluid chromatography(SFC)procedures,surface plasmon resonance(SPR)assays as well as novel nanoprobes-based biosensing techniques.In addition,a comparison is made between the advantages and disadvantages of different approaches while presenting critical challenges and prospects in pharmacokinetic studies and therapeutic drug monitoring.

C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 pathway as a therapeutic target and regulatory mechanism for spinal cord injury

Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.

Development and refinement of diagnostic and therapeutic strategies for managing patients with cardiogenic stroke:An arduous journey

Cardioembolic stroke,referred to as cardiogenic stroke,is a clinical syndrome in which emboli from the heart pass through the circulatory system and cause cerebral artery embolism and corresponding brain dysfunction.Compared to other subtypes of ischemic stroke,cardiogenic stroke presents with more etiologies,greater severity,worse prognosis,and a higher recurrence rate.In this minireview,we provide new insights into the etiological classification,diagnostic methods,and interventions of cardiogenic stroke.

Histopathological study of hepatocellular carcinoma after transcatheter hepatic arterial embolization

AIMS To study the histopathological changes in hepatocellular carcinoma (HCC) after transcatheter arterial embolization (TAE). METHODS Histopathological analysis was made in 39 cases of liver neoplasms after TAE and 11 cases of liver neoplasms after digital selective angiography (DSA), including pathological type, histological grade, necrotic degree, capsule, times of treatment, injured vessel and lymphocyte infiltration. RESULTS Six cases with 100% necrosis, 14 cases with 30% 95% necrosis, 19 cases with 0% 5% necrosis after TAE and 11 cases without necrosis after DSA were found histologically. The necrosis was related to the pathological type, capsule, injured vessels, but not to the histological grade, time of treatment and lymphocyte infiltration of the liver neoplasms. CONCLUSIONS TAE is an effective therapy for the late stage HCC. The encapsulated HCC is a preferable indicator for TAE.

Segmental transcatheter arterial embolization for primary hepatocellular carcinoma

AIM To evaluate the therapeutic effects of segmental transcatheter arterial embolization for primary hepatocellular carcinoma, and to recognize the menifestation and clinical value of lipiodol overflow into portal veins surrounding the tumors. METHODS A total of 50 cases of nonresectable primary hepatocellular carcinoma underwent segmental transcatheter arterial embolization. Two methods of superselective segmental catheterization were used, one was the method of wire guiding, and the other the technic of co axial infusion catheter. RESULTS The 1 , 2 , 3 and 4 year cumulative survival rates of 50 cases with segmental transcatheter arterial embolization for primary hepatocellular carcinoma were 83 8%, 65 4%, 42 9% and 24 5% respectively. The incidence of the lipiodol overflow into portal veins was 64%. The overflow of lipiodol into portal veins, represented as 3-5 grade branches of portal veins visualized by lipiodol, was “star like” or “tree like”, and there was a relatively large vessel in the center surrounded with radicalized small branches of vessels. CONCLUSION The lipiodol overflow into portal veins was one of the signs of complete embolization for tumors, and may play a partial role in embolizating the portal venous supply for hepatocellular carcinoma.

MDCT angiography to evaluate the therapeutic effect of PTVE for esophageal varices

Abstract AIM:To evaluate the role of multi-detector row computed tomography(MDCT) angiography for assessing the therapeutic effects of percutaneous transhepatic variceal embolization(PTVE) for esophageal varices(EVs).METHODS:The subjects of this prospective study were 156 patients who underwent PTVE with cyanoacrylate for EVs.Patients were divided into three groups according to the filling range of cyanoacrylate in EVs and their feeding vessels:(1) group A,complete obliteration,with at least 3 cm of the lower EVs and peri-/EVs,as well as the adventitial plexus of the gastric cardia and fundus filled with cyanoacrylate;(2) group B,partial obliteration of varices surrounding the gastric cardia and fundus,with their feeding vessels being obliterated with cyanoacrylate,but without reaching lower EVs;and(3) group C,trunk obliteration,with the main branch of the left gastric vein being filled with cyanoacrylate,but without reaching varices surrounding the gastric cardia or fundus.We performed chart reviews and a prospective follow-up using MDCT images,angiography,and gastrointestinal endoscopy.RESULTS:The median follow-up period was 34 mo.The rate of eradication of varices for all patients was 56.4%(88/156) and the rate of relapse was 31.3%(41/131).The rates of variceal eradication at 1,3,and 5 years after PTVE were 90.2%,84.1% and 81.7%,respectively,for the complete group;61.2%,49% and 42.9%,respectively,for the partial group;with no varices disappearing in the trunk group.The relapsefree rates at 1,3 and 5 years after PTVE were 91.5%,86.6% and 81.7%,respectively,for the complete group;71.1%,55.6% and 51.1%,respectively,for the partial group;and all EVs recurred in the trunk group.Kaplan-Meier analysis showed P values of 0.000 and 0.000,and odds ratios of 3.824 and 3.603 for the rates of variceal eradication and relapse free rates,respectively.Cyanoacrylate in EVs disappeared with time,but those in the EVs and other feeding vessels remained permanently in the vessels without a decrease with time,which is important for the continued obliteration of the feeding vessels and prevention of EV relapse.CONCLUSION:MDCT provides excellent visualization of cyanoacrylate obliteration in EV and their feeding veins after PTVE.It confirms that PTVE is effective for treating EVs.

Percutaneous transsplenic embolization of esophageal and gastrio-fundal varices in 18 patients

AIM: Clinical application and potential complication of percutaneous transsplenic varices embolization (PTSVE) of esophageal or gastrio-fundal varices in patients with hepatocellular carcinoma (HCC) complicated with portal vein cancerous thrombosis (PVCT).METHODS: 18 patients with HCC complicated with PVCT and esophageal or gastrio-fundal varices who underwent PTSVE were collected. The rate of success, complication, mortality of the procedure and postoperative complication were recorded and analyzed.RESULTS: PTSVE were successfully performed in 16 of 18cases, and the rate of success was 89%. After therapy erythrocyte counts decreased in all of the natunts. 5 of patients needed blood transfusion, 2 patients requiredsurgical intervention because of and 11 patients with ascites were alleviated by diuresis. Among these 18patients, the procedure-related mortality was 11% (2/18),one died of acute hepatic failure on the forth day after procedure, another died of acute renal failure on the fifth day. The patients were follow up for 112 mon exceptone. 13of them died of their tumors but none of them experienced variceal bleeding.CONCLUSION: PTSVE is a relatively safe and effective method to treat esophageal or gastrio-fundal varices in HCCpatients with PVCT when percutaneous transhepatic varices embolization (PTHVE) of varices is impossible.

A case of ascending colon variceal bleeding treated with venous coil embolization

A 38-year-old female with a history of alcoholic liver cirrhosis visited our hospital with a massive hematochezia.An esophagogastroduodenoscopy did not demonstrate any bleeding source,and a colonoscopy showed a massive hemorrhage in the ascending colon but without an obvious focus.The source of the bleeding could not be found with a mesenteric artery angiography.We performed an enhanced abdominal computed tomography,which revealed a distal ascending colonic varix,and assumed that the varix was the source of the bleeding.We performed a venous coil embolization and histoacryl injection to obliterate the colon varix.The intervention appeared to be successful because the vital signs and hemoglobin laboratory data remained stable and because the hematochezia was no longer observed.We report here on a rare case of colonic variceal bleeding that was treated with venous coil embolization.

Source of blood supply of liver cavernous hemangioma and sclerosis and embolization treatment

AIM To investigate the source of blood supply of carvenous hemangioma of liver (CHL) and provide a feasibile treatment for CHL via hepatic artery. METHODS Ⅰ. Origin of blood supply of CHL: portovenography, hepatic arteriography and portal vein staining were performed in 5 patients. Two casts of hepatic blood vessels from resected specimen were observed. Ⅱ. Clinical data: Among 75 patients (30 males, 45 females, aged 25～57 years with a mean of 37 4). 56 were of solitary type (44 on the right lobe, 12 on the left with 4 having intraparenchymatoma) and 19 were of multiple type (9 on the right, 2 the left, 8 whole liver). Twenty two patients were treated by sclerosis, 50 by embolization via hepatic artery and 3 were excised. RESULTS In 5 cases with portography, the contrast medium did not enter the tumor, the tumor appeared as low denty area and the intrahepatic branches of portal vein were pushed aside. In 5 cases with portal vein staining, the normal liver parenchyma was stained deep blue, and the tumor was not stained. The tumor area appeared as a round vacant cavity in 2 specimen casts. In 72 patients treated with sclerosis a or embolization via hepatic artery or through interventional method, the tumors diminished by 10%～30% in diameter and no tumors grew larger. CONCLUSION The blood supply of CHL originates from the hepatic artery. Tumors treated with sclerosis and emblization decreased in size or got fiberized.

A study of portal vein embolization with absolute ethanol injection in cirrhotic rats

AIM To investigate the effects of portal vein embolization (PVE) with absolute ethanol injection on the cirrhotic livers.METHODS Absolute ethanol was injected intraportally into normal and cirrhotic SD rats and the changes of the animals in anatomy, pathology, liver function as well as portal hemodynamics were observed.RESULTS At a dose of 0.05mL/100g of ethanol, the survival rate was 100% in normal rats compared with 40.9% in cirrhotic rats. PVE in the cirrhotic rats with 0.03mL/100g of ethanol, caused significant hypertrophy in non-embolized lobes, mild or moderate damage to the hepatic parenchyma, slight and transient alterations in liver function, portal pressure and portal flow.CONCLUSION PVE with absolute ethanol injection in the setting of liver cirrhosis could be safe at an appropriate dose, and precautions aimed at preserving liver function were preferable.INTRODUCTIONPortal vein embolization (PVE) plays an important role in the management of hepatocellular carcinoma (HCC). We modified the conventional method of transcatheter embolization and developed a new PVE technique with ethanol injection via a fine needle in experimental study[1] and subsequent clinical application under guidance of portoechography[2]. To further elucidate the therapeutic basis of this technique, particularly its effects on the cirrhotic liver, we observed the alterations in liver anatomy, pathology, biochemistry and portal hemodynamics in cirrhotic rats undergoing PVE with ethanol injection.

Development of enterohepatic fistula after embolization in ileal gastrointestinal stromal tumor: A case report

Gastrointestinal stromal tumor(GIST)is a rare mesenchymal tumor of the gastrointestinal tract that has been associated with the formation of fistulas to adjacent organs in few case reports.However,GIST with enterohepatic fistula has not been reported.Here we report the case of an enterohepatic fistula that occurred after embolization of a liver mass originating in the distal ileum.An 87-year-old woman was hospitalized for melena.On initial conventional endoscopy,a bleeding focus in the gastrointestinal tract was not found.Because of massive hematochezia,enteroscopy was performed through the anus.A protruding,ulcerative mass was found in the distal ileum that was suspected to be the source of the bleeding;a biopsy sample was taken.Electrocoagulation was not successful in controlling the bleeding;therefore,embolization was performed.After embolization,the patient developed a high fever and severe abdominal tenderness with rebound tenderness.Follow-up abdominopelvic computed tomography revealed an enterohepatic fistula between the liver and distal ileum.The fistula was treated surgically by segmental resection of the distal ileum and unlooping of the liver mass.

Hepatic adenylate energy charge levels in patients with hepatoma after hepatic artery embolization

AIM To evaluate hepatic energy charge levels of the patients with hepatoma after hepatic artery embolization and its relation to postoperative complications. METHODS Sixty nine patients with hepatoma were continuously measured for their arterial blood ketone body ratio (AKBR) and compared with their postoperative clinical course or conventional liver function test after various hepatic artery embolization. RESULTS AKBR in high radiation dose or jaundice group drastically decreased at 1-3 days and recovered slowly. Patients were classified into three groups according to the value of AKBR: group A (35 cases), AKBR remained higher than 0 7; group B (31 cases), AKBR had transiently dropped to 0 4 0 7 and then increased to preoperative value; and group C (3 cases), AKBR decreased steadily to below 0 4. The occurrence rate of various complications were 5 7%, 32 3% and 100% in the three groups, respectively ( P <0 005). CONCLUSION The AKBR which reflects hepatic mitochondria redox state is more reliable as a direct indicator to assess hepatic tolerance for embolization than routine liver function test.

Uterine artery embolization in association with methotrexate infusion for the treatment of tubal ectopic pregnancy

Objective To investigate the safety, feasibility, and effectiveness of uterine artery embolization in association with methotrexate(MTX) infusion for the treatment of tubal ectopic pregnancy. Methods Fifty-one patients with tubal ectopic pregnancy were referred for interventional management. All patients received super-selective arteriography of the uterine artery, were infused with 50–100 mg methotrexate(MTX) through a catheter, and underwent embolization of the uterine artery with a gel-foam pledge. Clinical presentation, findings of physical examination, β-HCG values, and the size of the ectopic mass were documented for comparison. The concentration of MTX in blood was evaluated at 0.5, 6, 12, 24, 36, and 48 hours after the procedure. Results Forty-seven out of the 51 patients had clinical resolution of their tubal pregnancy(92.2%). The average time for the β-HCG value to decrease and come back to normal was 9.16 ± 2.54 days(mean +/-SD). MTX levels in peripheral blood could not be detected for patients who received 50 or 75 mg MTX at 36 hours after the procedure, while the MTX level was 0.01 μmol/L at 48 hours after the procedure for patients who received 100 mg. Out of the 4 cases whose ectopic mass size was ≥5 cm, 3 failed to respond to the treatment; however, those whose ectopic mass size was ≤5 cm responded positively to the treatment, regardless of the β-HCG concentration and abdominal bleeding, except for 1 patient who had to undergo laparoscopy for severe abdominal pain and who showed a reduction in her β-HCG level. Conclusion Uterine artery embolization in association with methotrexate infusion is safe and effective in the treatment of tubal ectopic pregnancy, especially for those women with mild to moderate bleeding, or for those at risk of a major hemorrhage. The selection criterion of mass size >5 cm should, therefore, be carefully considered.

Early- and intermediate-term outcome of transarterial embolization for symptomatic hepatic focal nodular hyperplasia

Purpose: To evaluate the early-and intermediate-term outcome in patients with symptomatic hepatic focal nodular hyperplasia(FNH) treated with transarterial embolization using bleomycin-iodinated oil and polyvinyl alcohol(PVA) particles. Materials and methods: In this two-center retrospective study between January 2005 and December 2013, 27 consecutive patients with symptomatic hepatic FNH underwent superselective catheterization by microcatheter techniques and embolization using bleomycin-iodinated oil combined with PVA. Early-term(3–41 months) follow-up of TAE was performed in terms of symptom control, changes in lesion size, and complications. Intermediate-term(45–112 months) follow-up was carried out to assess symptom control and reinterventions for recurrence. Results: Embolization was performed in 27 patients with 31 lesions. Technical success was achieved in all cases. The follow-up period ranged from three to 112 months. At early-term follow-up, mean lesion diameters were decreased significantly from 6.4±2.7 cm pre-intervention to 3.6±1.8 cm at 3-9 months after embolization(P<0.001). A total of 7 lesions had complete resolution during the whole follow-up period. At intermediate-term follow-up, local recurrence was found in 1 treated lesion at 54-months. Contrast-enhanced scans showed complete lack of residual arterial blood supply in the majority of lesions during the follow-up period. There was no major complication associated with the procedure. Conclusion: Transarterial embolization using bleomycin-iodinated oil and PVA is a feasible, safe and effective alternative in both early-and intermediate-terms for the treatment of symptomatic hepatic FNH.

Successful embolization of an intrahepatic portosystemic shunt using balloon-occluded retrograde transvenous obliteration:A case report

BACKGROUND A congenital intrahepatic portosystemic shunt(IPSVS)is a rare vascular abnormality that is characterized by an anomalous intrahepatic venous tract that connects the intrahepatic portal vein with the hepatic venous system.Hepatic encephalopathy is an indication for IPSVS embolization,which is technically challenging because rapid blood flow through shunts can induce the migration of embolization material to systemic veins.This case report discusses the efficacy of percutaneous balloon-occluded retrograde transvenous obliteration for treating patients with IPSVSs.CASE SUMMARY A 75-year-old woman presented with a six-month history of repeated hepatic encephalopathy due to an IPSVS without liver cirrhosis.We successfully embolized the IPSVS using percutaneous balloon-occluded retrograde transvenous obliteration with interlocking detachable coils.After the procedure,the patient exhibited no symptoms of hepatic encephalopathy for 14 mo.CONCLUSION Balloon-occluded retrograde transvenous obliteration with detachable coils can be effective for the endovascular treatment of an IPSVS.

Transcatheter Arterial Embolization Combined with Anti-vascular Agent Combretastatin A4 Phosphate Inhibits Growth and Vascularization of Liver Tumor in an Animal Model

Objective This study aimed to investigate the effect of combretastatin A4 phosphate(CA4P)on proliferation,migration,and capillary tube formation of human umbilical vein endothelial cells(HUVECs)and the efficacy of transcatheter arterial embolization combined with CA4P in the treatment of rabbit VX2 liver tumor.Methods The effects of different concentrations of CA4P on proliferation,migration and capillary tube formation of HUVECs were investigated by cell proliferation assay,wound healing assay and capillary tube formation assay,respectively.Thirty-two rabbits implanted with liver VX2 tumors were randomly divided into 4 groups.After catheterization of the left hepatic artery,the infusion was performed using normal saline(group A),CA4P aqueous solution(group B),lipiodol and polyvinyl alcohol particles(group C),and CA4P lipiodol emulsion and polyvinyl alcohol particles(group D),respectively.Half of the animals in each group were euthanized for immunohistochemical analysis to evaluate microvessel density(MVD)at 3 days post-treatment.The other half were examined by MRI and histology to evaluate tumor growth and necrosis at 7 days post-treatment.Results CA4P could inhibit the proliferation,migration,and tube formation of HUVECs in cell experiments.After interventional treatment,the level of MVD in group D was lower than that in group C(P<0.01).The tumor volume in group C or D was lower than that in group A or B(P<0.01).The tumor necrosis rate was higher in group D than in the other groups.Conclusion The study suggests that CA4P could inhibit the proliferation,migration,and capillary tube formation of HUVECs,and transcatheter arterial embolization combined with CA4P could inhibit the growth of VX2 tumor and obviously induce tumor necrosis.

Preoperative rectal tumor embolization as an adjunctive tool for bloodless abdominoperineal excision:A case report

BACKGROUND Abdominoperineal excision(APE)-related hemorrhage can be challenging due to difficult access to pelvic organs and the risk of massive blood loss.The objective of the present study was to demonstrate the use of preoperative embolization(PE)as a strategy for blood preservation in a patient with a large low rectal tumor with a high risk of bleeding,scheduled for APE.CASE SUMMARY A 56-year-old man presented to our institution with a one-year history of anal bleeding and rectal tenesmus.The patient was diagnosed with bulky adenocarcinoma limited to the rectum.As the patient refused any clinical treatment,surgery without previous neoadjuvant chemoradiation was indicated.The patient underwent a tumor embolization procedure,two days before surgery performed via the right common femoral artery.The tumor was successfully devascularized and no major bleeding was noted during APE.Postoperative recovery was uneventful and a one-year follow-up showed no signs of recurrence.CONCLUSION Therapeutic tumor embolization may play a role in bloodless surgeries and increase surgical and oncologic prognoses.We describe a patient with a bulky low rectal tumor who successfully underwent preoperative embolization and bloodless abdominoperineal resection.

Sishengtang decoction in alleviation of toxic and side effects of transarterial embolization

AIM To observe the therapeutic effects of Sishengtang decoction in alleviating the toxic and side effects of transarterial embolization (TAE). METHODS Fifty four patients with liver cancer were divided randomly into Sishengtang decoction group (34 cases) and control group (20 cases). The changes of clinical symptoms and peripheral hemogram and some cellular immune functions were observed before and two weeks after TAE. RESULTS Sishengtang decoction was superior to the control group in improving the digestive tract reaction. The leucocytes of peripheral blood and cellular immune functions (activities of NK cells and LAK cells) of control group decreased obviously after TAE, while that of Sishengtang decoction group decreased slightly, without obvious difference as compared with that of preoperation. CONCLUSIONS Sishengtang decoction might improve the clinical symptoms and increase the leucocytes of peripheral blood and the cellular immune functions of TAE patients.

Hepatocellular Carcinoma with Tumor Thrombus in Portal Vein: Finding in Ultrasonography, Computed Tomography, Angiography and Chemoembolization

Transcatheter hepatic artery chemoembolization (TACE) was performed in 41 patients with hepatocellular carcinoma (HCC) accompanied with portal tumor thrombus (PTT). The primary tumors and the PTTs had been detected with ultrasonography (US), computed tomography (CT) and digital subtraction angiography (DSA) before TACE. The purpose of this article is to compare the sensitivity of these methods. Eighty cases of HCC without PTT detected by DSA during the same period were studied as a control group. The PTTs were found in 37 of 41 (90.2%) cases with DSA, whereas the detection rate was 81.1% with US and 41.0% with CT. The internal left lobe of liver was invaded by tumor in 23 of 41 (56.1%) patients with PTT, but it is only 26.3% in the control group (P<001). The primary tumor located in the internal left lobe was significantly smaller than that in the right lobe (P<001). No serious dysfunction of the liver occurred during the treatment. It is concluded that DSA and US are more sensitive than CT to the detection of PTT, that tumor in the internal left lobe of the liver more easily invades the portal vein, and that TACE should be performed as actively as possible even if the portal vein has been invaded.

Duodenal obstruction after successful embolization for duodenal diverticular hemorrhage: A case report

We present a 69-year-old woman with a duodenal obstruction after successful selective transcatheter arterial embolization (TAE) for a duodenal diverticular hemorrhage. Two weeks after TAE, the patient showed abrupt symptoms of duodenal obstruction. Resolving hematomas after successful selective transcatheter arterial embolization should be thoroughly observed because they might result in duodenal fibrotic encasement featuring inflammatory duodenal wall thickening, duodenal deformity, dysmotility, and fi nally obstruction.