Evaluation of pancreatic chymotrypsin activity for on-site prediction of clinically relevant postoperative pancreatic fistula.

OBJECTIVES: Although the risk of complications due to postoperative pancreatic fistula (POPF) have been evaluated based on the amylase level in drained ascitic fluid, this method has much room for improvement regarding diagnostic accuracy and facility of the measurement. This study aimed to investigate the clinical value of measuring pancreatic chymotrypsin activity for rapid and accurate prediction of POPF after pancreaticoduodenectomy. METHODS: In 52 consecutive patients undergoing pancreaticoduodenectomy, the chymotrypsin activity in pancreatic juice was measured by calculating the increase in fluorescence intensity during the first 5 min after activation with an enzyme-activatable fluorophore. The predictive value for clinically relevant POPF (CR-POPF) was compared between this technique and the conventional method based on the amylase level. RESULTS: According to receiver operating characteristic analyses, pancreatic chymotrypsin activity on postoperative day (POD) 3 measured with a multiplate reader had the highest predictive value for CR-POPF (area under the curve [AUC], 0.752; P < 0.001), yielding 77.8 % sensitivity and 68.8 % specificity. The AUC and sensitivity/specificity of the amylase level in ascitic fluid on POD 3 were 0.695 (P = 0.053) and 77.8 %/41.2 %, respectively. Multivariable analysis identified high pancreatic chymotrypsin activity on POD 3 as an independent risk factor for CR-POPF. Measurement of pancreatic chymotrypsin activity with a prototype portable fluorescence photometer could significantly predict CR-POPF (AUC, 0.731; P = 0.010). CONCLUSION: Measurement of pancreatic chymotrypsin activity enabled accurate and rapid prediction of CR-POPF after pancreaticoduodenectomy. This can help surgeons to implement appropriate drain management at the patient's bedside without delay.

Novel Benchmark Values for Open Major Anatomic Liver Resection in Non-cirrhotic Patients: A Multicentric Study of 44 International Expert Centers.

OBJECTIVE: This study aims at establishing benchmark values for best achievable outcomes following open major anatomic hepatectomy for liver tumors of all dignities. BACKGROUND: Outcomes after open major hepatectomies vary widely lacking reference values for comparisons among centers, indications, types of resections, and minimally invasive procedures. METHODS: A standard benchmark methodology was used covering consecutive patients, who underwent open major anatomic hepatectomy from 44 high-volume liver centers from 5 continents over a 5-year period (2016-2020). Benchmark cases were low-risk non-cirrhotic patients without significant comorbidities treated in high-volume centers (≥30 major liver resections/year). Benchmark values were set at the 75th percentile of median values of all centers. Minimum follow-up period was 1 year in each patient. RESULTS: Of 8044 patients, 2908 (36%) qualified as benchmark (low-risk) cases. Benchmark cutoffs for all indications include R0 resection ≥78%; liver failure (grade B/C) ≤10%; bile leak (grade B/C) ≤18%; complications ≥grade 3 and CCI ® ≤46% and ≤9 at 3 months, respectively. Benchmark values differed significantly between malignant and benign conditions so that reference values must be adjusted accordingly. Extended right hepatectomy (H1, 4-8 or H4-8) disclosed a higher cutoff for liver failure, while extended left (H1-5,8 or H2-5,8) were associated with higher cutoffs for bile leaks, but had superior oncologic outcomes, when compared to formal left hepatectomy (H1-4 or H2-4). The minimal follow-up for a conclusive outcome evaluation following open anatomic major resection must be 3 months. CONCLUSION: These new benchmark cutoffs for open major hepatectomy provide a powerful tool to convincingly evaluate other approaches including parenchymal-sparing procedures, laparoscopic/robotic approaches, and alternative treatments, such as ablation therapy, irradiation, or novel chemotherapy regimens.

Pancreas-sparing partial duodenectomy as an alternative to emergency pancreaticoduodenectomy for a major duodenal perforation: a case report.

A 71-year-old woman underwent endoscopic submucosal dissection for early duodenal cancer at the second portion of the duodenum and developed acute peritonitis due to delayed duodenal perforation. Emergency laparotomy was performed. A huge perforation formed at the descending duodenum without ampulla involvement. Pancreas-sparing partial duodenectomy (PPD) with gastrojejunostomy was performed (250 min operative time) with 50 mL of intraoperative blood loss. She required intensive care for 3 days and was discharged on postoperative day 21 with no severe complications. Emergency treatment for a major duodenal injury or perforation remains challenging because of high morbidity and mortality. An appropriate treatment should be considered according to the nature of the defect. Although PPD is an acceptable procedure for patients with a duodenal neoplasm, its use in emergency surgery is rarely reported. PPD is more reliable than primary repair or anastomosis using a jejunal wall, and less invasive than pancreaticoduodenectomy, for emergency treatment. We performed PPD in this patient because the duodenal perforation was too large to reconstruct and did not involve the ampulla. PPD can be a safe and feasible alternative surgical procedure to pancreaticoduodenectomy for a major duodenal perforation, especially in patients with a duodenal perforation that does not involve the ampulla.

Modified Intestinal Derotation Procedure with Reversed Kocherization to Facilitate Mesopancreas Excision During Pancreaticoduodenectomy.

BACKGROUND: Although intestinal derotation procedure has advantages of facilitating mesopancreas excision during pancreaticoduodenectomy, the wide mobilization takes time and risks injuring other organs. This article describes a modified intestinal derotation procedure in pancreaticoduodenectomy and its clinical impact on short-term outcomes. METHODS: The modified procedure comprised the pinpoint mobilization of the proximal jejunum following reversed Kocherization. Among 99 consecutive patients who underwent pancreaticoduodenectomy between 2016 and 2022, the short-term outcomes of pancreaticoduodenectomy with the modified procedure were compared with those of conventional pancreaticoduodenectomy. The feasibility of the modified procedure was investigated based on the vascular anatomy of the mesopancreas. RESULTS: Compared with conventional pancreaticoduodenectomy (n = 55), the modified procedure (n = 44) involved less blood loss and shorter operation time (p < 0.001 and 0.017, respectively). Severe morbidity, clinically relevant postoperative pancreatic fistula, and prolonged hospitalization occurred less often with the modified procedure compared with conventional pancreaticoduodenectomy (p = 0.003, 0.008, and < 0.001, respectively). According to preoperative image findings, most (72%) patients had a single inferior pancreaticoduodenal artery sharing a common trunk with the first jejunal artery. The inferior pancreaticoduodenal vein drained into the jejunal vein in 71% of the patients. The first jejunal vein ran behind the superior mesenteric artery in 77% of the patients. CONCLUSIONS: By combining our modified intestinal derotation procedure with preoperative recognition of the vascular anatomy of mesopancreas, mesopancreas excision during pancreaticoduodenectomy can be performed safely and accurately.

Lengthened Efferent Limb in Braun Enteroenterostomy Reduces Delayed Gastric Emptying After Pancreaticoduodenectomy.

BACKGROUND: Delayed gastric emptying (DGE) is a common complication after pancreaticoduodenectomy (PD), but a method to prevent DGE has not been established. This study aims to demonstrate a novel technique utilizing a lengthened efferent limb in Billroth-II (B-II) reconstruction during PD and to evaluate the impact of the longer efferent limb on DGE occurrence. METHODS: Patients who underwent PD with B-II reconstruction were divided into two groups: PDs with lengthened (50-60 cm) efferent limb (L group) and standard length (0-30 cm) efferent limb (S group). Postoperative outcomes were compared. DGE was defined and graded according to the International Study Group of Pancreatic Surgery criteria. RESULTS: Among 283 consecutive patients who underwent PD from 2002 to 2021, 206 patients were included in this study. Patients who underwent Roux-en-Y reconstruction (n = 77) were excluded. Compared with the S group, the L group included older patients and those who underwent PD after 2016 (p = 0.025, < 0.001, respectively). D2 lymphadenectomy, antecolic route reconstruction, and Braun enteroenterostomy were performed more frequently in the L group (p = 0.040, < 0.001, < 0.001, respectively). The rate of DGE was significantly decreased to 6% in the L group, compared with 16% in the S group (p = 0.027), which might lead to a shorter hospital stay in the L group (p < 0.001). Multivariable analysis identified two factors as independent predictors for DGE: intraabdominal abscess [odds ratio (OR) 5.530, p = 0.008] and standard efferent limb length (OR 2.969, p = 0.047). CONCLUSION: A lengthened efferent limb in Braun enteroenterostomy could reduce DGE after PD.

New Diagnostic Modality Combining Mass Spectrometry and Machine Learning for the Discrimination of Malignant Intraductal Papillary Mucinous Neoplasms.

BACKGROUND: An intraductal papillary mucinous neoplasm (IPMN) is a pancreatic tumor with malignant potential. Although we anticipate a sensitive method to diagnose the malignant conversion of IPMN, an effective strategy has not yet been established. The combination of probe electrospray ionization-mass spectrometry (PESI-MS) and machine learning provides a promising solution for this purpose. METHODS: We prospectively analyzed 42 serum samples obtained from IPMN patients who underwent pancreatic resection between 2020 and 2021. Based on the postoperative pathological diagnosis, patients were classified into two groups: IPMN-low grade dysplasia (n = 17) and advanced-IPMN (n = 25). Serum samples were analyzed by PESI-MS, and the obtained mass spectral data were converted into continuous variables. These variables were used to discriminate advanced-IPMN from IPMN-low grade dysplasia by partial least square regression or support vector machine analysis. The areas under receiver operating characteristics curves were obtained to visualize the difference between the two groups. RESULTS: Partial least square regression successfully discriminated the two disease classes. From another standpoint, we selected 130 parameters from the entire dataset by PESI-MS, which were fed into the support vector machine. The diagnostic accuracy was 88.1%, and the area under the receiver operating characteristics curve was 0.924 by this method. Approximately 10 min were required to perform each method. CONCLUSION: PESI-MS combined with machine learning is an easy-to-use tool with the advantage of rapid on-site analysis. Here, we show the great potential of our system to diagnose the malignant conversion of IPMN, which would be a promising diagnostic tool in clinical settings.

Radical antegrade modular pancreatosplenectomy enhances local control of the disease in patients with left-sided pancreatic cancer.

BACKGROUND: Radical antegrade modular pancreatosplenectomy (RAMPS) was developed to enhance curability in patients with left-sided pancreatic cancer. However, no evidence is available regarding the prognostic superiority of RAMPS compared with conventional distal pancreatectomy (cDP). Here, we aimed to assess the oncological benefit of RAMPS by comparing surgical outcomes between patients who underwent cDP and RAMPS with propensity score (PS) adjustment. METHODS: Clinical data of 174 patients undergoing cDP and RAMPS between 2009 and 2016 at two high-volume centers were analyzed with PS matching. Recurrence-free survival (RFS), overall survival (OS), and local recurrence rates were compared between patients who underwent cDP and RAMPS. RESULTS: The cDP and RAMPS groups were successfully matched with baseline characteristics. No differences were found in the 3-year RFS and OS rates between the two groups (3-year RFS: cDP 46% vs RAMPS 40%, p = 0.451, 3-year OS: cDP 57% vs RAMPS 53%, p = 0.692). However, the 3-year local recurrence rate was lower in the RAMPS (10%) than that in the cDP group (34%) (hazard ratio 0.275, 95% confidence interval 0.090-0.842, p = 0.02). CONCLUSION: RAMPS is oncologically superior to conventional procedure in achieving local control of the disease in patients with left-sided pancreatic cancer.

A multicenter phase II trial evaluating the efficacy of bevacizumab plus mFOLFOX6 for R0 surgical resection in advanced colorectal liver metastases harboring mutant-type KRAS: NEXTO-mt trial.

BACKGROUND: The effect of bevacizumab plus mFOLFOX6 on downsizing of liver metastases for curative resection has not been well assessed for patients with advanced colorectal liver metastases (CRLMs). This multicenter phase II trial aimed to examine the efficacy and safety of bevacizumab plus mFOLFOX6 for advanced CRLMs harboring mutant-type KRAS. METHODS: Patients with advanced CRLMs (tumor number of ≥5 and/or technically unresectable) harboring mutant-type KRAS were included. Surgical indication was evaluated every 4 cycles of bevacizumab plus mFOLFOX6. Liver resection was planned if the CRLMs were resectable. The primary endpoint was R0 resection rate. The secondary endpoints included overall survival (OS), recurrence-free survival, progression-free survival, and safety. RESULTS: Between 2013 and 2017, 29 patients from six centers were registered. The rates of complete and partial responses were 0% and 62.1%, respectively. R0 and R1 resections were performed in 19 and 1 patient, respectively (R0 resection rate: 65.5%). No mortality occurred. During the median follow-up of 30.7 months, the 3-year OS rate for all the patients was 64.4% with the median survival of 49.1 months. CONCLUSION: For advanced CRLMs harboring mutant-type KRAS, bevacizumab plus mFOLFOX6 achieved a high R0 resection rate, leading to favorable survival.

Impact of Tumor Size on the Outcomes of Patients with Resectable Distal Pancreatic Cancer: Lessons Learned from a Series of 158 Radical Resections.

BACKGROUND: Neoadjuvant therapy is used for borderline resectable pancreatic ductal adenocarcinoma (PDAC) with high risk of incomplete resection and early recurrence. Because distal PDAC is rare, the optimal criteria for neoadjuvant therapy specific for distal PDAC remain unclear. We hypothesized large distal PDAC would recur earlier than small distal PDAC. OBJECTIVE: The aim of this study was to identify the risk factors for failure of upfront resection for resectable distal PDAC. METHODS: The study cohort comprised 158 patients with resectable distal PDAC who underwent radical resection. The long-term outcomes were recurrence-free survival (RFS), disease-specific survival (DSS), and post-recurrence survival (PRS). RESULTS: R0 resection was achieved in 92% of patients, and median DSS for the entire cohort was 31 months. Among 103 patients who developed recurrence, 32 (31%) developed recurrence within 6 months. The median PRS and DSS for those with early recurrence was 6 and 10 months, respectively, compared with 11 and 30 months, respectively, for those with late recurrence (p = 0.017 and p < 0.001, respectively). Patients with tumors > 4 cm had higher rates of R1 resection (16%) and concomitant resection of another organ (19%) than those with smaller tumors (4% and 2%, p = 0.009 and p < 0.001, respectively). In multivariate analysis, tumor > 4 cm remained a significant predictor of early recurrence (p < 0.001, hazard ratio [HR] 6.51), shorter RFS (p = 0.018, HR 1.71), and shorter DSS (p = 0.002, HR 2.07). CONCLUSION: Tumor size > 4 cm is a reliable predictor of early recurrence after resection of distal PDAC, and neoadjuvant therapy may help select patients who can benefit from radical resection.

Understanding conditional cumulative incidence of complications following liver resection to optimize hospital stay.

BACKGROUND: After liver resection, the in-hospital observation periods associated with minimal risks for complications and unplanned readmission remains unclear. This study aimed to assess changes in risks of complications over time. METHODS: Surgical complexity of liver resection was stratified into grades I (low complexity), II (intermediate), and III (high). The cumulative incidence rate and risk factors for complication ≥ Clavien-Dindo grade II (defined as treatment-requiring complications) were assessed. RESULTS: Of 581 patients, grade I, II, and III resections were performed in 81 (13.9%), 119 (20.5%), and 381 patients (65.6%). Complexity grades (I vs. III, hazard ratio [HR] 0.45, P = 0.007; II vs. III, HR 0.60, P = 0.011) and background liver status (HR 1.76, P = 0.004) were risk factors for treatment-requiring complications. The cumulative incidence rate of treatment-requiring complications was higher after grade III resection than grade I resection (38.1% vs. 16.1%, P < 0.001) or grade II resection (38.1% vs. 25.2%, P = 0.019). Without cirrhosis/chronic hepatitis, the cumulative incidence rate of treatment-requiring complications decreased to less than 10% on postoperative day (POD) 3 after grade I resection, POD 5 after grade II resection, and POD 10 after grade III resection. CONCLUSION: Conditional complication risk analysis stratified by surgical complexity may be useful for optimizing in-hospital observation.

Impact of Abdominal Incision Type on Postoperative Pain and Quality of Life Following Hepatectomy.

BACKGROUND: The aim of this prospective study was to analyze the impact of abdominal incision type on postoperative pain and quality of life (QOL) in hepatectomy. METHODS: In patients undergoing hepatectomy by open, hybrid, or pure laparoscopic approaches, we classified abdominal incisions as: pure laparoscopic (LAP), midline (MID), J-shaped (J), and J-shaped incision plus thoracotomy (TRC). Postoperative pain was measured on postoperative day (POD) 3, 7, 30, and 90 using a visual analog scale (VAS). QOL was evaluated using the short-form-36 questionnaire preoperatively and on POD 30 and 90. RESULTS: We categorized 165 patients into LAP (n = 9, 5%), MID (n = 21, 13%), J (n = 95, 58%), and TRC (n = 40, 24%) groups. Median VAS scores on PODs 3/7/30/90 were: LAP, 27.5/7.5/10/10; MID, 30/10/15/5; J, 50/27.5/20/10, and TRC, 50/30/30/19. The J and TRC groups had significantly higher VAS scores vs. MID on PODs 3 and 7; the LAP and MID groups did not differ significantly. No significant positive correlations were observed between incision length and postoperative VAS, when we stratified patients into two groups according to the presence or absence of a transverse incision. Physical QOL summary scores did not return to preoperative levels even on POD 90, in patients with an additional transverse incision. Mental QOL summary scores worsened with postoperative complications rather than with abdominal incision type. CONCLUSIONS: Transverse incisions, rather than incision length, led to worse midline incision pain and poorer QOL recovery post-hepatectomy. A hybrid approach may be a considerable option when pure laparoscopic hepatectomy is technically difficult. TRIAL REGISTRATION: This study was registered in the UMIN Clinical Trials Registry (registration number: UMIN000017467; http://www.umin.ac.jp/ctr/index.htm ).

High-performance Collective Biomarker from Liquid Biopsy for Diagnosis of Pancreatic Cancer Based on Mass Spectrometry and Machine Learning.

Background: Most pancreatic cancers are found at progressive stages when they cannot be surgically removed. Therefore, a highly accurate early detection method is urgently needed. Methods: This study analyzed serum from Japanese patients who suffered from pancreatic ductal adenocarcinoma (PDAC) and aimed to establish a PDAC-diagnostic system with metabolites in serum. Two groups of metabolites, primary metabolites (PM) and phospholipids (PL), were analyzed using liquid chromatography/electrospray ionization mass spectrometry. A support vector machine was employed to establish a machine learning-based diagnostic algorithm. Results: Integrating PM and PL databases improved cancer diagnostic accuracy and the area under the receiver operating characteristic curve. It was more effective than the algorithm based on either PM or PL database, or single metabolites as a biomarker. Subsequently, 36 statistically significant metabolites were fed into the algorithm as a collective biomarker, which improved results by accomplishing 97.4% and was further validated by additional serum. Interestingly, specific clusters of metabolites from patients with preoperative neoadjuvant chemotherapy (NAC) showed different patterns from those without NAC and were somewhat comparable to those of the control. Conclusion: We propose an efficient screening system for PDAC with high accuracy by liquid biopsy and potential biomarkers useful for assessing NAC performance.

Benzoxazole-Based Metal Complexes to Reverse Multidrug Resistance in Bacteria.

Bacteria often show resistance against antibiotics due to various mechanisms such as the expression of efflux pumps, biofilm formation, or bacterial quorum sensing (QS) controls. For successful therapy, the discovery of alternative agents is crucial. The objective of this study was to evaluate the efflux pump, anti-biofilm, and QS inhibiting, as well as antibacterial effects of 2-trifluoroacetonylbenzoxazole ligands (1-3) and their metal complexes (4-12) in bacteria. The ligand 2 and its Zn(II) complex 5, and furthermore the Cu(II) complex 7 of ligand 1, exerted remarkable antibacterial activity on the Staphylococcus aureus 272123 (MRSA) strain. In the minimum inhibitory concentration (MIC) reduction assay the ligand 3, the Zn(II) complex 5 of ligand 2, and the Cu(II), Ni(II), Mg(II), Fe(III) complexes (7, 8, 9, 12) of ligand 1 enhanced the antibacterial activity of ciprofloxacin in MRSA. An increased ethidium bromide accumulation was detected for ligand 3 in MRSA while the Fe(III) complex 12 of ligand 1 decreased the biofilm formation of the reference S. aureus ATCC 25923 strain. The Zn(II) and Ag(II) complexes (3 and 4) of ligand 1 and ligand 3 inhibited the QS. Based on our results, the ligands and their metal complexes could be potential alternative drugs in the treatment of infectious diseases.

Repeat Hepatectomy for Early Recurrence of Colorectal Liver Metastases-Prognostic Impacts Assessed from the Recurrence Pattern.

BACKGROUND: It is unclear how early liver recurrence negatively affects survival in patients undergoing surgery for colorectal liver metastases (CLM) and whether to perform re-hepatectomy for early recurrence is still controversial. We aimed to evaluate the prognostic value of re-hepatectomy for early recurrence of CLM. METHODS: We reviewed 634 patients undergoing initial hepatectomy for CLM between 2004 and 2015. In 131 patients (20.7%), liver recurrence occurred within 6 months after surgery (early recurrence group [ER]). Recurrence pattern and survivals of ER were compared with those of 150 patients (23.7%) who had liver recurrence more than 6 months after surgery (late recurrence group [LR]). Re-hepatectomy was indicated for resectable disease regardless of the timing of recurrence without using preoperative chemotherapy. RESULTS: The 5-year overall survival (OS) rates after initial hepatectomy in ER (24.0%) were worse than those in LR (57.7%, p < 0.01). Although the incidence of concomitant extrahepatic recurrence was not different between ER and LR, the rate of re-hepatectomy for recurrence confined to the liver in ER (72.5% [58/80]) was lower than that in LR (88.9% [96/108], p < 0.01). In ER, re-hepatectomy was found to independently improve survival (HR: 6.479, p < 0.01), offering the 5-year OS rate after re-hepatectomy of 45.2%. The sites and timing of re-recurrence after re-hepatectomy were not different between ER and LR. CONCLUSIONS: Impaired survival of early liver recurrence is attributed to extensive liver recurrence. However, re-hepatectomy indicated based on resectability is associated with improved survival in patients with early recurrence, tempering the re-recurrence mode.

On the Electronic Nature of Bis((Z)-1-(benzo[d]oxazol-2-yl)-3.3.3-trifluoroprop-1-en-2-ate)palladium.

The electronic nature of the recently reported complex, bis((Z)-1-(benzo[d]oxazol-2-yl)-3.3.3-trifluoroprop-1-en-2-ate)palladium, is re-investigated by a combination of spectroscopy (NMR, IR, magnetic moment, etc.) and Density Functional Theory (DFT: B3LYP 6-31G*/LANL2DZ). In contrast to the recent report, the title complex displays all the properties of diamagnetism and hence retains the properties of a formally Pd(II) square planar complex with a bis-κ2-N,O-donor ligand set. A modified synthetic route is also presented which improves the yield of the compound.

Left kidney mobilization technique during radical antegrade modular pancreatosplenectomy (RAMPS).

PURPOSE: Radical antegrade modular pancreatosplenectomy (RAMPS) has been accepted as a standard operation for distal pancreatic cancer. While enbloc retroperitoneal dissection in the "medial to lateral" direction is one of the most important steps in this oncologic procedure, it is technically challenging due to the depth of organs under the left costal margin, and poor exposure of the resecting organs in this area will increase the risk of incomplete oncologic dissection. METHODS: To improve exposure of the left upper quadrant organs, left kidney was completely mobilized during RAMPS, and all the left upper quadrant organs were elevated and medialized by lap sponges packed in the retro-renal space. The operative and oncologic outcomes for patients who underwent our modified RAMPS with left kidney mobilization were evaluated. RESULTS: One hundred and forty-four patients with distal pancreatic cancer underwent this procedure from 2005 through 2016. The median operation time was 310 min (range, 132-899), and blood loss was 440 ml (25-2430). There was no complication associated to left kidney mobilization. The median number of harvested lymph nodes was 27 (3-87). While 77% of the tumors had microscopic retroperitoneal invasion, 96% of patients achieved negative retroperitoneal margin. CONCLUSIONS: Left kidney mobilization is useful for safe and oncologically sound lateral retroperitoneal dissection during RAMPS for distal pancreatic cancer.

Benzoxazole-based Zn(II) and Cu(II) Complexes Overcome Multidrug-resistance in Cancer.

BACKGROUND/AIM: Multidrug resistance (MDR) represents a significant impediment to successful cancer treatment. In this study, novel metal [Zn(II), Cu(II), Mg(II), Ni(II), Pd(II), and Ag(I)] complexes of 2-trifluoroacetonylbenzoxazole previously synthesized and characterized by our group were tested for their MDR-reversing activity in comparison with the free ligands in L5178Y mouse T-lymphoma (MDR) cells transfected with human ATP-binding cassette sub-family B member 1 (ABCB1; P-glycoprotein) gene. MATERIALS AND METHODS: Cytotoxic and antiproliferative effects of the complexes were assessed by the thiazolyl blue tetrazolium bromide (MTT) method. Modulation of ABCB1 activity was measured by rhodamine 123 accumulation assay using flow cytometry. The apoptosis-inducing activity of some complexes was also tested on the multidrug resistant L5178Y mouse T-lymphoma cells, using the annexin-V/propidium iodide assay. RESULTS: When compared to the free ligand, a remarkable enhancement in MDR reversal and cytotoxic activity was found for the Zn(II) and Cu(II) complexes. The activity of the complexes proved to be up to 29- and 5-fold higher than that of the ligands and the ABCB1 inhibitor verapamil as positive control, respectively. The complexes possessed a remarkable potential to induce apoptosis of MDR cells. CONCLUSION: Our results suggest that the Zn(II) and Cu(II) complexes display significant MDR-reversing activity in a dose-dependent manner and possess strong cytotoxic activity and a remarkable potential to induce apoptosis in MDR L5178Y mouse T-lymphoma cells.