Trastuzumab immunogenicity development in patients' sera and in laboratory animals.

BACKGROUND: Immunogenicity is a major challenge in drug development and patient care. Clinicians and regulators are familiar with immunogenicity concerns of monoclonal antibody (mAb) therapeutics, growth factors and enzyme replacements. Although most small therapeutic molecules are unlikely to trigger undesirable immunogenic responses against themselves upon their administration, the biological therapeutic agents are likely to induce such kind of immunogenicity. This imparts a problem that has to be considered upon judging their risk-benefit ratio. In this article, we tested the immunogenicity developed in patients' sera due to the use of trastuzumab and that developed in laboratory animals injected with this recombinant humanized IgG1 monoclonal antibody. METHODS: We studied trastuzumab immunogenicity by: I in vitro detection of anti-trastuzumab antibody (Ab) levels in patient's serum samples withdrawn at different points during trastuzumab treatment course; I.1 using an Affinity Capture Elution (ACE) assay, the assay is both sensitive and highly tolerant to free drug; I.2 using MTT cytotoxicity method against MCF-7 cell line as confirmatory method used in sample showed high level of anti-trastuzumab Ab and to determine neutralizing activity of the anti-trastuzumab Ab. II in vivo immunogenicity testing of trastuzumab in lab animals. RESULTS: In vitro analysis of patients' sera for antibodies developed against trastuzumab revealed that this monoclonal antibody has low immunogenicity since most samples showed low levels of anti-trastuzumab antibodies that decreased progressively along the treatment course. Only 1% of samples showed high levels of anti-trastuzumab antibodies which might affect treatment course. In vivo immunogenicity testing in mice showed also low immunogenicity of trastuzumab that could support the in vitro clinical assessment applied in our study. CONCLUSIONS: The study gives an evidence for the low trastuzumab immunogenicity when assessed in Egyptian patients under treatment with this biological therapeutic agent. This supports its prescription and continuous use across the approved indications as biological therapeutic agent.

The significance of concurrent MYC and BCL2 expression in Egyptian patients with diffuse large B-cell NHL.

This study aimed to investigate the frequency of MYC/BCL2 co-expression using immunohistochemistry (IHC) in Egyptian patients with diffuse large B-cell lymphoma (DLBCL) and its impact on treatment outcomes, overall survival (OS), and disease-free survival (DFS). A total of 100 adult patients with newly diagnosed DLBCL were included in the study and treated with the R-CHOP regimen. The cases were classified into germinal center B-cell (GCB) and non-germinal center B-cell (non-GCB) subtypes based on IHC. Our results showed that a subset of the studied cases didn't achieve complete remission (CR) after chemotherapy (22%). Co-expression of MYC and BCL2 was observed in 20% of the cases, with most of them belonging to the non-GCB subtype. The CR rate was significantly lower in the double-expressor (DE) group (45%), while no significant difference was observed in CR between the GCB and non-GCB cases. The DE group was associated with advanced stage, extra-nodal involvement, and high-risk R-International Prognostic Index (R-IPI). Both the non-DE and GCB groups demonstrated better DFS, while the non-DE group only showed better OS. Both non-DE status and GCB subtype were identified as independent factors affecting DFS. In conclusion, the concurrent expression of MYC and BCL2 in DLBCL indicates an inferior outcome and lower chemotherapy response. The current chemotherapeutic strategy has not effectively improved the outcomes of this aggressive lymphoma subtype. Therefore, the identification of these patients is crucial for selecting appropriate treatment options.

Once Daily Versus Twice Daily External Beam Accelerated Partial Breast Irradiation: A Randomized Prospective Study.

PURPOSE: The aim of the current study was to compare toxicity, cosmesis, and local control between the once daily and the twice daily fractionation schemes for external beam accelerated partial breast irradiation. METHODS AND MATERIALS: From December 2012 to June 2018, we enrolled 113 patients with ductal carcinoma in situ or invasive breast cancer, node negative disease, and tumors less than 3 cm in size to receive accelerated partial breast irradiation (APBI) to a total dose of 38.5 Gy over 10 fractions given either once (oAPBI) or twice daily (tAPBI). Sixty patients were included in the tAPBI arm and 53 patients were included in the oAPBI arm. RESULTS: Median follow-up was 74 months (range, 24-105). The median pain score during treatment was 3 out of 10 in the oAPBI and 5 in the tAPBI (P = .001). No differences were observed in GIII early skin toxicity (P = .4) or GI early pulmonary toxicity (P = 1.0) between the 2 treatment arms. GIII late skin toxicity developed in 3.8% and 11.7% of patients in the oAPBI and tAPBI arms, respectively (P = .001). GIII subcutaneous fibrosis developed in 1.9% and 8.3% of patients in the oAPBI and tAPBI, respectively (P = .001). The rate of patients with adverse cosmesis (poor/fair) was 7.5% at 12 months and at 24 months in the oAPBI arm compared with 21.7% and 26.7% in the tAPBI arm (P = .03 and .008, respectively). CONCLUSIONS: oAPBI is a safe, well-tolerated schedule with more favorable outcomes than the tAPBI schedule with regards to late toxicity and cosmesis.

64Cu-DOTATATE PET/CT for Imaging Patients with Known or Suspected Somatostatin Receptor-Positive Neuroendocrine Tumors: Results of the First U.S. Prospective, Reader-Masked Clinical Trial.

Studies demonstrate that the investigational 64Cu-DOTATATE radiopharmaceutical may provide diagnostic and logistical benefits over available imaging agents for patients with somatostatin receptor (SSTR)-positive neuroendocrine tumors (NETs). Accordingly, we aimed to prospectively determine the lowest dose of 64Cu-DOTATATE that facilitates diagnostic-quality scans and evaluated the diagnostic performance and safety in a phase III study of patients with SSTR-expressing NETs. Methods: A dose-ranging study was conducted on 12 patients divided into 3 dose groups (111 MBq [3.0 mCi], 148 MBq [4.0 mCi], and 185 MBq [5.0 mCi] ± 10%) to determine the lowest dose of 64Cu-DOTATATE that produced diagnostic-quality PET/CT images. Using the 64Cu-DOTATATE dose identified in the dose-ranging study, 3 independent nuclear medicine physicians who were masked to all clinical information read PET/CT scans from 21 healthy volunteers and 42 NET-positive patients to determine those with disease or no disease, as well as those with localized versus metastatic status. Masked-reader evaluations were compared with a patient-specific standard of truth, which was established by an independent oncologist who used all previously available pathology, clinical, and conventional imaging data. Diagnostic performance calculated for 64Cu-DOTATATE included sensitivity, specificity, negative predictive value, positive predictive value, and accuracy. Inter- and intrareader reliability, as well as ability to differentiate between localized and metastatic disease, was also determined. Adverse events were recorded from 64Cu-DOTATATE injection through 48 h after injection. Results: The dose-ranging study identified 148 MBq (4.0 mCi) as the optimal dose to obtain diagnostic-quality PET/CT images. After database lock, diagnostic performance from an initial majority read of the 3 independent readers showed a significant 90.9% sensitivity (P = 0.0042) and 96.6% specificity (P < 0.0001) for detecting NETs, which translated to a 100.0% sensitivity and 96.8% specificity after correcting for an initial standard-of-truth misread. Excellent inter- and intrareader reliability, as well as ability to distinguish between localized and metastatic disease, was also noted. No adverse events were related to 64Cu-DOTATATE, and no serious adverse events were observed. Conclusion:64Cu-DOTATATE PET/CT is a safe imaging technique that provides high-quality and accurate images at a dose of 148 MBq (4.0 mCi) for the detection of somatostatin-expressing NETs.

Chest Ultrasound in Predication of Weaning Failure.

AIM: Failure of weaning from mechanical ventilation (MV) is a common problem that faces the intensivist despite having some prediction indices. Application of chest ultrasonography (US) may help in weaning and prediction of its outcome. METHODS: 100 patients on invasive MV fulfilling criteria of weaning shifted to spontaneous breathing trial (SBT) (using PSV 8 cm H2O) for 1 hour. Weaning failure was defined as; Failed SBT, reintubation and/or ventilation or death within 48 hours. Echocardiography was used to get Ejection fraction, E/A ratio, Doppler tissue imaging (DTI) &, lung ultrasound (LUS) was used to assess LUS score, diaphragm ultrasound was used to assess diaphragmatic thickening fraction (DTF). RESULTS: Mean age 57.1 ± 14.5, 62% were males. Weaning was successful in 80% of patients. LUS score was significantly higher in the failed weaning group: (10.8 ± 4.2) vs (16.5 ± 4.2 cm), (p: 0.001). (DTF) Was significantly higher in the successful weaning group: (43.0 ± 10.7) vs (28.9 ± 2.8 cm), (p: 0.001). DTF can predict successful weaning using Receiver operating characteristic (ROC) curves with the cutoff value: ≥ 29.5 with sensitivity 88.0% and specificity 80.0% with a p-value < 0.001.LUS score can predict weaning failure by using a ROC curve with cutoff value: ≥ 15.5 with sensitivity 70.0% and specificity 82.5 % with a p-value < 0.001.). CONCLUSION: The use of bedside chest US (to assess lung and diaphragm) of great benefit throughout the weaning process.

Clinico-pathological features of breast carcinoma in elderly Egyptian patients: a comparison with the non-elderly using population-based data.

BACKGROUND: Breast cancer (BC) is a major worldwide health care problem that mostly afflicts the elderly population in the more developed countries. It is not known how common is breast cancer among elderly Egyptian patients and whether this differs from the disease in younger patients. AIMS: To study the clinico-pathological features of BC in elderly Egyptian patients (⩾65years of age) among the population of an Egyptian Governorate, Gharbiah, and to compare these features with those of younger patients (<65years). METHODS: This is a cross sectional study that compares elderly BC (EBC) and the non-elderly BC (NEBC) using the information from the Gharbiah Population-based Cancer registry (GPCR) during the years 1999-2007. RESULTS: Out of 6078 BCs, 12% were EBCs and 88% were NEBCs. Between 1999 and 2007, the crude incidence rate (CIR, per 100,000 populations) of EBC increased from 47 to 71 and that of NEBC increased from 16 to 17. Compared to NEBC patients, EBC patients were more likely to have a positive family history and present with a distant disease and less likely to present with a localized disease. EBCs were more likely to have lung metastases and less likely to have liver metastases. Histology, grade, hormone and HER-2 receptor statuses were comparable in both groups. Apart from hormonal therapies, the elderly were less likely to receive surgery, radiotherapy or chemotherapy. CONCLUSION: EBC patients in Egypt present with advanced disease and are less likely to receive surgery, radiotherapy or chemotherapy compared to NEBC patients.

Does fasting during Ramadan trigger non-adherence to oral hormonal therapy in breast cancer patients?

PURPOSE: To estimate the effect of fasting during Ramadan (the ninth lunar month) on adherence to oral hormonal therapies (OHT) among breast cancer (BC) patients. PATIENTS AND METHODS: During Ramadan 2010, 139 BC patients were interviewed at the Egyptian National Cancer Institute. They were asked about fasting as well as intake of OHT in Ramadan and in the preceding month. RESULTS: The median age was 50years and most patients were postmenopausal with good performance status and non-metastatic disease. The median number of fasting days was 18% and 93% of patients were fasting 80% or more of Ramadan. Tamoxifen and aromatase inhibitors were used in 64% and 36%, respectively. Adherence to OHT during Ramadan and its preceding month were 94.2% and 95.7%, respectively (p=0.77). In univariate analysis, non-adherence prior to Ramadan and shorter duration of OHT were predictors of non-adherence during Ramadan (P<0.001, 0.003, respectively). Fasting, age, performance status, presence of metastases and type of hormonal therapy were not good predictors of adherence. CONCLUSIONS: While most of patients receiving OHT for BC are fasting during Ramadan, this does not negatively impact compliance with treatment.

MicroRNAs and metastasis-related gene expression in Egyptian breast cancer patients.

AIM AND BACKGROUND: MicroRNAs (miRNAs) are a class of naturally occurring small noncoding RNAs that regulate gene expression, cell growth, differentiation and apoptosis by targeting mRNAs for translational repression or cleavage. The present study was conducted to study miRNAs in Egyptian breast cancer (BC) and their relation to metastasis, tumor invasion and apoptosis in addition to their association with the ER and PR statuses. METHODS: Real Time RT-PCR was performed to identify the miRNA expression level of eight miRNAs and eight metastatic-related genes in 40 breast cancer samples and their adjacent non-neoplastic tissues. The expression levels of each miRNA relative to U6 RNA were determined. Also, miRNA expression profiles of the BC and their corresponding ANT were evaluated. RESULTS: The BC patients showed an up-regulation in miRNAs (mir-155, mir-10, mir-21 and mir-373) with an upregulation in MMP2, MMp9 and VEGF genes. We found down regulation in mir-17p, mir-126, mir-335, mir-30b and also TIMP3, TMP1 and PDCD4 genes in the cancer tissue compared to the adjacent non-neoplastic tissues. Mir -10b, mir -21, mir-155 and mir373 and the metastatic genes MMP2, MMP9 and VEGF were significantly associated with an increase in tumor size (P<0.05). No significant difference was observed between any of the studied miRNAs regarding lymph node metastasis. Mir-21 was significantly over-expressed in ER-/PR- cases. CONCLUSION: Specific miRNAs (mir-10, mir-21, mir-155, mir-373, mir-30b, mir-126, mir-17p, mir-335) are associated with tumor metastasis and other clinical characteristics for BC, facilitating identification of individuals who are at risk.

Prognostic value of serum vascular endothelial growth factor in Egyptian females with metastatic triple negative breast cancer.

OBJECTIVES: The aim of this work was to explore the value of serum vascular endothelial growth factor-A (VEGF-A) in patients with metastatic triple negative breast cancer (TNBC) treated with chemotherapy. The primary end point was overall survival (OS). Secondary end points were response rate (RR), progression-free survival (PFS) and VEGF-A level at baseline, mid-therapy and at the end of therapy. DESIGN AND METHODS: Female patients aged 18 years or above with histologically proven metastatic TNBC were included. Serum VEFG-A levels were measured at baseline, after the 3rd and 6th cycles of FAC chemotherapy regimen (Fluorourcil, Adriamycin, and Cyclophamide). RESULTS: The overall RR was 57%. The median PFS and OS were 7 and 11.2 months, respectively (95% CI: 4.3-9.7 and 3.8-18.5 months, respectively). Patients whose disease progressed despite therapy had a significantly higher baseline VEGF-A level than those who did not progress. VEGF-A level did not drop with continuation of therapy. Patients with high VEGF-A level had a significantly lower PFS but not OS than patients with low levels. CONCLUSION: The outcome of metastatic TNBC is poor with FAC chemotherapy regimen. Alternative chemotherapeutic regimens and novel therapeutic approaches including targeting of VEGF and/or its receptors are warranted.