Thyrosine Kinase Inhibitors Research Articles

Prognostic Impact of Persistent Measurable Residual Disease in Patients with Acute Myeloid Leukemia FLT3+ Treated with Intensive Chemotherapy Plus Midostaurin - a Retrospective Study of the Polish Adult Leukemia Group (PALG)

Background: Measurable residual disease (MRD) is detected during morphological remission after standard chemotherapy in acute myeloid leukemia (AML) patients (pts). It is a strong prognostic factor for relapse and shorter overall survival (OS). Immunophenotyping by multiparameter flow cytometry (MFC) is currently the most commonly used method in AML pts. There is still a lack of studies evaluating MRD in specific AML populations in the era of targeted therapies, including thyrosine kinase inhibitors. A retrospective study in adult pts with a newly diagnosed AML FLT3+ treated with intensive chemotherapy plus midostaurin has been performed to evaluate the prognostic impact of positive MRD (MRD+) on RFS and OS. Objectives: To assess the prognostic impact of MRD status during the clinical course of AML FLT3+ on RFS and OS. Patients and methods: Seventy three pts with AML FLT3 were treated in Polish hematological centers between 2018 and 2021. Bone marrow aspiration was performed after induction and consolidation treatment to assess response and MRD by MFC. MRD+ was defined as ≥ 0.1% abnormal cells within mononucleated cells by MFC with diagnostic leukemia-associated immunophenotype (LAIP) and different from normal (DfN) aberrant immunophenotype approaches. Results: The median age of the pts was 55 (range: 18-74). Induction regimen was DA "3+7" in 50 (70%), DA-90 in 8 (11%), DAC in 11 (15%), other in 2 (4%) pts. Fifty seven (78%) pts achieved first composite complete remission (CRc=CR+CRi) after 1 or 2 courses of induction, 12 (17%) had primary refractory disease (PRD) and 2 (3%) pts died in aplasia. Median number of consolidation courses was 2 (range: 1-4). Fifty one (89%) pts with CR1 fulfill the criteria for MRD analysis after 1 or 2 courses of induction and 34 (48%) pts after consolidations. Thirty four pts had 2 timepoints evaluation: after induction and at the end of consolidation courses. MRD+ was reported in 35 (68%) of pts after induction (median 0.5; IQR 0.25-0.85) and in 19 (52%) of pts at the end of consolidations (median 0.64; IQR 0.22-1.99). Analysis of 4 pts groups was performed: Group 1.: MRD+ after induction and at the end of consolidations (persistent MRD+)(n=16; 47%); Group 2.: MRD+ after induction with conversion to MRD- at the end of consolidations (n=6; 18%); Group 3.: MRD- after induction with conversion to MRD+ at the end of consolidations (n=2; 6%); Group 4.: MRD- after induction and at the end of consolidations (persistent MRD-)(n=10; 29%); Baseline clinical characteristics were similar between 4 groups regarding age, FLT3-ITD and FLT3-TKD frequency, FLT3-ITD allelic ratio (AR), WBC, PLT, peripheral blood and bone marrow blast percentage, AML type: de novovs sAML vs tAML (p-values > 0.05). The probability of 1- year RFS was significantly lower in pts with persistent MRD+ (group 1.) vs group 2. vs 3. vs 4. (27% vs 83% vs 50% vs 78%; p=0.034, respectively). Relapse rate after 1 year was in group 1. vs 2. vs 3. vs 4.: 73% vs 16% vs 50% vs 20% (p=0.015), respectively. The shorter OS, but insignificant, was noted in group 1. vs 2. vs 3. vs 4. (p=0.49). A univariate analysis revealed that allo-HSCT (hazard ratio [HR] 0.345; 95% confidence interval (CI), 0.152-0.784; p=0.011) and male sex (HR, 0.433; 95% CI, 0.217-0.861; p=0.017) are predictors for longer OS. MRD- at the end of consolidations (HR, 0.211; 95% CI, 0.066-0.669; p=0.008), persistent MRD- (HR, 0.252; 95% CI, 0.070-0.909; p=0.035), allo-HSCT (HR, 0.416; 95% CI, 0.183-0.947; p=0.0368) are predictors for longer RFS. However, older age (HR, 1.049; 95% CI, 1.018-1.081; p=0.0017) and higher WBC (HR, 1.005; 95% CI, 1.002-1.008; p=0.0022) are predictors for shorter RFS. Conclusions: We observed high rate of CR1 MRD+ AML FLT3 pts after induction (68%) and at the end of consolidations (52%). Significantly lower RFS and higher relapse rate, but not OS, were noted in pts with persistent MRD+ in comparison to pts in other MRD groups. Longer follow-up period and larger studies are necessary to confirm our preliminary findings.

Rationale Efficacy and Safety Evidence of Lenvatinib and Pembrolizumab Association in Anaplastic Thyroid Carcinoma.

Anaplastic thyroid carcinoma (ATC) are highly aggressive malignant tumors with poor overall prognosis despite multimodal therapy. As ATC are extremely rare, no randomized controlled study has been published for metastatic disease. Thyrosine kinase inhibitors, especially lenvatinib and immune checkpoint inhibitors such as pembrolizumab, are emerging drugs for ATC. Few studies have reported the efficacity of pembrolizumab and lenvatinib association, resulting in its frequent off-label use. In this review, we discuss rationale efficacy and safety evidence for the association of lenvatinib and pembrolizumab in ATC. First, we discuss preclinical rationale for pembrolizumab monotherapy, lenvatinib monotherapy and synergistic action of pembrolizumab and lenvatinib in the metastatic setting. We also discuss clinical evidence for immunotherapy and pembrolizumab in ATC through the analysis of studies evaluating immunotherapy, lenvatinib and pembrolizumab lenvatinib association in ATC. In addition, we discuss the safety of this association and potential predictive biomarkers of efficiency.

Hypertensive toxicity of thyrosine kinase inhibitors; Friend or Foe?

Tyrosine kinase inhibitors (TKIs) are widely used in Oncology practice. Hypertension may develop during cancer treatment and TKIs are well known drugs that are associated with drug related hypertensive toxicity. TKI related hypertensive toxicity is not always the indicator of worse clinical outcomes and it may be the sign of treatment efficacy.

Long-term survival of patients with anaplastic thyroid cancer after multimodal treatment.

BackgroundAnaplastic thyroid cancer (ATC) is among the most aggressive human malignancies, with a mean survival time of 6 months regardless of the treatment.MethodsThis retrospective study used the single-centre database system of the Gangnam Severance Hospital. The management and outcome data of 23 patients with a definitive histological diagnosis of ATC were reviewed.ResultsThe 23 long-term survivors were 11 men and 12 women, with a mean age of 58 years. Nine patients had distant metastases at the time of diagnosis. Surgical debulking or complete resection of the tumour was performed for 19 patients, and chemotherapy was administered to 15 patients, radiotherapy to 18 patients, and tyrosine kinase inhibitors to 6 patients. In total, 14 patients were treated with a combination of surgery and radiotherapy with or without chemotherapy. Only 5 patients were treated with surgery alone. Overall, 15 patients underwent R0 resection, 2 underwent R1 resection, and 2 underwent R2 resection. The median survival was 1,090 days, the median follow-up was 646 days, and the 2- and 3-year survival rates were 59.7% and 35.8%, respectively. A total of 10 patients died: 7 with local disease and 3 with distant metastasis.ConclusionsAlthough ATC is typically an incurable disease, patients with ATC who underwent multimodality treatments including resection, chemotherapy, radiotherapy, and thyrosine kinase inhibitors would survive more than 1 year.

Therapeutic effects of tyrosine kinase inhibitors and subtypes of BCR-ABL1 transcripts in Japanese chronic myeloid leukemia patients with three-way chromosomal translocations

We analyzed the clinical responses to thyrosine kinase inhibitors (TKIs) and the molecular and cytogenetic characteristics of 18 chronic myeloid leukemia (CML) patients with 3-way chromosomal translocations. The patients were 14 men and 4 women, aged 23–75 years (median 57 years). The Sokal risk was low in 12 patients, intermediate in 4 patients, and high in 2 patients. Newly identified translocation breakpoints were seen in 7 of the 18 patients. Three patients had the same breakpoints of t(9;22;11)(q34;q11.2;q23).The best responses to TKIs were partial cytogenic response (PCyR) in 2 patients, complete cytogenic response (CCyR) in 3 patients, molecular response (MR) 3.0 in 7 patients, MR 4.0 in 3 patients, and MR 4.5 or higher in 3 patients. A total of 66.7% of patients did not achieve MR 4.0 or higher. In 3 patients in whom TKIs resulted in MR 4.5 or higher for more than 2 years, TKI treatment was discontinued. However, all of them exhibited a loss of MR3.0, at 2, 6, and 20 months after the discontinuation of treatment, respectively, and TKI treatment needed to be restarted. According to Kaplan-Meier survival curve analysis, the overall survival (OS) was 100 months in 56% of the patients. The 60-months cumulative incidences of CCyR, MR3.0, MR4.0 and MR4.5 were 88.9%, 72.2%, 33.3%, and 16.7%, respectively. In the 11 analyzable patients, the BCR-ABL1 mRNA subtype was e14a2 type in 4 patients and e13a2 type in 7 patients.

Mir-217 Reverses the TKI Drug-Resistance of K562 Cells By the Downregulation of Heme Oxygenase-1

Upregulation of Heme oxygenase-1 (HO-1) strengthens drug-resistance to apoptotic death in the several kinds of cancer cells. Our recent study shows the higher levels of HO-1 expression in the thyrosine kinase inhibitors (TKI) resistance K562 cell line and cells from Imatinb-insensitive CML patients. The cause of HO-1 upregulating, though, is still unclear yet.MicroRNAs (miRNAs) play a significant role in the pathogenesis of cancer. They also are known as potential biomarkers and therapeutic targets. In the hematological neoplasm, miRNAs take part in not only cancer development, but also drug resistance. However, the problem has not been solved yet is how the microRNA involved in.This study found that the expression level of microRNAs were much different depended on if it is Imatinb-insensitive or not. The phenomenon was observed both in the K562 and CML patients. The mir217 was one of these microRNAs that significantly deceased when the K562 had been induced to resist the Imatinb. Meanwhile,TKI-resistance K562 cells can be in association with an increase in levels of HO-1 and a decrease in levels of miR-217. In the TKI-resistant K562 cells, the decreased of miR-217 upregulated the expression of HO-1 through a 3'-untranslated region(UTR) of HO-1 and induced the resistance against TKI. Interestingly, TKI-resistant K562 cells exposed to miR-217 mimic can partially make the cells be sensitized to TKI again in association with upregulation of miR-217 and downregulation of HO-1 in vitro. The IC50 of the TKI-resistant K562 cells exposed in 7.5uM Imatinb for 48 hours also decreased after transfecting miR-217 mimic for 48 hours.In our on-going experiment, the express level and interaction of HO-1 and miR-217 will be tested in K562 tumors growing in immune-deficient mice that were treated with the combination of mir-217 inhibitor, expression HO-1 virus and TKI. The express of HO-1 and miR-217 also will be examined in the TKI-insensitive CML patients and the mir217 and HO-1 regulated mechanism will be investigated in vivo.According to our results, the reversibility of the mir-217 downregulating Heme oxygenase-1 in the K562 cells with TKI drug tolerance likely provides a potentially exciting miRNA therapeutic strategy.MiRNAs therapy could be utilized as a powerful therapy which would focus to the drug-resistance patients. Drug-resistance cancer cells may be sensitized to former conventional or targeted chemotherapy. DisclosuresNo relevant conflicts of interest to declare.

Downregulation of miR‐217 correlates with resistance of ph+ leukemia cells to ABL tyrosine kinase inhibitors

This study found that long-term exposure of chronic myelogenous leukemia (CML) K562 cells to BCR/ABL thyrosine kinase inhibitors (TKI) caused drug-resistance in association with an increase in levels of DNA methyltransferases (DNMT) and a decrease in levels of microRNA miR-217. These observations are clinically relevant; an increase in levels of DNMT3A in association with downregulation of miR-217 were noted in leukemia cells isolated from individuals with BCR/ABL TKI-resistant Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) and CML. Further studies with TKI-resistant K562 cells found that forced expression of miR-217 inhibited expression of DNMT3A through a miR-217-binding site within the 3′-untranslated region of DNMT3A and sensitized these cells to growth inhibition mediated by the TKI. Of note, long-term exposure of K562 cells to dasatinib (10 nM) together with 5-Aza-2′-deoxycytidine (5-AzadC) (0.1 μM) potently inhibited proliferation of these cells in association with upregulation of miR-217 and downregulation of DNMT3A in vitro. In addition, a decrease in levels of DNMT3A and an increase in levels of miR-217 were noted in K562 tumors growing in immune-deficient mice that were treated with the combination of 5-AzadC and dasatinib. Taken together, Ph+ leukemia cells acquire TKI resistance via downregulation of miR-217 and upregulation of DNMT3A. Inhibition of DNMT3A by forced expression of miR-217 or 5-AzadC may be useful to prevent drug resistance in individuals who receive TKI.

Megakariocytic Hypoplasia Due To TKIs In a CML Patient Can Be Overcome By TPO Receptor Agonist Eltrombopag

Background Patients who develop severe thrombocytopenia while treated with TK inhibitors may be forced to stop them, face a worse prognosis, and eventually require a treatment with a bone marrow transplant. Eltrombopag is a TPO receptor agonist that stimulates megakaryocytic proliferation. Case 62-year-old man presented in October 2008 with splenomegaly and leukocytosis. The bone marrow biopsy was diagnostic of CML. Imatinib was started at 400 mg daily resulting in hematological response and resolution of splenomegaly, but severe thrombocytopenia necessitated 50 % dose reduction. Thrombocytopenia was not responsive to Prednisone, and a trial of platelets transfusions with the standard dose of Imatinib had to be stopped because of thrombocytopenia below 10 K and the risk of bleeding – reducing the dose of the TKI was improving the platelet count. Treatment with Dasatinib and with Nilotinib also necessitated 50 % dose reductions because of thrombocytopenia. These reduced TKI dosing resulted in the best Quantitative RT-PCR for bcr/abl product reduction level at – 1.01. Bone marrow biopsy in December 2010 showed no morphologic evidence of CML, and no dysplasia; it was normocellular marrow with erythroid hyperplasia and megakaryocytic hypoplasia. Cytogenetic analysis and FISH showed presence of the Philadelphia chromosome rearrangement. The patient declined the treatment with a Bone marrow transplant. In April 2011 a TPO agonist Eltrombopag 50 mg daily was started, given on two weeks on two weeks off schedule. As platelets remained adequate since then, the Nilotinib was escalated to the full dose of 400 mg twice daily. The patient tolerated the treatment well. Results The patient required about half-a-year support with Eltrombopag; after that it was discontinued as the platelet count remained above 40 K. No dose reduction of Nilotinib was necessary. In January 2012 the patient reached the milestone of Complete Cytogentic Response with the level of bcr/abl transcript minus 2 or less, which continued to decrease and now the patient is achieving a Major Molecular Response. Conclusion Treatment of CML with Tyrosine Kinase Inhibitors – Imatinib, Dasatinib, or Nilotinib in our patient – can be complicated by severe thrombocytopenia. These patients’ next treatment option may be a Bone marrow transplant. Limited use of Eltrombopag can improve thrombocytopenia, and allow these patients to continue TKIs with attainment of the treatment milestons. Disclosures: Off Label Use: Eltrombopag. It is used in thrombocytopenia, in ITP. In this presentation it was used to treat thrombocytopenia secondary to Thyrosine Kinase Inhibitors in Chronic Myelogenous Leukemia.

Everolimus (E) and octreotid (O) in metastatic high-risk MEN IIb disease: A case report.

e13565 Background: Multiple endocrine neoplasia (MEN) type IIB is characterized by missense mutation in exon 16 of the RET-proto-onkogen. Malignant c-cell-(medullar)-carcinoma of the thyroid gland (MTC) is part of the disease. Prognostic factors for metastatic MTC (m-MTC) are tumor grading, vessel- and peri-neural infiltration, age and performance status (PS). Irradiation and chemotherapy have limited activity in m-MTC. Thyrosine-kinase inhibitors like vandetanib, sorafenib or sunitinib were not admitted in Germany in 2011, August. As mTor-pathway seems to play a role in m-MTC E was suggested to be a treatment alternative. In somatostatin receptor (SR) positive tumors O might be beneficial. Methods: In 2011, August, a 23 years old man presented with metastatic MEN IIB disease after palliative irradiation therapy. ECOG-PS was 2 to 3, Calcitonin was 3.615 pg/ml, CEA was 467 ng/ml. The patient (pt) had a non-resectable m-MTC, SR positive, with esophageal, pleural, tracheal and lymph node infiltration still with metabolic activity in PET-CT. Grading was G3 with strong vessel and peri-neural infiltration. Right adrenal tumor and tongue tumor were present. After written informed consent the pt started treatment with E 10 mg/day orally in 2011, November. A loperamide resistant diarrhea was treated with O 20 mg/4 weeks i. m. additionally since 2012, July. Results: During treatment with E Calcitonin and CEA levels continuously decreased and CT scans every 3 months demonstrated a continuous shrinkage of all tumor sites, especially after additional treatment with O, which also was associated with an improved PS. Since 2012, October, ECOG PS was 0 enabling the patient to go to work again. Since 2012, October no relevant treatment related side effects were present. Conclusions: E showed efficacy as single agent treatment in a young man with metastatic high risk MEN IIB disease, the addition of O seems to reduce side effects and to improve efficacy of single agent E in this case. Further investigation is needed to verify these results

Treatment of advanced thyroid cancer refractory to therapy

Radioiodine treatment constitutes the most effective therapeutic option of advanced differentiated thyroid cancer. Unfortunately, about 30% cancers do not show radioiodine uptake or do not respond to therapy. Thyrosine kinase inhibitors (TKI), among them axitinib, cabozantinib, lenvatinib, motesanib, pazopanib, sorafenib, sunitynib and vandetanib, constitute a new group of drugs implemented to therapy of both differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC). They inhibit growth factor receptors which play crucial role in processes of growth, differentiation and maturation of neoplastic cell. Detailed information related to mechanism of action of each drug as well as to conducted clinical trials are given in the table below: Table 1 Until now the only registered drug in advanced MTC is vandetanib. Its efficacy has been proved in phase III study. Significant prolongation of progression free survival (PFS) was observed for patients receiving vandetanib compared with placebo group (30.5 months vs. 19 months, respectively). Published results of phase II studies have preliminarily proved the efficacy of axitinib, sorafenib and sunitinib in DTC (beneficial therapeutic effects of partial regression or disease stabilization was noticed in 68%, 76% and 75% cases, respectively). The highest response rate (partial regression) was obtained in DTC patients treated with pazopanib (49%). Whereas, in phase II clinical trials with cabozantynib, motesanib and sorafenib carried out in MTC, disease control was achieved in 90%, 83% and 94% patients, respectively. The most common side effects are skin reactions such as photosensitivity, rash, hand-food syndrome, arterial hypertension, gastrointestinal – diarrhea, nausea, vomiting, stomatitis and decrease in body weight. Majority of them have slight or moderate intensiveness (G1 and G2 according to Common Terminology Criteria for Adverse Events). The tolerability of TKI is acceptable and does not affect the quality of life.

Antiangiogenic Therapeutic Approaches in Multiple Myeloma

Angiogenesis is a constant hallmark of multiple myeloma (MM) progression and has prognostic potential. The pathophysiology of MM-induced angiogenesis involves both direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment. An improved understanding of the importance of angiogenesis-related signaling in MM has allowed for the rational use of antiangiogenic therapies in this tumor. This review article summarizes the literature data concerning the employment of the most important antiangiogenic therapeutic agents actually used in preclinical models and clinical settings for the treatment of MM.

Outcome After Failure to Second Generation Thyrosine Kinase Inhibitors(TKI) Treatment as Frontline Therapy for Patients with Chronic Myeloid Leukemia (CML) In Chronic Phase(CP).

AbstractAbstract 3442 Background:Imatinib has been the standard frontline therapy for patients with CML in early CP. 2nd generation TKIs (nilotinib, dasatinib) have been reported to be more effective than imatinib as frontline therapy in rates of response and transformation. Nilotinib has received regulatory approval for this indication and others (dasatinib, bosutinib) may come soon. Although fewer patients are expected to experience failure to therapy with the use of these agents, these patients will represent a management challenge. The characteristics, management and outcome of patients who fail therapy with 2nd generation TKI used as initial therapy has not been reported. Aim:To analyze the characteristics of patients who fail therapy with 2nd generation TKI used as initial therapy, their management, and outcome after failure to initial therapy. Methods:Two parallel studies of 2nd generation TKI as initial therapy for CML early CP are being conducted at MDACC, one with nilotinib and one with dasatinib. The study with nilotinib includes also patients in accelerated phase (AP) that have received no other prior therapy. The records of all patients who were taken off therapy from these trials were reviewed to investigate the reasons for failure, subsequent management and outcome. Results:A total of 172 pts have been treated with dasatinib (n=82) or nilotinib (n=90; 9 in AP) since 2005. After a median follow-up of 18.9 months, 23 pts (14%) have discontinued therapy: 13 (16%) pts in the nilotinib study (2 of them treated in AP), and 10 (12%) in the dasatinib study. Their median age 48 years (range:19–73) and they had received therapy with nilotinib or dasatinib for a median of 5.2 (0.03-48) months. Reasons for nilotinib treatment discontinuation include: toxicity 4 pts (elevated lipase, acute pancreatitis + atrial fibrillation, pericardial effusion and acute renal failure, one each), transformation to blast phase (BP) 3 pts (2 of them treated in AP), and other reasons 6 pts (2 each for insurance issues, patient request and non-compliance). Reasons for discontinuation of dasatinib include: toxicity 5 pts (2 pleural effusion, 1 prolonged thrombocytopenia, 1 bone pain, 1 congestive heart failure), 2 pts for loss of response, and 3 pts for pts' choice. Best response to frontline treatment with nilotinib or dasatinib was 6 (26%) pts major molecular response, 6 (26%) pts complete cytogenetic response, 1 (4%) pt partial cytogenetic response, 3 (13%) pts minor cytogenetic response, 1 (4%) pt with no response and 6 (26%) pts nonevaluable. At the time of failure 18 pts were in CP, 4 pts in BP (one pt transformed shortly after discontinuation) and 1 AP. At the time of treatment interruption, 14 pts had BCR-ABL sequencing and 2 were found to have mutations (F359C, Y253H); 3 pts had new additional chromosomal abnormalities (ie, clonal evolution). Subsequent treatment after failure to initial therapy include: imatinib in 8 pts, nilotinib in 2 pts, dasatinib 1 pt, Hyper CVAD with dasatinib 1 pt, Hyper CVAD with imatinib 1 pt, stem cell transplant 2 pts, bafetinib 1 pt, and unknown 4 pts (lost to follow-up). One pt died shortly after failure without further therapy. Best response to subsequent therapies were 1 pt with CMR (after stem cell transplant), 7 pts with MMR (3 pts after imatinib, 1 pt after dasatinib, 1 pt after nilotinib, 1 pt after Hyper CVAD with imatinib and 1 pt after stem cell transplant), 1 pt CHR, 1 pt minor CyR, 3 pts without response, and 8 pts were not evaluable. Of the 5 pts that achieved MMR with subsequent TKI, all were in CP and had discontinued initial therapy because of toxicity (4 pts) or personal reasons (1pt). Median duration of ongoing subsequent treatment is 8 months (range 1.7–25). The survival rate after a median follow-up of 3.9 months since failure to frontline therapy is 87%. Conclusion:Failure after frontline therapy with second generation TKI is an uncommon event, most frequently associated with toxicity or patient preference. Most of these patients respond well to alternative TKI. This adequate response should alleviate the fear of not having available effective therapy if patients fail to respond to 2nd generation TKI when used as frontline therapy. Disclosures:Kantarjian:BMS: Research Funding; NOVARTIS: Research Funding. Cortes:BMS: Research Funding; NOVARTIS: Research Funding; Pfizer: Consultancy, Research Funding.

Vascular remodeling in pulmonary arterial hypertension: Multiple cancer-like pathways and possible treatment modalities

Most patients with severe pulmonary arterial hypertension (PAH) demonstrate persistent structural alterations in small pulmonary arterioles at the time of diagnosis, including marked proliferation of pulmonary artery endothelial cells (ECs), smooth muscle cells (SMCs) and fibroblasts. Rai et al. have recently proposed a paradigm shift to explain the pathobiology of small vessel disease in severe PAH patients as a quasi-neoplastic process. Indeed, the vascular lesions of patients with severe PAH exhibit some cancer-like characteristics: decreased population of apoptotic cells and overexpression of antiapoptotic proteins. Nevertheless they lack the capability for tissue invasion and metastasis. The article reviews pathomechanisms of vascular lesions in PAH comparing them with each of the cancer defining mechanisms and indicates the potential utility of antineoplastic drugs as antiproliferative treatment in PAH. PDGF has been identified as a novel potential therapeutic target and the successful treatment of experimental PAH with a PDGF receptor tyrosine kinase inhibitor has been demonstrated recently. These findings justify further clinical trials concerning thyrosine kinase inhibitors as future PAH therapies. However, the drugs currently developed for malignant neoplasms to target neoplastic proliferation should be tested carefully in PAH patients due to their cardiac and pulmonary toxicity.

Abstract 2124: The analysis of EGFR genetic heterogeneity on mixed adenocarcinoma of the lung

Abstract Background: The epidermal growth factor receptor thyrosine kinase inhibitors (EGFR-TKIs) are effective for non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, every patient eventually relapse even if the treatment of EGFR-TKIs was effective remarkably. It have been reported a secondary T790M mutation, MET amplification and some mechanisms attribute to the drug resistance. Intratumor EGFR genetic heterogeneity has also been considered as a potential cause of the acquired resistance. We previously reported a patient with mixed adenocarcinoma of the lung that had different EGFR mutations in papillary, acinar and BAC subtypes. In this study, we analyzed EGFR mutations in each histological subtypes of mixed adenocarcinoma after surgery and pre EGFR-TKIs treatment. Material and Methods: We recruited twelve mixed adenocarcinoma patients who were treated surgical therapy. Tumor cells in different histological subtypes were microdissected from paraffin-embedded surgical specimens with AS LMD system. Genomic DNA was extracted from each sampled area. EGFR mutations, limited to exon19 deletions and L858R mutations, were examined using the simple polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP) methods. Results: Acinar, BAC and papillary sanmples were microdissected from six, ten and eleven tumor tissues. Exon19 deletions and L858R mutation were detected in five and one tissues. From acinar, BAC and papillary samples, one exon19 deletion, two exon19 deletions and three exon19 delitions and one L858R were detected. Out of the six mixed adenocarcinoma, five tissues consisted both mutated and non-mutated cells. Conclusions: Our results indicates that 41% of lung adenocarcinoma with mixed subtypes have intratoumor genetic heterogeneity. EGFR mutations were detected most frequently in papillary samples. There may be some relations between histological subtype and EGFR mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2124.

Gibt es eine nichtchirurgische Therapie der Gallenwegskarzinome?

Nonsurgical treatment aims at controlling disease and improving survival and quality of life in patients with nonresectable, recurrent metastatic cholangiocarcinomas. After R0 resection, percutaneous or intraluminal radiotherapy with adjuvant radiochemotherapy may improve survival. Available data, however, are still unsatisfactory, and the efficacy of adjuvant radiochemotherapy after R0 resection remains to be confirmed. Exclusive chemotherapy fails to improve survival postoperatively while, in adequate patients, neoadjuvant chemotherapy can improve R0 resection results. Palliative chemotherapy yielded improved survival and quality of life in only one small prospective randomized trial and cannot be generally recommended at present. Previous biliary stenting for relieving jaundice is mandatory. Beyond established regimens employing 5-fluorouracil/leukovorin and gemcitabine plus platin-based agents, ongoing trials are focussing on topoisomerase-and thyrosine kinase inhibitors. Palliative stenting of malignant bile duct stenoses may eliminate or at least relieve jaundice and pruritus. Single stenting is sufficient for distal bile duct stenoses. In patients with liver metastasis and life expectancy of <6 months, temporary plastic prostheses with 4-6-month patency are sufficient. When the prognosis is for >6 months, self-expanding permanent metal stents, with their significantly longer patency, are superior. In hilar tumors, obstruction of plastic prostheses occurs earlier than in distal bile duct stenoses. Thus, patients with Bismuth II-IV tumors benefit from self-expanding metal stents. These may be inserted by an endoscopic, retrograde approach, percutaneously, or by a combined rendez-vous maneuver. The superiority of bilateral vs unilateral stenting has yet to be proven in Bismuth II-IV tumors. Photodynamic therapy followed by stenting appears to improve survival rates by delaying stent occlusion rather than by regression of the tumoric disease itself.