Intravenous versus subcutaneous Trastuzumab in the treatment of breast cancer

Poster presented at the 44th ESCP Symposium on Clinical Pharmacy. Lisbon, 28-30 October 2015

Clinical Studies on conformal radiotherapy combined with epidermal growth factor receptor-tyrosine kinase inhibitor in second-line treatment of non-small cell lung cancer

Purpose: To study the effect of conformal radiotherapy combined with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in the second-line treatment of non-small cell lung cancer (NSCLC). Methods: A total of 316 patients attending Shanghai Pulmonary Hospital affiliated to Tongji University, were divided into two groups: 106 patients were treated with conformal radiotherapy combined with EGFR-TKI (gefitinib, 250 mg/day; or erlotinib, 150 mg/day), while 210 patients were treated with EGFRTKI alone. Some factors, including adverse reactions (AR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and one-year and two-year survival rate, were evaluated. Results: No obvious difference was observed in AR between the two groups (p > 0.05). In the combination therapy group, complete response (CR) was 5 cases, partial response (PR) 43 cases, and stable disease (SD) 47 cases, progressive disease (PD) was 11 cases, response rate (RR) was 45.3 %, and DCR 89.6 %. Median PFS in the combination therapy group and targeted therapy group was 6.5 and 5.0 months, respectively. On the other hand, median OS in the combination therapy group and targeted group was 14.1 and 12.6 months, respectively. One-year survival rate of the combination therapy group and EGFR-TKI group was 60.3 and 50.0 %, respectively, while the two-year survival rate was 26.3 and 19.0 %, respectively. Conclusion: Conformal radiotherapy combined with EGFR-TKI can be used as an effective second-line treatment for NSCLC.

Clinical efficacy of paclitaxel in the treatment of mid-stage and advanced malignant gastric cancer, and effect of nursing interventions

Purpose: To investigate the clinical efficacy of paclitaxel combined with additional chemotherapy for mid-stage and advanced malignant tumors, and the benefits afforded by scientific nursing. Methods: Patients with mid-stage and advanced gastric cancer were randomly divided into test and control groups. Control group was given intravenous chemotherapy (400 mg/m2 fluorouracil and 2500 mg/m2 cisplatin) and nursed conventionally, while the test group was additionally treated with 80 mg/m2 paclitaxel and underwent special scientific nursing. Clinical effects and changes in the rates of apoptosis and cell proliferation were recorded. The effect of applying scientific nursing on therapeutic outcomes was also evaluated. Results: The overall rate of treatment effectiveness, clinical control rate, mean apoptosis and proliferation rates in the test group were 56.40, 92.30, (7.10 ± 3.17 and 28.70 ± 3.22 %, respectively, while, in the control group, the values were 38.50, 64.10, 25.40 ± 2.67 and 32.60 ± 2.93 %, respectively. The differences were all statistically significant (p < 0.05). In terms of nursing efficacy, the test group had a lower pain score and higher quality-of-life scores (Karnofsky performance status score) than control group. There was no significant difference in the incidence of adverse reactions between the two groups (p > 0.05). Conclusion: Paclitaxel has a significant effect when used to treat mid-stage and advanced gastric cancer. Moreover, additional nursing not only enhances the therapeutic effect but also improves prognosis and quality-of-life.

Healthcare providers’ knowledge, attitude and behaviour towards breast cancer diagnosis and treatment in Malaysia – a mini systematic review

Breast cancer is the most common cancer among women in Malaysia. Therefore, it is important for the public to be educated on breast cancer and to know the steps that need to be taken to detect it early. Healthcare providers are in a unique position to provide public health education due to their good knowledge of health issues and their roles in healthcare. A systematic review of studies conducted from 2008 till 2015 was undertaken to analyze the knowledge, attitudes and behavior of Malaysian healthcare providers regarding breast cancer, in an attempt to obtain an overall picture of how wellequipped the healthcare providers are to provide optimal breast cancer education, and to ascertain their perceptions and actual involvement in such education. The systematic review was conducted via a primary search of various databases and journal websites, and a secondary search of references cited in eligible studies. Criteria for eligibility include studies conducted in Malaysia and published from the year 2008 to 2015, and written in English language. A total of fifteen articles were identified and reviewed but only two studies were eligible for this review. The findings suggest that future and current Malaysian healthcare providers have moderate knowledge of breast cancer, showed a positive disposition towards involvement in breast cancer education, but displayed poor involvement.

Effect of investigation intensity and treatment differences on prostate cancer survivor's physical symptoms, psychological well-being and health-related quality of life: a two country cross-sectional study.

Aim: To investigate effects on men's health and well-being of higher prostate cancer (PCa) investigation and treatment levels in similar populations. Participants: PCa survivors in Ireland where the Republic of Ireland (RoI) has a 50% higher PCa incidence than Northern Ireland (NI). Method: A cross-sectional postal questionnaire was sent to PCa survivors 2–18 years post-treatment, seeking information about current physical effects of treatment, health-related quality of life (HRQoL; EORTC QLQ-C30; EQ-5D-5L) and psychological well-being (21 question version of the Depression, Anxiety and Stress Scale, DASS-21). Outcomes in RoI and NI survivors were compared, stratifying into ‘late disease’ (stage III/IV and any Gleason grade (GG) at diagnosis) and ‘early disease’ (stage I/II and GG 2–7). Responses were weighted by age, jurisdiction and time since diagnosis. Between-country differences were investigated using multivariate logistic and linear regression. Results: 3348 men responded (RoI n=2567; NI n=781; reflecting population sizes, response rate 54%). RoI responders were younger; less often had comorbidities (45% vs 38%); were more likely to present asymptomatically (66%; 41%) or with early disease (56%; 35%); and less often currently used androgen deprivation therapy (ADT; 2%; 28%). Current prevalence of incontinence (16%) and impotence (56% early disease, 67% late disease) did not differ between RoI and NI. In early disease, only current bowel problems (RoI 12%; NI 21%) differed significantly in multivariate analysis. In late disease, NI men reported significantly higher levels of gynaecomastia (23% vs 9%) and hot flashes(41% vs 19%), but when ADT users were analysed separately, differences disappeared. For HRQoL, in multivariate analysis, only pain (early disease: RoI 11.1, NI 19.4) and financial difficulties (late disease: RoI 10.4, NI 7.9) differed significantly between countries. There were no significant between-country differences in DASS-21 or index ED-5D-5L score. Conclusions: Treatment side effects were commonly reported and increased PCa detection in RoI has left more men with these side effects. We recommended that men be offered a PSA test only after informed discussion.

Prediction Nomogram for 68Ga-PSMA-11 PET/CT in different clinical settings of PSA failure after radical treatment for Prostate Cancer

Objective The objective of this study was to develop a clinical nomogram to predict gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA-11-PET/CT) positivity in different clinical settings of PSA failure. Materials and methods Seven hundred three (n = 703) prostate cancer (PCa) patients with confirmed PSA failure after radical therapy were enrolled. Patients were stratified according to different clinical settings (first-time biochemical recurrence [BCR]: group 1; BCR after salvage therapy: group 2; biochemical persistence after radical prostatectomy [BCP]: group 3; advanced stage PCa before second-line systemic therapies: group 4). First, we assessed 68Ga-PSMA-11-PET/CT positivity rate. Second, multivariable logistic regression analyses were used to determine predictors of positive scan. Third, regression-based coefficients were used to develop a nomogram predicting positive 68Ga-PSMA-11-PET/CT result and 200 bootstrap resamples were used for internal validation. Fourth, receiver operating characteristic (ROC) analysis was used to identify the most informative nomogram’s derived cut-off. Decision curve analysis (DCA) was implemented to quantify nomogram’s clinical benefit. Results 68Ga-PSMA-11-PET/CT overall positivity rate was 51.2%, while it was 40.3% in group 1, 54% in group 2, 60.5% in group 3, and 86.9% in group 4 (p < 0.001). At multivariable analyses, ISUP grade, PSA, PSA doubling time, and clinical setting were independent predictors of a positive scan (all p ≤ 0.04). A nomogram based on covariates included in the multivariate model demonstrated a bootstrap-corrected accuracy of 82%. The nomogram-derived best cut-off value was 40%. In DCA, the nomogram revealed clinical net benefit of > 10%. Conclusions This novel nomogram proved its good accuracy in predicting a positive scan, with values ≥ 40% providing the most informative cut-off in counselling patients to 68Ga-PSMA-11-PET/CT. This tool might be important as a guide to clinicians in the best use of PSMA-based PET imaging.

Robotic Approach in the Treatment of Locally Advanced (Stage IIIA-pN2) non Small Cell Lung Cancer after Induction Therapy

Introduction: Despite there are already many studies on robotic surgery as minimally invasive approach for non-small cell lung cancer (NSCLC) patients, the use of this technique for stage III disease is still poorly described. These are the preliminary results of our prospective study on safety and effectiveness of robotic approach in patients with locally advanced NSCLC, in terms of postoperative complications and oncological outcome. Methods: Since 2016, we prospectively investigated, using standardized questionnaire and protocol, 21 consecutive patients with NSCLC stage IIIA-pN2 (diagnosed by EBUS-TBNA) who underwent lobectomy and radical lymph node dissection with robotic approach after induction treatment. Then, we performed a matched case-control study with 54 patients treated with open surgery during the same period of time, with similar age, clinical and pathological tumor stage. Results: The individual matched population was composed of 14 robot-assisted thoracic surgery and 14 patients who underwent open surgery. The median time range of resection was inferior in the open group compared to robotic lobectomy (148 vs 229 minutes; P=0.002). Lymph nodes resection and positivity were not statistically significantly different (p=0.66 and p=0.73 respectively). No difference was observed also for PFS (P=0.99) or OS (P=0.94). Conclusions: Our preliminary results demonstrated that the early outcomes and oncological results of N2-patients after robotic lobectomy were similar to open surgery. Considering the advantages of minimally invasive surgery, robotic assisted lobectomy should be a safe approach also to patients with local advanced disease.

Association between pre-treatment indicators and compliance to neoadjuvant/perioperative chemotherapy in operable gastric cancer

Background and aims: perioperative treatment is currently the gold standard approach for locally advanced gastric cancer (GC). Unfortunately, the phenomenon of patients dropping out of treatment has been frequently observed. The primary aims of this study were to verify if routine blood parameters, the inflammatory response markers, sarcopenia, and the depletion of adipose tissues were associated with compliance with neoadjuvant/perioperative chemotherapy. Methods and study design: sarcopenia and adipose indices were calculated with a CT scan before starting chemotherapy and before surgery. Blood samples were considered before the first and second cycles of chemotherapy. Results: A total of 84 patients with localized operable GC, were identified between September 2010 and January 2021. Forty-four patients (52.4%) did not complete the treatment according to the number of cycles planned/performed. Eight patients (9.5%) decided to suspend chemotherapy, seven patients (8.3%) discontinued because of clinical decision-making, 14 patients (16.7%) because of toxicity, and 15 patients (17.9%) for miscellaneous causes. Sarcopenia before starting chemotherapy was found to be present in 38 patients (50.7%) while it was in 47 patients (60%) at the CT scan before the gastrectomy. In multivariable analysis, both for changes tending to have a value of PLR at basal and in the second control a higher one than the cut-off (OR = 5.03, 95% CI: 1.34 - 18.89, p-value = 0.017), and for PLR which increased from a lower to a higher value in second control with respect to the cut off (OR = 4.64, 95% CI: 1.02 -21.02, p-value = 0.047) resulted associated with incomplete compliance. Conclusions: among the biological indicators, changes in the value of PLR with a tendency towards increasing compared to the cut-off appear to be an immediate indicator of incomplete compliance with neoadjuvant/perioperative treatment. More information is needed to reduce the causes of interruption.

Analysis of extracellular vesicles from patients with advanced pancreatic cancer identifies miRNAs with predictive value for treatment with gemcitabine + nab-paclitaxel

Pancreatic cancer (PC) is the seventh leading cause of cancer death. Despite recent therapy advancements, 5-year survival is 11%. Resistance to therapy is common, and no predictive factors, except for BRCA1/2 and PALB2 mutations, can drive treatment selection. Based on the easy isolation of extracellular vesicles (EVs) from blood and the role of EV-borne miRNAs in chemoresistance, we analyzed EVs and their miRNA content in order to identify predictive factors. First, we analyzed samples from 28 PC patients and 7 healthy subjects, in order to establish methods for isolation and analysis of EVs and their miRNA content. We observed a significantly different expression of 28 miRNAs, including oncogenic or tumor suppressor miRNAs, showing the ability of our approach to detect candidate biomarkers. Then, we analyzed samples of 21 advanced PC patients, collected before first-line treatment with gemcitabine + nab-paclitaxel, and compared findings in responders and non-responders. EVs have been analyzed with Nanoparticle tracking analysis, flow cytometry and RNA-Seq; then, laboratory results have been matched with clinical data. Nanoparticle tracking analysis did not show any significant difference. Flow cytometry showed a lower expression of SSE4 and CD81 in responders. Finally, miRNA analysis showed 25 upregulated and 19 downregulated miRNAs in responders. In particular, in responders we observed upregulation of miR-141-3p, miR-141-5p, miR-200a-3p, miR-200b-3p, miR-200c-3p, miR-375-3p, miR-429, miR-545-5p. These miRNAs have targets with a previously reported role in PC. In conclusion, we show the feasibility of the proposed approach to identify EV-derived biomarkers with predictive value for therapy with gemcitabine + nab-paclitaxel in PC. Our findings highlight the possibility to exploit liquid biopsy for personalized treatment in PC, in order to maximize chances of response and patients’ outcome. These findings are worthy of further investigation: in the same setting, with different chemotherapy schedules, and in different disease settings such as preoperative therapy.

Preclinical evaluation of a MYCN-specific inhibitor for the treatment of small cell lung cancer

Small cell lung cancer (SCLC) is the most aggressive form of lung cancer, characterized by rapid growth, early metastasis and acquired drug resistance. SCLC is usually sensitive to initial treatment, however, most patients relapse within few months; thus more effective therapies are urgently needed. Key genetic alterations very frequently observed in SCLC include loss of TP53 and RB1 and mutations in the MYC family genes (MYC, MYCL or MYCN). One of them is amplified and overexpressed in a mutually exclusive manner and represents the most prominent activating oncogene alteration in this malignancy. In particular, MYCN amplification is associated with tumor progression, treatment failure and poor prognosis. Given the role of MYCN in SCLC and its restricted expression profile, MYCN represents a promising therapeutic target; although it is considered undruggable by traditional approaches. An innovative approach to target the oncogene concerns specific MYCN expression inhibition, acting directly at the level of DNA, through an antigene peptide nucleic acid (agPNA) oligonucleotide, called BGA002. This thesis focused on the study of BGA002, as a possible targeted therapeutic strategy for the treatment of MYCN-related SCLC. In this context, BGA002 proved to be a specific and highly effective inhibitor. Furthermore, MYCN silencing induced alterations in many downstream pathways and led to apoptosis, in concomitance with autophagy reactivation. Moreover, systemic administration of BGA002 was effective in vivo as well, significantly increasing survival in MNA mouse models, even in the scenario of multidrug-resistance. In addition, BGA002 treatment successfully reduced N-Myc protein expression and, more importantly, caused a massive diminishment in tumor vascularization in the multidrug-resistant model. Overall, these results proved that MYCN inhibition by BGA002 may represent a new promising precision medicine approach, to treat MYCN-related SCLC.

Low-density Lipoprotein Cholesterol And Radiotherapy-induced Carotid Atherosclerosis In Subjects With Head And Neck Cancer.

Radiotherapy (RT) is a risk factor for accelerated carotid artery atherosclerotic disease in subjects with head and neck cancer. However, the risk factors of RT-induced carotid artery remodeling are not established. This study aimed to investigate the effects of RT on carotid and popliteal arteries in subjects with head and neck cancer and to evaluate the relationship between baseline clinical and laboratory features and the progression of RT-induced atherosclerosis. Eleven men (age = 57.9 ± 6.2years) with head and neck cancer who underwent cervical bilateral irradiation were prospectively examined by clinical and laboratory analysis and by carotid and popliteal ultrasound before and after treatment (mean interval between the end of RT and the post-RT assessment = 181 ± 47 days). No studied subject used hypocholesterolemic medications. Significant increases in carotid intima-media thickness (IMT) (0.95 ± 0.08 vs. 0.87 ± 0.05 mm; p < 0.0001) and carotid IMT/diameter ratio (0.138 ± 0.013 vs. 0.129 ± 0.014; p = 0.001) were observed after RT, while no changes in popliteal structural features were detected. In addition, baseline low-density lipoprotein cholesterol levels showed a direct correlation with RT-induced carotid IMT change (r = 0.66; p = 0.027), while no other studied variable exhibited a significant relationship with carotid IMT change. These results indicate that RT-induced atherosclerosis is limited to the irradiated area and also suggest that it may be predicted by low-density lipoprotein cholesterol levels in subjects with head and neck cancer.

Correlation Between Testosterone And Psa Kinetics In Metastatic Prostate Cancer Patients Treated With Diverse Chemical Castrations.

To assess total testosterone and prostatic-specific antigen (PSA) kinetics among diverse chemical castrations, advanced-stage prostate cancer patients were randomized into three groups of 20: Group 1, Leuprolide 3.75 mg; Group 2, Leuprolide 7.5 mg; and Group 3, Goserelin 3.6 mg. All groups were treated with monthly application of the respective drugs. The patients' levels of serum total testosterone and PSA were evaluated at two time periods: before the treatment and 3 months after the treatment. Spearman's rank correlation coefficient was utilized to verify the hypothesis of linear correlation between total testosterone and PSA levels. At the beginning the patients' age, stage, grade, PSA, and total testosterone were similar within the three groups, with median age 72, 70, and 70 years in Groups 1, 2, and 3, respectively. Three months after the treatment, patients who received Leuprolide 7.5 mg presented significantly lower median total testosterone levels compared with Goserelin 3.6 mg and Leuprolide 3.75 mg (9.5 ng/dL vs. 20.0 ng/dL vs. 30.0 ng/dL, respectively; p = .0072), while those who received Goserelin 3.6 mg presented significantly lower PSA levels compared with Leuprolide 7.5 mg and Leuprolide 3.75 mg (0.67 vs. 1.86 vs. 2.57, respectively; p = .0067). There was no linear correlation between total testosterone and PSA levels. Overall, regarding castration levels of total testosterone, 28.77% of patients did not obtain levels ≤50 ng/dL and 47.80% did not obtain levels ≤20 ng/dL. There was no correlation between total testosterone and PSA kinetics and no equivalence among different pharmacological castrations.

Comparative Study Of Planned And Unplanned Excisions For The Treatment Of Soft Tissue Sarcoma Of The Extremities.

Unplanned excision of soft tissue sarcomas is common because benign soft tissue lesions are very frequent. This study evaluated the impact of unplanned resections on overall survival, local recurrence and distant metastasis in patients with soft tissue sarcomas of the extremities. In total, 52 patients who were diagnosed with soft tissue sarcomas between May 2001 and March 2011 were analyzed in a retrospective study. Of these patients, 29 (55.8%) had not undergone previous treatment and the remaining 23 (44.2%) patients had undergone prior resection of the tumor without oncological planning. All subsequent surgical procedures were performed at the same cancer referral center. The follow-up ranged from 6 to 122 months, with a mean of 39.89 months. Age, lesion size and depth, histological grade, surgical margins, overall survival, local and distant recurrence and adjuvant therapies were compared. Residual disease was observed in 91.3% of the re-resected specimens in the unplanned excision group, which exhibited greater numbers of superficial lesions, low histological grades and contaminated surgical margins compared with the re-resected specimens in the planned excision group. No differences were observed in local recurrence and 5-year overall survival between the groups, but distant metastases were significantly associated with planned excision after adjustment for the variables. There was no difference between patients undergoing unplanned excision and planned excision regarding local recurrence and overall survival. The planned excision group had a higher risk of distant metastasis, whereas there was a high rate of residual cancer in the unplanned excision group.

Decreased Expression Of Stem Cell Markers By Simvastatin In 7,12-dimethylbenz(a)anthracene (dmba)-induced Breast Cancer.

Simvastatin, a competitive inhibitor of HMG-CoA reductase widely used in the treatment and prevention of hyperlipidemia-related diseases, has recently been associated to in vitro anticancer stem cell (CSC) actions. However, these effects have not been confirmed in vivo. To assess in vivo anti-CSC effects of simvastatin, female Sprague-Dawley rats with 7,12-dimethyl-benz(a)anthracene (DMBA)-induced mammary cancer and control animals were treated for 14 days with either simvastatin (20 or 40 mg/kg/day) or soybean oil (N = 60). Tumors and normal breast tissues were removed for pathologic examination and immunodetection of CSC markers. At 40 mg/kg/day, simvastatin significantly reduced tumor growth and the expression of most CSC markers. The reduction in tumor growth (80%) could not be explained solely by the decrease in CSCs, since the latter accounted for less than 10% of the neoplasia (differentiated cancer cells were also affected). Stem cells in normal, nonneoplastic breast tissues were not affected by simvastatin. Simvastatin was also associated with a significant decrease in proliferative activity but no increase in cell death. In conclusion, this is the first study to confirm simvastatin anti-CSC actions in vivo, further demonstrating that this effect is specific for neoplastic cells, but not restricted to CSCs, and most likely due to inhibition of cell proliferation.