scholarly journals Radiological dynamics and SITC-defined resistance types of advanced melanoma during anti-PD-1 monotherapy: an independent single-blind observational study on an international cohort

2021 ◽  
Vol 9 (2) ◽  
pp. e002092
Author(s):  
Xue Bai ◽  
Michelle Kim ◽  
Gyulnara Kasumova ◽  
Lu Si ◽  
Bixia Tang ◽  
...  
Keyword(s):  
Massachusetts General Hospital ◽  
Clinical Manifestations ◽  
Clinical Trial Design ◽  
Tumor Burden ◽  
Advanced Melanoma ◽  
Bivariate Analysis ◽  
Real World Data ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Single Blind

BackgroundAlthough the Society for Immunotherapy of Cancer (SITC) Immunotherapy Resistance Taskforce recently defined primary and secondary resistance to anti-programmed cell death protein 1 (anti-PD-1) therapy, there is lack of real-world data regarding differences in these resistance subtypes with respect to radiological dynamics and clinical manifestations.MethodsWe performed single-blind re-evaluations of radiological images by independent radiologists on a retrospectively assembled cohort of patients with advanced melanoma (n=254, median follow-up 31 months) receiving anti-PD-1 monotherapy at Massachusetts General Hospital and Peking University Cancer Hospital. Radiological characteristics and timing at multiple crucial time points were analyzed and correlated with each other and with survival. Primary and secondary resistance was defined as per the SITC Immunotherapy Resistance Taskforce definitions.ResultsThe most significant target lesion measurement change took place within the first 3 months after anti-PD-1 initiation. Patients with stable disease with versus without tumor shrinkage at the initial evaluation exhibited distinct disease trajectory, as the rate of further upgrade to a partial or complete remission (CR/PR) was 44% and 0%, respectively. Eleven per cent of PR patients ultimately achieved a CR. In multivariate analyses, deeper response depth was independently associated with a more limited progression pattern, fewer involved organs, lower tumor burden, slower growth rate at disease progression (PD) (all p≤0.001), and longer post-progression survival (PPS) (bivariate analysis, p=0.005). Compared with primary resistance, secondary resistance was associated with less widespread PD pattern, lower tumor burden and slower tumor growth (all p≤0.001). Patients with secondary resistance were less likely to receive further systemic therapy (28% vs 57%, p<0.001) yet had significantly better PPS (HR 0.503, 95% CI 0.288 to 0.879, p=0.02).ConclusionsRadiological dynamics were variable, yet significantly correlated with survival outcomes. SITC-defined primary and secondary resistance are distinct clinical manifestations in patients with melanoma, suggesting the possibility of resistance-type-based therapeutic decision-making and clinical trial design, once further validated by future prospective studies.

228 Radiological dynamics and resistance types in patients with advanced melanoma treated with anti-PD-1 monotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A246-A246
Author(s):  
Xue Bai ◽  
Michelle Kim ◽  
Gyulnara Kasumova ◽  
Lu Si ◽  
Bixia Tang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
General Hospital ◽  
Massachusetts General Hospital ◽  
Tumor Burden ◽  
Advanced Melanoma ◽  
Tumor Shrinkage ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Tumor Reduction ◽  
Peking University

BackgroundThe SITC Immunotherapy Resistance Taskforce recently defined primary and secondary resistance to anti-PD-1 therapy,1 yet there is little data that compares these two scenarios. In particular, detailed radiological dynamics of the different resistance types remain undescribed.MethodsWe performed independent single-blind reevaluations of available radiological image data on a retrospectively assembled cohort of advanced melanoma patients (n=254, median follow-up 31.3 months, figure 1) treated with anti-PD-1 monotherapy initiated between Sept 2009 and Aug 2018 at both Massachusetts General Hospital and Peking University Cancer Hospital. Radiological characteristics and timing at multiple crucial radiological landmarks were analyzed and correlated with each other and with survival. As per the SITC Taskforce, primary resistance was defined as a best response of stable disease (SD) lasting less than six months or disease progression (PD), secondary as PD following an initial partial or complete response (PR/CR) or SD lasting 6 months or greater.1ResultsThe most dramatic tumor reduction occurred within the first 3 months after anti-PD-1 initiation. A subpopulation of patients who had SD (28.6%, all with tumor shrinkage) experienced further tumor reduction and upgraded to CR/PR and 11.1% of patients with initial PR upgraded to CR. No patients without tumor shrinkage at the initial evaluation ultimately responded. Baseline tumor burden, response depth, timing of maximal response and PD pattern demonstrated great variation and were significantly correlated with each other and with survival. In multivariate analyses, deeper response depth was independently associated with a less widespread progression pattern, less involved organs, smaller target lesion size and slower tumor growth rate (all P≤.001) at PD, and longer post progression survival (PPS) (P=0.005). Compared to primary resistance, secondary resistance was correlated with less broad progression pattern, less tumor burden and slower tumor growth (all P≤.001). Patients with secondary resistance were more likely to receive further local/regional therapy (46.5% vs. 30.9%, P=0.07) rather than systemic therapy (27.9% vs. 56.9%, P<0.001), yet had a significantly longer PPS (HR 0.503, 95% CI, 0.288–0.879, P=0.02). Median PPS was not reached (95% CI, 11.8 months to not reached) for patients with secondary resistance and was 10.3 months (95% CI, 7.7–16.1) for patients with primary resistance (figure 2).ConclusionsRadiological dynamics were heterogeneous, yet significantly correlated with survival. Patterns of progression and PPS of the SITC Immunotherapy Resistance Taskforce defined primary and secondary resistance are different. This distinction may be important for the design of clinical trials targeting a PD-1 resistant population.Abstract 228 Figure 1MGH, Massachusetts General Hospital. PUCH, Peking University Cancer HospitalAbstract 228 Figure 2PPS of patients with primary resistance was significantly longer than those developed secondary resistance (P=0.009), with median PPS of 10.3 months (95% CI, 7.7 to 16.1) and not reached (95% CI, 11.8 to not reached), respectivelyEthics ApprovalThis study has been conducted in compliance with local Institutional Review Board policies.ConsentNA.ReferenceKluger H, Tawbi H, Ascierto M, et al. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. J Immunother Cancer. 2020; 8:3000398.

scholarly journals Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce

2020 ◽  
Vol 8 (1) ◽  
pp. e000398 ◽  
Author(s):  
Harriet M. Kluger ◽  
Hussein A. Tawbi ◽  
Maria L. Ascierto ◽  
Michaela Bowden ◽  
Margaret K. Callahan ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Unmet Need ◽  
Death Receptor ◽  
Clinical Trial Design ◽  
Standard Of Care ◽  
Tumor Resistance ◽  
Primary Resistance ◽  
New Agents ◽  
Secondary Resistance ◽  
Programmed Death

As the field of cancer immunotherapy continues to advance at a fast pace, treatment approaches and drug development are evolving rapidly to maximize patient benefit. New agents are commonly evaluated for activity in patients who had previously received a programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor as standard of care or in an investigational study. However, because of the kinetics and patterns of response to PD-1/PD-L1 blockade, and the lack of consistency in the clinical definitions of resistance to therapy, the design of clinical trials of new agents and interpretation of results remains an important challenge. To address this unmet need, the Society for Immunotherapy of Cancer convened a multistakeholder taskforce—consisting of experts in cancer immunotherapy from academia, industry, and government—to generate consensus clinical definitions for resistance to PD-(L)1 inhibitors in three distinct scenarios: primary resistance, secondary resistance, and progression after treatment discontinuation. The taskforce generated consensus on several key issues such as the timeframes that delineate each type of resistance, the necessity for confirmatory scans, and identified caveats for each specific resistance classification. The goal of this effort is to provide guidance for clinical trial design and to support analyses of emerging molecular and cellular data surrounding mechanisms of resistance.

Molecular Correlates of Imatinib Resistance in Gastrointestinal Stromal Tumors

2006 ◽  
Vol 24 (29) ◽  
pp. 4764-4774 ◽  
Author(s):  
Michael C. Heinrich ◽  
Christopher L. Corless ◽  
Charles D. Blanke ◽  
George D. Demetri ◽  
Heikki Joensuu ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
Molecular Mechanisms ◽  
Clonal Evolution ◽  
Clinical Problem ◽  
Primary Resistance ◽  
Imatinib Resistance ◽  
Secondary Resistance ◽  
Stromal Tumors ◽  
Rnai Technology ◽  
Imatinib Resistant

Purpose Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem. Patients and Methods One hundred forty-seven patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib. Specimens from pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Secondary kinase mutations of KIT or PDGFRA that were identified in imatinib-resistant GISTs were biochemically profiled for imatinib sensitivity. Results Molecular studies were performed using specimens from 10 patients with primary and 33 patients with secondary resistance. Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those typically found in untreated GISTs. Secondary kinase mutations were rare in GISTs with primary resistance but frequently found in GISTs with secondary resistance (10% v 67%; P = .002). Evidence for clonal evolution and/or polyclonal secondary kinase mutations was seen in three (18.8%) of 16 patients. Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical KIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on KIT kinase activity for activation of critical downstream signaling pathways. Conclusion Different molecular mechanisms are responsible for primary and secondary imatinib resistance in GISTs. These findings have implications for future approaches to the growing problem of imatinib resistance in patients with advanced GISTs.

Treatment beyond progression with immune checkpoint inhibitors in advanced melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21541-e21541
Author(s):  
Pawel Sobczuk ◽  
Anna Malgorzata Czarnecka ◽  
Mateusz Spalek ◽  
Pawel Teterycz ◽  
Monika Dudzisz-Śledź ◽  
...  
Keyword(s):  
Multimodal Treatment ◽  
Multidisciplinary Treatment ◽  
Objective Response ◽  
Real Life ◽  
Tumor Burden ◽  
Advanced Melanoma ◽  
Disease Stage ◽  
Treatment Beyond Progression ◽  
Melanoma Patients ◽  
Metastatic Sites

e21541 Background: Immunotherapy (ITH) holds the possibility of tumor burden decrease after initial RECIST defined progression (PD). Clinical concept of treating of selected patients (pts) beyond PD is supported by this pseudoprogression phenomenon. The aim of this study was to evaluate real-life practice and outcomes related to treatment beyond progression (TBP) in melanoma patients. Methods: We evaluated advanced melanoma pts who started anti-PD1 treatment between 12/2015 and 12/2018 and identified pts who received TBP and had subsequent imaging to evaluate the tumor burden. Survival analyses were performed using the Kaplan-Meier method, Log-rank, chi-square and Fisher exact tests were used for comparison between groups. Data cut-off was 02/2021. Results: Of 399 subsequent melanoma pts treated, 57 (14%) patients received TBP. Anti-PD1 was 1st line treatment in 61.4% and 2nd line - in 38.6% of patients. 71.9% patients were diagnosed with skin, 7.0% - mucosal and 21.1% with FPI melanoma and 47.4% were BRAF mutated, 56.1% were male and 12.3% had 3 or more metastatic sites at treatment initiation. In this cohort median time to 1st PD (TTFP) was 4.43 months(m), while to 2nd PD (TTSP) – 8.01 m. On TBP 26.3% pts achieved objective response (OR), and next 42.1% - SD. 1st PD was reported most often as increase in 3 or more targets or one new lesion – both 22.8%; and in 24.6% cases involved central nervous system. In 56.8% second PD was observed in the same targets as 1st PD. 61.4% patients received multimodal treatment of ITH combined with radiation therapy – in 49.1%, surgery - 5.3% and both - 7.0%. There was no correlation of TTSP with gender, ECOG, initial disease stage or TNM, BRAF mutation, number of metastatic sites or pattern of progression. Multimodal treatment resulted in 13.6 m TTSP, while ITH alone - 8.0 m (p = 0.056). 1st line OR correlated with DCR on TBP while TTFP > 6 m correlated with TTSP (HR = 0.53, 95%CI 0.28-0.99). Patients with 1st line CR – had median TTSP 16.4 m, with PR – 23.5 m, while those with PD – 5.1 m. Median OS after 1st PD was 26 months and correlated with OR on TBP. Conclusions: Selected clinically fit melanoma patients despite evidence of first radiographic progression may benefit from continued treatment with PD-1 inhibitors. Multidisciplinary treatment should be offered to these patients including radiosurgery or stereotactic radiotherapy of progressing loci. Molecular biomarkers of TTSP should be analyzed in prospective studies.

scholarly journals Transcriptional expression of secondary resistance genes ccdB and repA2 is enhanced in presence of cephalosporin and carabapenem in Escherichia coli

2020 ◽  
Author(s):  
Somorita Baishya ◽  
Chandrayee Deshamukhya ◽  
Jayalaxmi Wangkheimayum ◽  
Bhaskar Jyoti Das ◽  
Anand Anbarasu ◽  
...  
Keyword(s):  
Resistance Genes ◽  
In Silico ◽  
Antibiotic Susceptibility ◽  
Regulatory Protein ◽  
Carbapenem Resistance ◽  
Diffusion Method ◽  
Resistant Bacteria ◽  
Transcriptional Expression ◽  
Primary Resistance ◽  
Secondary Resistance

Abstract Background: The issue of carbapenem resistance in E.coli is very concerning and it is speculated that cumulative effect of both primary resistance genes and secondary resistance genes that act as helper to the primary resistance genes are the reason behind their aggravation. Therefore, here we attempted to find the role of two secondary resistance genes (SRG) ccdB and repA2 in carbapenem resistance in E. coli (CRE).Methods: Influential genes belonging to secondary resistome that act as helper to the primary resistance genes like blaNDM and blaCTX-M in aggravating β-lactam resistance were selected from an earlier reported in silico study. Transcriptional expression of the selected genes in clinical isolates of E.coli that were discretely harboring blaNDM-1, blaNDM-4, blaNDM-5, blaNDM-7 and blaCTX-M-15 with and without carbapenem and cephalosporin stress (2µg/ml) was determined by real time PCR. Cured mutants sets that were lacking (i) primary resistance genes, (ii) secondary resistance genes and (iii) both primary and secondary resistance genes were prepared by SDS treatment. These sets were then subjected to antibiotic susceptibility testing by Kirby Bauer disc diffusion method.Results: Out of the 21 genes reported in the in silico study, 2 genes viz. repA2 and ccdB were selected for transcriptional expression analysis. repA2, coding replication regulatory protein, was downregulated in response to carbapenems and cephalosporins. ccdB, coding for plasmid maintenance protein, was also downregulated in response to carbapenems except imipenem and cephalosporins. Following plasmid elimination assay increase in diameter of zone of inhibition under stress of both antibiotics was observed as compared to uncured control hinting at the reversion of antibiotic susceptibility by the-then resistant bacteria. Conclusion: SRGs repA2 and ccdB help sustenance of blaNDM and blaCTX-M under carbapenem and cephalosporin stress.

scholarly journals Antibiotic Resistance of Helicobacter pylori Strains Isolated From Pediatric Patients in Southwest China

2021 ◽  
Vol 11 ◽  
Author(s):  
Juan Li ◽  
Jianjun Deng ◽  
Zhiling Wang ◽  
Hong Li ◽  
Chaomin Wan
Keyword(s):  
Helicobacter Pylori ◽  
Antibiotic Resistance ◽  
Pediatric Patients ◽  
Southwest China ◽  
Pediatric Population ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Treatment Naïve ◽  
H Pylori ◽  
Resistance Rates

The number of antibiotics that are appropriate for Helicobacter pylori eradication in children is limited. Profiling regional or population-specific antibiotic resistance is essential in guiding the H. pylori eradication treatment in children. The aim of this study was to evaluate the antibiotic resistance in H. pylori strains isolated from children and adolescents in Southwest China. Gastric biopsies from 157 pediatric patients with or without previous H. pylori eradication treatment were collected for H. pylori culture. Susceptibility to amoxicillin (AML), clarithromycin (CLR), metronidazole (MTZ), levofloxacin (LEV), tetracycline (TET), furazolidone (FZD), and rifampicin (RIF) was determined by E-test or a disk diffusion assay. A total of 87 patients from three ethnic groups (Han/Tibetan/Yi) were H. pylori culture positive (55.4%). The overall resistance rates were 55.2% for CLR, 71.3% for MTZ, 60.9% for RIF, and 18.4% for LEV. No isolate was found to be resistant to AML, TET, and FZD. Among the 53 treatment-naïve pediatric patients, primary resistance rates to clarithromycin, metronidazole, levofloxacin, and rifampicin were 45.3, 73.6, 15.1, and 60.4%, respectively. Among the 34 treatment-experienced patients, secondary resistance rates to clarithromycin, metronidazole, levofloxacin, and rifampicin were 70.6, 67.6, 23.5, and 61.8%, respectively. Isolates exhibiting simultaneous resistance to clarithromycin and metronidazole were 28.3 and 52.9% among the treatment-naïve and treatment-experienced patients, respectively. In conclusion, among pediatric patients in Southwest China, resistance rates were high for clarithromycin, metronidazole, levofloxacin, and rifampicin, whereas nil resistance was found to amoxicillin, tetracycline, and furazolidone. Our data suggest that the standard clarithromycin-based triple therapy should be abandoned as empiric therapy, whereas the bismuth quadruple therapy (bismuth/PPI/amoxicillin/tetracycline) would be suitable as first-line empiric treatment regimen for this pediatric population. Tetracycline and furazolidone may be considered for treating refractory H. pylori infections in adolescent patients.

Primary and secondary resistance mechanisms in first, second and third generation tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21142-e21142
Author(s):  
Moushumi Suryavanshi ◽  
Sakshi Mattoo ◽  
Sanjeev Kumar Sharma ◽  
Anurag Mehta ◽  
Ullas Batra
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Egfr Amplification ◽  
2Nd Generation ◽  
Met Amplification ◽  
Egfr Mutant ◽  
Exon 19

e21142 Background: Different molecular mechanisms of on target and off target primary and secondary resistance have been observed in EGFR mutant NSCLC patients after first(1st), second(2nd) and third (3rd) generation of tyrosine kinase inhibitors(TKIs). Next generation sequencing(NGS) offers a comprehensive method of detecting these mechanisms to decide next line of treatment. Methods: We retrospectively analyzed 430 samples of NSCLC for primary and secondary resistance to 1st, 2nd and 3rd TKIs. NGS was performed using thermofischer Ion Torrent Oncomine Focus 52 gene Assay. These cases were divided into 4 groups.1)Primary resistance to first and second generation TKIs 2)Primary resistance to 3rd generation TKI 3)Secondary resistance to 1st and 2nd generation TKI 4) Secondary resistance to 3rd generation TKI.Last group was further subgrouped into A when 3rd generation TKI was offered as second line after 1st or 2nd generation TKIs on detection of T790M and subgroup B when it was given as first line. Results: Group1 had 13 cases. There were 2 cases of complex EGFR exon 19 mutation p.Glu746_Leu747delinsValPro, 4 cases of EGFR exon 20 insertion, 1 case of dual EGFR L833V & H835L mutation, 2 cases with EGFR amplification with EGFR exon 19 del and PIK3CA C420_P421del along with EGFR exon 19 del. Four cases had no additional abnormality. Group 2 had 5 cases:1 case had L858R and E709A dual mutation, 2 cases had KRAS G13C and KRAS G12V along with EGFR exon 19 del. One case had EGFR amplification and one case had MET amplification along with EGFR exon 19 del respectively.Group 3 had 34 cases including 10 cases of EGFR L858R and 24 cases of exon 19 deletion.T790M mutation was detected in 8 patients, MET amplification in 7 cases,one case had both T790M and MET amplification. One case lost the primary EGFR exon 19 del. Others mutations detected were KRAS G13C, PIK3CA H1047R, TP53 R213Q and TP53 C242fs. Group3 had 15 cases with 7 cases in subgroup A and 9 cases in subgroup B. In subgroup A T790M mutation was lost in 6 out of 7 cases.One case which lost T790M developed ALK translocation.One case of EGFR exon 19 del retained EGFR T790M with EGFR C797S in cis allele. Other mutations detected were PIK3CA E542K and KRAS G12C. In subgroup B one case showed EGFR C797S(both cis and trans) besides the primary EGFR exon 19 del. One case showed BRAF G469A along with EGFR exon 19 del. Other mutations detected were CTNNB1 D32N, KRAS G12V, and PIK3CA E542K. Conclusions: Primary and secondary acquired resistance is unavoidable in EGFR mutant advanced NSCLC on any generation of TKIs. NGS offers an advantage in diagnosing mechanism of resistance for further choice of therapy.

scholarly journals Anorectal diseases in patients with Antiphospholipid syndrome: a cross-sectional study

2020 ◽  
Vol 60 (1) ◽  
Author(s):  
E. Cunha ◽  
V. Guzela ◽  
G. G. M. Balbi ◽  
C. Sobrado ◽  
D. Andrade
Keyword(s):  
Surgical Treatment ◽  
Antiphospholipid Syndrome ◽  
Clinical Manifestations ◽  
Warfarin Dose ◽  
The United States ◽  
Bivariate Analysis ◽  
Cross Sectional ◽  
Significance Level ◽  
Anal Bleeding ◽  
Internal Hemorrhoids

Abstract Background Hemorrhoid disease (HD) is one of the most common gastrointestinal complaints worldwide, affecting 4.4% of the general population in the United States. Since antiphospholipid syndrome (APS) may lead to intra-abdominal thrombosis, one may expect that this condition can impact the risk for HD development. Additionally, as APS patients are more prone to thrombosis and treatment with anticoagulants may increase risk of bleeding, one may also infer that rates of HD complications may be higher in this scenario. Nevertheless, no data in these regards have been published until now. The objective of the present study is to evaluate frequency of HD and describe its complications rates in antiphospholipid syndrome APS patients. Methods We consecutively invited patients who fulfilled APS criteria to undergo proctological examination. After examination, patients were divided in two groups, based on the presence of HD, and compared regarding different clinical manifestations and antiphospholipid profile. We performed the analysis of the data, using chi-square and Mann Whitney U when applicable and considering a significance level of 0.05. Multivariate regression analysis included age and variables with p < 0.10 in the bivariate analysis. Results Forty-one APS patients agreed to undergo proctological examination. All were female and overall median age was 43 (36–49). Seventeen (41.4%) patients were diagnosed with HD, with the following frequency distribution: 7 internal (41.2%), 4 external (23.5%) and 5 mixed hemorrhoids (29.4%). Of the internal hemorrhoids, 5 patients were classified as grade I (71.4%), 1 grade II (14.3%), and 1 grade IV (14.3%). Prior gestation (p = 0.067) and constipation (p = 0.067) correlated with a higher frequency of HD. In multivariate analysis, constipation remained as an important risk factor (OR 3.92,CI95% 1.03–14.2,p = 0.037). Five out of 17 patients (29.4%) reported anal bleeding, but it did not correlate with warfarin dose (p = 0.949). Surgical treatment was indicated for 10 patients (58.8%). Other anorectal findings were anal fissure, plicoma, condyloma and one chlamydial retitis. Conclusion We found an unexpected high frequency of hemorrhoids in APS patients, with a great proportion requiring surgical treatment.

Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: a phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer.

1996 ◽  
Vol 14 (6) ◽  
pp. 1877-1884 ◽  
Author(s):  
A D Seidman ◽  
D Hochhauser ◽  
M Gollub ◽  
B Edelman ◽  
T J Yao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Drug Exposure ◽  
Metastatic Breast ◽  
Response Duration ◽  
Pharmacokinetic Profile ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Median Response

PURPOSE A phase II trial of paclitaxel infused over 96 hours in patients with metastatic breast cancer with demonstrated disease progression (PD) during short-infusion taxane treatment was performed to evaluate schedule-dependent activity with prolonged drug exposure. The tolerability of this strategy and its pharmacokinetic profile and pharmacodynamic correlates were also investigated. PATIENTS AND METHODS Paclitaxel was administered to 26 patients with metastatic breast cancer at 120 to 140 mg/m2 intravenously over 96 hours. Twenty-three patients had demonstrated PD while receiving prior 3-hour paclitaxel, two during 1-hour docetaxel, and one during infusions of docetaxel and then paclitaxel. Twenty-one patients (81%) had no prior response to the short taxane infusion (primary resistance) and five (19%) had prior partial responses (PRs) of brief duration before PD (secondary resistance). Plasma paclitaxel concentrations were assessed at 24, 48, 72, and 96 hours. RESULTS After delivery of 195 cycles, seven of 26 assessable patients (26.9%; 95% confidence interval, 11.6% to 47.8%) had major objective responses, with a median response duration of 6 months (range, 1 to 13). The predominant toxicities were neutropenia (76% grade > or = 3) and stomatitis (15% grade > or = 3). Despite omission of premedications, no significant hypersensitivity reactions occurred. The median steady-state paclitaxel concentration (Css) in 23 assessable patients was 0.047 mumol/L (range, .023 to .176). Patients who experienced grade 4 neutropenia had significantly decreased paclitaxel clearance and higher Css than those with grade 1 to 3 neutropenia (P < .05). Pretreatment elevation of hepatic transaminases was associated with delayed clearance (P < .01) and increased myelo-suppression and mucosal toxicity. CONCLUSION Paclitaxel demonstrates activity against metastatic breast cancer when administered over 96 hours to patients with disease that recently had progressed during short taxane exposure. Delayed paclitaxel clearance and consequent increased toxicity occurred in patients with hepatic dysfunction. The activity observed supports preclinical data that suggest variability in efficacy and resistance patterns to paclitaxel based on duration of exposure.

scholarly journals Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update

2019 ◽  
Vol 20 (24) ◽  
pp. 6141 ◽  
Author(s):  
Luana Bavaro ◽  
Margherita Martelli ◽  
Michele Cavo ◽  
Simona Soverini
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Dismal Prognosis

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene, which encodes a constitutive active tyrosine kinase considered to be the pathogenic driver capable of initiating and maintaining the disease. Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1, some patients may not respond (primary resistance) or may relapse after an initial response (secondary resistance). In a small proportion of cases, development of resistance is accompanied or shortly followed by progression from chronic to blastic phase (BP), characterized by a dismal prognosis. Evolution from CP into BP is a multifactorial and probably multistep phenomenon. Increase in BCR-ABL1 transcript levels is thought to promote the onset of secondary chromosomal or genetic defects, induce differentiation arrest, perturb RNA transcription, editing and translation that together with epigenetic and metabolic changes may ultimately lead to the expansion of highly proliferating, differentiation-arrested malignant cells. A multitude of studies over the past two decades have investigated the mechanisms underlying the closely intertwined phenomena of drug resistance and disease progression. Here, we provide an update on what is currently known on the mechanisms underlying progression and present the latest acquisitions on BCR-ABL1-independent resistance and leukemia stem cell persistence.

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