PIK3CA mutations have been identified in approximately up to 40% of breast cancer cases and PIK3CA targeting has already been incorporated in treatment algorithms, especially in the second line of ER+/HER2- patients. HeSMO launched a national program to provide PIK3CA mutation testing, which is officially not reimbursed, with the aim to identify mutations in the PIK3CA gene, and, therefore, lead to more therapeutic options. All HR+/HER2- patients with a diagnosis of metastatic breast cancer were eligible to participate in this program. The result of the test was obtained using the COBAS® PIK3CA method, a diagnostic test specifically designed to detect mutations in the PIK3CA gene in tumor tissue samples (FFPE) attained by biopsy or surgically, which detects 17 different mutations in the PIK3CA gene, including the most commonly occurring in Exons 9 and 20. From June 2022 to March 2023, 149 patients from across the country were tested within this program. Sixty one (61) patients (40.94%) were detected with mutation in PIK3CA gene and 88 (59.06%) without mutation (Table). 23 patients had Exon 9 mutations (37.70%), 33 in Exon 20 (54.10%), and 8 had mutations in the remaining Exons 1, 4 and 7 (13.11%). In 1 sample 4 mutations were detected: (Exon 7/9/20), and 2 mutations in another 2 samples (Exon 9: E545X, Q546X and Exons 1/20), while in all other samples just 1 mutation was detected in each. Table: 439PPIK3CA mutation results of HeSMO’s programExonMutationSamplesMutation percentage in all patients detected with PIK3CA gene mutation (61)Mutation percentage in all patients tested (149)Exon 1R88Q23,28%1,34%Exon 4N345K34,92%2,01%Exon 7C420R34,92%2,01%Exon 9E542K711,48%4,70%Exon 9E545X1219,67%8,05%Exon 9Q546X23,28%1,34%Exon 9E545X, Q546X11,64%0,67%Exon 9E542K, E545X11,64%0,67%Exon 20H1047X3252,46%21,48%Exon 20G1049R11,64%0,67% Open table in a new tab In our series, 40.94% of the patients tested, were detected with mutations in PIK3CA gene, in accordance with published data. Apart from the significant implications for treatment possibilities in a substantial patients’ population, these results provide valuable epidemiological data and strengthen our efforts for reimbursement of PIK3CA mutation testing in Greece.

Angiogenesis plays an essential role in many physiological and pathological processes. Auranofin (Ridaura®), an important gold(I) complex, is used to treat rheumatoid arthritis. However, the effect of auranofin on blood vessel formation is still unclear. In this study, we investigated the anti-angiogenic activity of auranofin on human umbilical vein endothelial cells (HUVEC) in vitro and zebrafish in vivo. Our results showed that auranofin could inhibit the proliferation, migration and tube formation of HUVECs and disrupted the formation of intersegmental vessels and the subintestinal vessels of zebrafish embryos. Auranofin inhibited the phosphorylation of vascular endothelial growth factor 2 (p-VEGFR2) on HUVECs and suppressed the vascular endothelial growth factor (VEGF) signaling pathway (vegfa, flt-1, kdr) but not thioredoxin reductase (TrxR) on zebrafish. Our study suggested that auranofin might serve as a potential anti-angiogenic compound candidate.

Exaggerated BP response to exercise is believed to predict future hypertension and probably cardiovascular and all-cause mortality. We studied specific stress-test parameters related to autonomic nervous activity in the heart. We evaluated retrospectively, 48 subjects, group A (36 male,12 female, mean age 58,42±11,29yrs), undergoing exercise testing for various reasons, with exaggerated blood pressure response to exercise. All of them exercised a symptoms limited exercise test according the Bruce protocol using a 2000 Marquette treadmill. Hypertensive response was defined as systolic blood pressure>220mmHg and/or diastolic blood pressure>105mmHg during peak exercise. Positive for ischemia or non-diagnostic tests were excluded from the analysis. We compared them with 115 subjects, group C(59 male,56 female, mean age 52,01±10,62yrs) with normal blood pressure response to exercise, who underwent the exercise test in the same period. The parameters analyzed were: exercise time(ET),the ratio achieved heart rate to predicted heart rate(AHR/PHR),heart rate recovery(HRR)defined as the difference between achieved peak heart rate and the heart rate at 1′ recovery time, and QTc during rest(QTcR),peak exercise(QTcP),1′ recovery time (QTc1RT). Our findings using paired t-test(SPSS version 10.0)are shown below:Our results suggest the hypothesis that sympathovagal tone is altered in healthy individuals with hypertensive response to exercise.

Normotensives with exaggerated blood pressure response during exercise have impaired test parameters associated with autonomic nervous activity. We studied the short and long term effects of the angiotensin receptor blocker irbesartan on these parameters. 48 subjects(36 male,12 female, mean age 58,42 ± 11,29yrs)-group A- free from known cardiovascular diseases and negative for myocardial ischemia, undergoing exercise testing for various reasons, with exaggerated blood pressure response during exercise(systolic blood pressure≥ 220mmHg and/or diastolic blood pressure ≥105mmHg during peak exercise) received daily 300mg irbesartan. The symptoms limited exercise test according the Bruce protocol using a Marquette 2000 treadmill was then performed again at 40 days,1 year.Control group-C- consisted of 38 subjects(19 male, 19 female, mean age 51,58± 10,32yrs) with normal blood pressure response to exercise. We studied: peak systolic blood pressure (PSBP), peak diastolic blood pressure (PDBP),exercise time(ET),heart rate recovery(HRR),defined as the difference between achieved heart rate and heart rate at 1′ of recovery time.At the baseline group A-as compared to group C- had exaggerated blood pressure response, reduced exercise time and delayed heart rate recovery. Our results,using paired t-test(SPSS version 10.0) are shown below: (See Table) Both short and long term administration of irbesartan in normotensives with hypertensive response during exercise have favorable effects on exercise test parameters associated with impaired autonomic nervous activity.

Excessive increases in blood pressure during exercise have been found to be one of the best predictors of future hypertension and cardiovascular (probably and all-cause) mortality. We studied whether high blood pressure response during exercise is associated with delayed heart rate recovery and reduced exercise tolerance in normotensive subjects (well known markers of future major cardiovascular events). We evaluated 78 subjects (free from known cardiovascular diseases and negative for myocardial ischemia), undergoing exercise testing for various reasons, who presented with hypertensive response to exercise. All subjects exercised -symptoms limited- according the Bruce protocol using a 2000 Marquette treadmill. Hypertensive response was defined as systolic blood pressure ≥ 200mmHg and/or diastolic blood pressure ≥95mmHg during peak exercise (group A: 30 subjects,14 male,16 female, mean age 58,3±11,8yrs). Exaggerated blood pressure response at exercise was defined, separately from group A, as systolic blood pressure ≥220mmHg and/or diastolic blood pressure ≥105mmHg during peak exercise (group B: 48 subjects, 36 male, 12 female, mean age 58,42±11,29yrs). Control group (group C: 38 subjects, 19 male, 19 female, mean age 51.58±10,32yrs) had normal blood pressure response to exercise. The parameters analyzed were: exercise time (ET), the ratio achieved heart rate/predicted heart rate (AHR/PHR), and heart rate recovery (HRR) defined as the difference between achieved peak heart rate and heart rate at 1′ recovery time. Our findings- using paired t-test,SPSS version 10.0- are shown in the table. There is a significant reduction in exercise time in both groups A and B (p<0,001 and p=0,009 respectively),a significant impairment in HRR in group B(p=0,007), but not in group A .The ratio AHR/PHR is not affected. Exaggerated blood pressure response during exercise is associated with reduced exercise capacity and delayed HRR in normotensive subjects.

Zarkos, I.1; Vrana, I.1; Thireos, E.2; Lemonis, S.1; Livieratos, G.1; Nearchou, N.3; Mitropoulou, A.1; Fakarou, E.1; Tolis, C.1; Tolis, V.1 Author Information

: Monday, June 14, 2004: ORAL SESSIONS: Poster Session 19: Therapeutics and Clinical Pharmacology

Cancer is the second cause of death in developed countries. Many efforts to educate the public to more tumor free life-style and screening practice have been therefore adopted. Considering the high costs of diagnostic procedures and educational programs a cancer prevention/screening practice monitoring system is required to reduce costs, to assist health making policy decisions, and to tailor more targeted interventions whenever indicated. We, therefore, realized a computerized data-base able to assist medical personnel in health intervention monitoring and making policy at community level with a focus on the European region. An international medical board provided the translation of medical-related contents in English, French, German, Greek, Italian, Rumanian, Spanish and Turkish. The electronic system recognizes and finds relationships between screening events or secondary prevention tests and various causes of medical examinations (symptoms, diseases, professions, presence and type of health insurance, sex, age, medical history, family history, educational level, knowledge about cancer screening and prevention, patient location, type of community, region of provenance, etc). Due to its multi-language standardized characteristics its application may bridge European countries in cancer screening monitoring policy.

A phase I pharmacokinetics and dose-finding study and a phase II study of the combination of pegylated liposomal doxorubicin HCl (PLD) and paclitaxel were conducted in patients with recurrent or metastatic head and neck cancer (HNC). Sixty patients with recurrent or metastatic disease were enrolled in the study: 11 patients in the phase I study and 49 patients in the phase II study. In the phase I study, the initial dose level of PLD was 35 mg/m as a 1-h infusion with escalating increments of 5 mg/m until the maximum tolerated dose (MTD) was reached. A fixed dose of paclitaxel (175 mg/m) was administered as a 3-h infusion. The combination was administered every 28 days. Pharmacokinetic studies performed on 10 patients indicated that the sequence of drug administration did not cause clinically significant modifications in the pharmacokinetics of either drug. The MTD for PLD was 45 mg/m (dose level 3) and the dose-limiting toxicity was febrile neutropenia, occurring in three of five patients. The phase II dose of PLD was 40 mg/m (dose level 2) and a total of 214 cycles were delivered. Grade 3 or 4 neutropenia was observed in 26% patients and febrile neutropenia occurred in 16% of patients. Grade 3 palmar-plantar erythrodysesthesia (PPE) was recorded in only one patient. The overall response rate was 28% for patients with non-nasopharyngeal tumors [95% confidence interval (CI) 15-45%] and 28.6% for the study population (95% CI 17-43%). The median survival for the study population was 9.7 months; 1-year survival was 38%. We conclude that the recommended dose for the combination of PLD and paclitaxel is 40 and 175 mg/m every 28 days, without granulocyte colony stimulating factor support. The combination of paclitaxel with PLD demonstrated activity in recurrent or metastatic HNC, a favorable toxicity profile and relative ease of administration.

The QT interval corrected for heart rate (QTc) is believed to reflect sympathovagal balance. This study tested the hypothesis that QTc interval length at rest, during exercise and during recovery time is altered in normotensives with an exaggerated blood pressure response during exercise (unknown if it impairs sympathovagal tone). We evaluated 78 subjects (free from known cardiovascular diseases and negative for myocardial ischemia), undergoing exercise testing for various reasons, who presented with hypertensive response to exercise. All subjects exercised -symptoms limited- according the Bruce protocol using a 2000 Marquette treadmill. Hypertensive response was defined as systolic blood pressure ≥ 200mmHg and/or diastolic blood pressure ≥95mmHg during peak exercise (group A:30 subjects,14 male,16 female, mean age 58,3±11,8yrs). Exaggerated blood pressure response at exercise was defined, separately from group A, as systolic blood pressure ≥220mmHg and/or diastolic blood pressure ≥105mmHg during peak exercise ( group B:48 subjects,36 male, 12 female, mean age 58,42±11,29yrs). Control group (group C: 38 subjects,19 male,19 female, mean age 51.58±10,32yrs) had normal blood pressure response to exercise. We studied the QTc interval length during rest(QTcR), peak exercise( QTcP), 1′ recovery time(QTcRT1),2′ rec. time(QTcRT2),3′ rec. time(QTcRT3). QTc intervals were calculated using the Bazzett's formula :QTc =QT/√RR. All QTc intervals are measured in msec. Our findings- using paired t-test,SPSS version 10.0- are shown in the table. In our study excessive blood pressure response to exercise in normotensive individuals is not associated with any QTc alterations before, during, or after exercise.

Zarkos, I.1; Vrana, I.1; Thireos, E.2; Livieratos, G.1; Lemonis, S.1; Nearchou, N.3; Mitropoulou, A.1; Tolis, C.1; Tolis, V.1 Author Information

Breast cancer is the most common cancer and the second greatest cause of cancer-related death among women in the United States. Capecitabine is a selectively tumor-activated fluoropyrimidine carbamate that is converted to 5-fluorouracil by the sequential activity of these enzymes, the final of which is thymidine phosphorylase, which is overexpressed in many human cancers. Capecitabine as a single agent and in combination with other drugs is efficacious in previously treated and untreated metastatic breast cancer (MBC). The integration of capecitabine, either as a single agent or in combination with docetaxel, into adjuvant breast cancer therapy is justified due to its high antitumor activity in previously treated and untreated MBC, its tolerability, lack of cross-resistance with the anthracyclines and taxanes, and because combined docetaxel/ capecitabine improves the overall survival of patients with MBC. Capecitabine is being evaluated as preoperative therapy in patients with operable breast cancer, as adjuvant therapy in patients with high-risk node-negative or node-positive disease, and as oral single-agent therapy in women ≥ 65 years of age. This article is an overview of published studies of capecitabine in MBC and the studies that are planned or have been proposed to evaluate capecitabine as adjuvant therapy for breast cancer.

Multicentric Castleman’s disease is increasingly recognized as an aggressive illness with a rapidly fatal outcome in human immunodeficiency virus (HIV)-infected patients. In the absence of optimal therapy, various therapeutic interventions have been tested with disappointing results; only five reports with a successful outcome have been described. Presented herein is a 66-year-old HIV-infected man with multicentric Castleman’s disease. Early administration of cyclophosphamide, doxorubicin, vincristine and prednisone resulted in prolonged clinical recovery. The relevant literature is also reviewed.

Anticancer drugs exert at least part of their cytotoxic effect by triggering apoptosis, We previously identified chemotherapy-induced apoptosis in lung cancer cells and suggested a I-ore for p53 alternative or complementary pathways in this process. Recently, a role for the Fas/FasL (CD95/Apo1) signaling system in chemotherapy-induced apoptosis was proposed in some cell types. Ln the present work, the involvement of the Fas/FasL system in drug-induced apoptosis in lung cancer cells was investigated upon exposure to four cytotoxic drugs (cisplatin, gemcitabine, topotecan, and paclitaxel), We assessed the expression of Fas and Fast and the function of the Fas pathway in six lung cancer cell lines (H460, H322, GLC4, GLC4/ADR, H187, and N417), All lung cancer cell lines expressed Fas and Fast at RNA and protein levels, and apoptosis could be induced in four of six cell lines upon exposure to the Fas agonistic monoclonal antibody (mAb) CLB-CD95/15, Nevertheless, after drug exposure, no significant Fast up-regulation was observed, whereas the Fas expression was increased in the wild-type p53 cell line H460, but not in the other lines, proved to be mutant p53 by direct gene sequencing. Moreover, no correlation was observed in lung cancer cell lines between sensitivity to drugs and to a Fas agonistic mAb, and preincubation of cells with either the Fas-antagonistic mAb CLB-CD95/2 or a Fast-neutralizing mAb did not protect from drug-induced apoptosis, Taken together, these observation strongly argue against a role of the Fas/FasL signaling pathway in drug-induced apoptosis in lung cancer cells. Interestingly, caspase-8 activation was observed upon drug exposure, independently from Fas/FasL signaling.

Gemcitabine and paclitaxel are active agents in the treatment of non-small-cell lung cancer (NSCLC). To optimize treatment drug combinations, simultaneously and 4 and 24 h intervals, were studied using DNA flow cytometry and multiple drug effect analysis in the NSCLC cell lines H460, H322 and Lewis Lung. All combinations resulted in comparable cytotoxicity, varying from additivity to antagonism (combination index: 1.0–2.6). Gemcitabine caused a S (48%) and G1 (64%) arrest at IC-50 and 10 × IC-50 concentrations, respectively. Paclitaxel induced G2/M arrest (70%) which was maximal within 24 h at 10 × IC-50. Simultaneous treatment increased S-phase arrest, while at the 24 h interval after 72 h the first drug seemed to dominate the effect. Apoptosis was more pronounced when paclitaxel preceded gemcitabine (20% for both intervals) as compared to the reverse sequence (8%, P = 0.173 for the 4 h and 12%, P = 0.051 for the 24 h time interval). In H460 cells, paclitaxel increased 2-fold the accumulation of dFdCTP, the active metabolite of gemcitabine, in contrast to H322 cells. Paclitaxel did not affect deoxycytidine kinase levels, but ribonucleotide levels increased possibly explaining the increase in dFdCTP. Paclitaxel did not affect gemcitabine incorporation into DNA, but seemed to increase incorporation into RNA. Gemcitabine almost completely inhibited DNA synthesis in both cell lines (70–89%), while paclitaxel had a minor effect and did not increase that of gemcitabine. In conclusion, various gemcitabine–paclitaxel combinations did not show sequence dependent cytotoxic effects; all combinations were not more than additive. However, since paclitaxel increased dFdCTP accumulation, gemcitabine incorporation into RNA and the apoptotic index, the administration of paclitaxel prior to gemcitabine might be favourable as compared to reversed sequences. © 2000 Cancer Research Campaign

Background: Although hematologic malignancies and some solid tumors such as germ cell tumors and pediatric malignancies can be cured by cytotoxic treatment, the most prevalent solid tumors are relatively resistant to these interventions. Apoptosis is involved in the cell kill of anticancer drugs and p53 is believed to be of principal importance in this process. However p53 also plays a role in cell cycle arrest and DNA repair, cellular processes that can decrease the sensitivity to chemotherapy. Therefore, p53 may play a dual role after exposure to cytotoxic treatment, activating either mechanisms that lead to apoptosis or launching processes directing to DNA repair and survival of the cell.Design: In this article, we review in details the p53functions involved in the mediation of chemosensitivity. The preclinical and clinical data published in the recent years about the relation between p53 and chemosensitivity are discussed and the potential pitfalls associated to most of these studies, and that may account for the contradictory results produced so far are also mentioned.

Apoptosis is a major mode of cell death in response to cytotoxic drug treatment. A correlation between induction of apoptosis and chemosensitivity has been documented in some preclinical models. Topotecan (a topoisomerase I inhibitor) and gemcitabine (a deoxycytidine analogue), two active new drugs for the treatment of lung cancer, were evaluated for their growth inhibitory effect on human lung cancer cell lines and their effect on cell cycle perturbation, apoptosis and apoptosis-related genes. The cytotoxicities of topotecan and gemcitabine on the human lung cancer cell lines H460 (wild-type-p53) and H322 (mutant p53) were determined after 72 h drug exposure employing the MTT assay. The apoptotic index (AI) was assessed by three methods: analysis of morphological changes using May–Grünwald–Giemsa (MGG) staining, the TUNEL assay and FACS analysis. Cell cycle disturbances were studied by FACS and the number of cells expressing p53 and p21 were determined by immunohistochemistry. Both gemcitabine and topotecan had potent growth inhibitory effects in human lung cancer cell lines; combination treatment with these two drugs showed some additivity but no synergism. Induction of apoptosis after treatment was concentration- and time-dependent with both drugs and ic80 concentrations induced the highest values. The DNA histograms at 4, 24, 48 and 72 h indicate that topotecan at ic80 concentrations causes accumulation of cells in S and G2/M phases, whereas gemcitabine at ic80 concentrations causes, accumulation of cells in G1 phase. Both compounds induced p53 and p21 expression in the H460 cell line but not in the H322 cell line; the percentage of cells expressing p53 was highest at ic80 values, whereas the highest percentage of p21 positive cells could be induced with ic50 values. This could suggest that p53 induces cell cycle arrest at low drug concentrations, whereas p53 induces apoptosis at higher concentrations. In conclusion, p53-dependent and independent pathways of apoptosis exist in lung cancer cell lines. Activation of the p53 pathway depends on the induced cellular damage. Understanding the cell cycle disturbances induced by these drugs may help in the design of more rational treatment schedules.