Myocardial transcriptomic analysis of diabetic patients with aortic stenosis: key role for mitochondrial calcium signaling.

BACKGROUND: Type 2 diabetes (T2D) is a frequent comorbidity encountered in patients with severe aortic stenosis (AS), leading to an adverse left ventricular (LV) remodeling and dysfunction. Metabolic alterations have been suggested as contributors of the deleterious effect of T2D on LV remodeling and function in patients with severe AS, but so far, the underlying mechanisms remain unclear. Mitochondria play a central role in the regulation of cardiac energy metabolism. OBJECTIVES: We aimed to explore the mitochondrial alterations associated with the deleterious effect of T2D on LV remodeling and function in patients with AS, preserved ejection fraction, and no additional heart disease. METHODS: We combined an in-depth clinical, biological and echocardiography phenotype of patients with severe AS, with (n = 34) or without (n = 50) T2D, referred for a valve replacement, with transcriptomic and histological analyses of an intra-operative myocardial LV biopsy. RESULTS: T2D patients had similar AS severity but displayed worse cardiac remodeling, systolic and diastolic function than non-diabetics. RNAseq analysis identified 1029 significantly differentially expressed genes. Functional enrichment analysis revealed several T2D-specific upregulated pathways despite comorbidity adjustment, gathering regulation of inflammation, extracellular matrix organization, endothelial function/angiogenesis, and adaptation to cardiac hypertrophy. Downregulated gene sets independently associated with T2D were related to mitochondrial respiratory chain organization/function and mitochondrial organization. Generation of causal networks suggested a reduced Ca2+ signaling up to the mitochondria, with the measured gene remodeling of the mitochondrial Ca2+ uniporter in favor of enhanced uptake. Histological analyses supported a greater cardiomyocyte hypertrophy and a decreased proximity between the mitochondrial VDAC porin and the reticular IP3-receptor in T2D. CONCLUSIONS: Our data support a crucial role for mitochondrial Ca2+ signaling in T2D-induced cardiac dysfunction in severe AS patients, from a structural reticulum-mitochondria Ca2+ uncoupling to a mitochondrial gene remodeling. Thus, our findings open a new therapeutic avenue to be tested in animal models and further human cardiac biopsies in order to propose new treatments for T2D patients suffering from AS. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov ; Unique Identifier: NCT01862237.

Prevalence of Her2-neu status and its clinicopathological association in newly diagnosed gastric cancer patients.

BACKGROUND: This study aimed to report the prevalence of HER2-neu in newly diagnosed early or metastatic gastric cancer (GC) patients, to determine the percentage of patients achieving various IHC scores correlating with the ISH results and to establish a database for GC patients in Lebanon. METHODS: This was a national, multicenter, descriptive and cross-sectional study in patients with histologically confirmed early or metastatic GC newly diagnosed. All eligible patients underwent the IHC and ISH tests in a central laboratory. Demographics, medical history and histopathology data were collected. RESULTS: One hundred fifty-seven patients were included (mean age at diagnosis: 63 ± 14.1 years) during a 3.5 year period. The prevalence of HER2-neu over expression was 21% (95% CI: 15.3-27.4) using ICH and ISH. Agreement between IHC and ISH results was significantly substantial (kappa = 0.681; p-value < 0.001). Over expressed HER2-neu status was significantly associated with high ECOG performance status only. CONCLUSIONS: The prevalence of HER2-neu over expression in newly diagnosed early or metastatic GC patients seemed to be high in Lebanon. The database generated allows to monitor trends in the epidemiology and management of GC.

Ventricular septal rupture: insights into an old disease.

Ventricular septal rupture (VSR) is a serious complication of ST-elevation myocardial infarction (STEMI) and surgery is the reference treatment. We aimed at describing trends in management and mortality during the last four decades and reporting mortality predictors in these patients. We conducted a single-center retrospective study of patients sustaining a VSR from 1981 to 2020. We screened 274 patients and included 265 for analysis. The number of patients decreased over the years: 80, 88, 56, and 50 in each 10-year time span. In-hospital mortality decreased significantly since 1990 (logrank 0.007). The median age was 72.0 years IQR [66-78] and 188 patients (70.9%) were operated on. IABP was used more routinely (p < 0.0001). In-hospital mortality was assessed at 66.8% (177 patients) and main predictors of death were a time from MI to surgery < 8 days HR 2.7 IC95% [1.9-3.8] p < 0.0001, a Killip class > 2 HR 2.5 IC [1.9-3.4] p < 0.0001 and Euroscore 2 > 20 HR 2.4 IC [1.8-3.2] p < 0.0001. A "time from MI to surgery" of 8 days offers the best ability to discriminate between patients with or without mortality. The ability of "Euroscore 2 and Killip" to detect the patients most likely to wait 8 days for surgery was at 0.81 [0.73-0.89] p < 0.0001. Mortality remains high over the years. Euroscore 2, Killip class, and time from MI to surgery are the main mortality predictors. Patients with a Killip < 3 and a Euroscore < 20 should be monitored at least 8 days since MI before being referred to surgery.

Chest wall infarction following bilateral internal thoracic harvesting for coronary revascularization in a patient with previous aortic abdominal aneurysm surgery: A rare complication.

A 75 years old man with previous aortic abdominal aneurysm surgery through a transverse laparotomy underwent bilateral internal thoracic artery to coronary artery bypass grafting. He immediately thereafter developed a severe chest and upper abdominal walls ischemia with metabolic acidosis, and finally deep sternum wound infection and upper abdominal wall necrosis. He benefitted from sternal reconstruction and vaccum assisted treatment, with delayed pectus major flap reconstruction. Chest and abdominal wall infarction following bilateral internal thoracic artery (BITA) harvesting is a very rare but life-threatening complication. Caution use of BIMA should be in order in patients with inferior epigastric artery flow impairment.

Palbociclib safety and efficacy beyond Ribociclib-induced liver toxicity in metastatic hormone-receptors positive breast cancer patient.

CDK4/6 inhibitors in association with aromatase inhibitors have led to a paradigm shift in the management of metastatic positive hormone-receptors breast cancer. Liver toxicity is common with these agents, but no data are reported on the sequential use of these CDK4/6 inhibitors in case of confirmed efficacy and intolerable toxicity. In this article, we report the successful use of Palbociclib in a metastatic positive hormone-receptors breast cancer patient after initial response to Ribociclib, which was interrupted for grade 4 liver toxicity.

Management of patients with high-risk and advanced prostate cancer in the Middle East: resource-stratified consensus recommendations.

PURPOSE: Prostate cancer care in the Middle East is highly variable and access to specialist multidisciplinary management is limited. Academic tertiary referral centers offer cutting-edge diagnosis and treatment; however, in many parts of the region, patients are managed by non-specialists with limited resources. Due to many factors including lack of awareness and lack of prostate-specific antigen (PSA) screening, a high percentage of men present with locally advanced and metastatic prostate cancer at diagnosis. The aim of these recommendations is to assist clinicians in managing patients with different levels of access to diagnostic and treatment modalities. METHODS: The first Advanced Prostate Cancer Consensus Conference (APCCC) satellite meeting for the Middle East was held in Beirut, Lebanon, November 2017. During this meeting a consortium of urologists, medical oncologists, radiation oncologist and imaging specialists practicing in Lebanon, Syria, Iraq, Kuwait and Saudi Arabia voted on a selection of consensus questions. An additional workshop to formulate resource-stratified consensus recommendations was held in March 2019. RESULTS: Variations in practice based on available resources have been proposed to form resource-stratified recommendations for imaging at diagnosis, initial management of localized prostate cancer requiring therapy, treatment of castration-sensitive/naïve advanced prostate cancer and treatment of castration-resistant prostate cancer. CONCLUSION: This is the first regional consensus on prostate cancer management from the Middle East. The following recommendations will be useful to urologists and oncologists practicing in all areas with limited access to specialist multi-disciplinary teams, diagnostic modalities and treatment resources.

Overcoming the resistance to BRAF inhibitor by the double BRAF and MEK inhibitions in advanced melanoma: a case report.

The advent of BRAF and MEK inhibitors changed the landscape of the management of BRAF mutated melanoma patients. In this article, we report the case of a 51-year-old man with BRAF mutated locally advanced cutaneous melanoma of the head who demonstrated a limited response to initial anti-BRAF monotherapy followed by extensive surgery. Anti-PD1 therapy failed to reverse the disease progression. However, subsequent double inhibition of the BRAF and MEK pathways induced a fast and remarkable tumour response.

Lung cancer and immunotherapy: a real-life experience from second line and beyond.

Aim: This study assessed the efficacy of anti-PD-1/PD-L1 agents in real life when used in second line or beyond. Materials & methods: Patients with advanced non-small-cell lung cancer progressing after standard chemotherapy and receiving immunotherapy in the second line or beyond were included. Results: One hundred and ten patients were included with PD-L1 expression above 50%, between 1-49 and <1% in 38.6, 27.3 and 34.1% of patients, respectively. Checkpoint inhibitors were used as second, third and fourth line in 74.7, 21.8 and 3.5%, respectively. Partial response was observed in 25.6% of patients. Median progression-free survival was 4 months and median overall survival was 8.1 months. Conclusion: Immunotherapies are emerging as important tools in the oncologic field with good responses in real-life practice.

The Concept of Biosimilars: From Characterization to Evolution-A Narrative Review.

Biologic agents are currently the fastest emerging segment of drug expenditure. Unlike chemically synthesized small-molecule drugs, biologics are more complex, medicinal products produced by a living organism. They have become part of the standard of care in the treatment of a large variety of diseases, such as growth disorders, autoimmune diseases, cancer, cardiovascular illnesses, hemophilia, and rare genetic conditions, to name a few. Biosimilars, which are copies of biologics that are highly similar, were introduced in the market with an aim to offer efficacy that is not clinically different from the originator or reference product, at lower prices. We aim to clarify the concept of biosimilar, from definitions, history, market entry, challenges faced, and future evolution. For that purpose, we performed a literature search on the sites of the medicines regulatory agencies and PubMed from 1990 to 2014 with the keywords "biosimilars," "market," and "regulatory." In 2006, the first biosimilar, somatropin [rDNA origin], was marketed and led the way for biosimilar drug manufacturing. As a result, manufacturers have entered a diversified competition, facing challenges in manufacturing these complex agents, such as immunogenicity and efficiency. Biosimilars are set to evolve differently in various markets, namely the U.S., Japan, the European Union, and the "pharmerging" economies. IMPLICATIONS FOR PRACTICE: This article highlights the importance of biosimilars, as a cost-cutting strategy, in the delivery of state-of-the-art health care in developing countries, at a fraction of what a reference biological agent would cost.

Endotracheal bioimpedance cardiography improves immediate postoperative outcome: a case-control study in off-pump coronary surgery.

The feasibility and clinical utility of the endotracheal cardiac output monitor (ECOM) to optimize intraoperative hemodynamics and improve short-term outcome in off-pump coronary artery bypass grafting (OPCAB) is unknown. We aimed to compare ECOM with a standard of care in that specific surgical setting. Twenty consecutive adult ECOM-monitored patients undergoing OPCAB were prospectively included (ECOM group) and retrospectively compared to 42 patients scheduled for similar surgery without ECOM monitoring (Control group). The primary endpoint was the global rate of postoperative admission to the intensive care unit (ICU). Secondary endpoints were the time to extubation, the length of stay in ICU and in hospital, the postoperative levels of lactate and troponin and the feasibility of ECOM. The rate of postoperative admission to the ICU was 38/42 (90%) in the Control group versus 11/20 (55%) in the ECOM group, P = 0.008. None unexpected admission for hemodynamic instability was observed in the ECOM group. The time to extubation, the length of stay in ICU, and both troponin level at admission and lactate level at H6 were all significantly decreased in the ECOM group. On a scale ranging from 0 to 5, convenience and satisfaction regarding ECOM were 4.30 ± 1.17 and 3.45 ± 0.68, respectively. The systematic use of ECOM is associated with a significant reduction in the rate of admission to the ICU and an improvement in immediate outcome in OPCAB.

The role of palliative care in the last month of life in elderly cancer patients.

INTRODUCTION: One major health care issue encountered in elderly cancer patients is the alteration of the quality of life. The purpose of our study is to evaluate the administration of chemotherapy in the last month of life (CLML) and to evaluate the impact of the palliative care consult (PCC) in the elderly patients. METHODS: We conducted a retrospective observational study that included elderly patients diagnosed with an end-stage cancer and who were deceased between the 1st of January 2012 and the 31st of December 2015. Patient medical records were reviewed for patients' characteristics and management during the last month of life. RESULTS: This study enrolled 231 patients that fulfilled the eligibility criteria. CLML was administered in 91 patients (39.4 %) among which 43 patients (47.3 %) had their treatment within the last 2 weeks of life. Seventy-seven patients (33.3 %) had a palliative care consult (PCC) with a median duration of follow up of 13 days (range 2-56 days). Overall, PCC failed to decrease CLML administration, the duration of hospitalization, and ICU admissions. However, CLML administration decreased by 69 % among patients that had their PCC before receiving treatment (OR = 0.31; 95 % CI 0.15-0.63). PCC also led to a change in the pattern of treatment administered in the last month of life with less cytotoxic therapy (OR = 0.27 CI 95 % 0.09-0.9, p = 0.02) and higher rates of oral agents being prescribed (OR = 3.8; 95 % CI 1.3-11.3, p = 0.014). CONCLUSION: Our elderly patients seem to receive aggressive management similar to the general oncology population. Early PCC was shown throughout our results to decrease the aggressiveness of cancer treatment in elderly patients which seems to improve the quality of care of our patients.

Central Macular Thickness Monitoring after a Taxane-Based Therapy in Visually Asymptomatic Patients.

BACKGROUND: Taxanes are drugs used in various chemotherapeutical protocols to treat solid tumors. They have multiple systemic adverse effects, such as bone marrow suppression, alopecia, nausea, and vomiting, and may rarely cause ocular symptoms. In the past decade, a few reported cases have shown the occurrence of a cystoid macular edema with significant visual loss after the use of a taxane-based chemotherapy. The aim of this study was to compare the central macular thickness (CMT) before and after the initiation of a taxane-based therapy in visually asymptomatic patients and to elucidate the possible impact of these drugs on the vision of cancer patients. METHODS: Patients with a confirmed diagnosis of a solid tumor were screened for any ophthalmic disease before inclusion and had a baseline macular spectral domain optical coherence tomography (OCT; RTVue-100; Optovue Inc., Fremont, CA, USA) before the initiation of a taxane-based chemotherapy according to different protocols, such as 4EC-4T, 3FEC/3T, or 4TC. OCT was repeated after 4 cycles (or 3 months) of treatment, and CMT was compared to baseline. Patients presenting diabetic retinopathy, age-related macular degeneration or any condition that causes macular edema confirmed by ophthalmic examination were excluded. RESULTS: Fifty eyes of 25 patients were included; 92% of the subjects were female with a mean age of 48.52 years, 88% were diagnosed with breast cancer, 8% with esophageal cancer, and 4% with ovarian cancer. Docetaxel was the taxane administered to 92% of the patients. The received dose of docetaxel ranged between 110 and 160 mg. The other patients had paclitaxel in their protocols. No significant macular edema or drop in visual acuity were noted in any patient. Nevertheless, the mean CMT was found to be increased, particularly in the parafoveal and perifoveal areas (mean difference of +2.22 µm; p = 0.001). CONCLUSION: Taxane-based chemotherapy regimens seem to increase macular thickness, with a relative sparing of the fovea, in patients without significant macular edema. Further research is required to better explain the pathophysiology and possible impact of this phenomenon.

Phase II trial of weekly Docetaxel, Zoledronic acid, and Celecoxib for castration-resistant prostate cancer.

Background Treatment options for patients with metastatic castration-resistance prostate cancer are unsatisfactory. Docetaxel monotherapy offers promising results with a tolerable toxicity profile. However, enhancing the clinical index of Docetaxel-based therapy remains the ultimate goal. Methods We conducted a phase II, open label, multinational prospective trial to evaluate the efficacy of weekly Docetaxel combined with Zoledronic acid and Celecoxib. Eligible patients received 25 mg/m(2) Docetaxel weekly for 3 consecutive weeks every 4 weeks, 4 mg Zoledronic acid every 4 weeks, and 200 mg oral Celecoxib twice daily. Enrollment was terminated prematurely upon the publication of reports of cardiac toxicity associated with cyclooxygenase (COX) 2 inhibitors. Results Our study enrolled 22 patients with a median of 4.7 cycles per patient. The median overall survival (OS) was 9.8 months (range 0.7 to 24.1 months) with 36 % and 4.5 % survival rates at 1 and 2 years, respectively. Our patients had a biologic response in 40.1 % of cases and a palliative response in 72.7 %. Among the eight patients with measurable disease, three had partial responses, two had stable disease, and three had progressive disease, leading to a response rate (RR) of 62.5 %. The observed toxicities were mild and limited to grade 3 events. Nine patients had anemia (40.1 %), 5 had sensory neuropathy (22.7 %) and 2 had stomatitis (9.1 %). Conclusion The combination of Docetaxel, Celecoxib, and Zoledronic acid failed to improve OS or to offer an acceptable biologic response. We do not believe that there is compelling evidence to include either Celecoxib or Zoledronic acid in further phase II/III trials.

Treatment of cancer patients in their last month of life: aimless chemotherapy.

PURPOSE: The use of chemotherapy in the last month of life (CLML) of cancer patients is considered an aggressive approach to be avoided. We examined the practice of CLML in Lebanese cancer patients, and we investigated patient and tumor characteristics that justify this practice. To our knowledge, this is the first study describing CLML of Middle Eastern patients with advanced cancer. METHODS: We conducted this study at Hotel-Dieu de France University Hospital (HDF), Lebanon. Cases eligible for this study were all individuals diagnosed with cancer who died at HDF between the 1st of January and the 31st of December 2014. Demographic and clinical characteristics of the patients were obtained from the hospital registration records. Data concerning the management plan, primary malignancy and stage, chemo-sensitivity, line, type, and timing of chemotherapy in the last month of life were also obtained. RESULTS: Among the 130 cancer patients who were enrolled, CLML was administered to a total of 55 patients (42.3 %), of whom 26 patients (50 %) received more than one cytotoxic drug. Oral drug was only given to 9 patients (16.4 %). Interestingly, CLML increased the risk of death in the last month of life (p = 0.02), yet progression of disease constituted the major cause of death in this subgroup (54.6 %). The only variable to have statistical significant correlation with CLML was performance status (p = 0.03). The type of tumor and recent diagnosis of less than 2 months were also correlated to CLML (p = 0.03 and 0.024, respectively). CONCLUSION: The high percentage of patients receiving CLML underlines the difficulty of end-of-life discussions in patients from Middle Eastern societies. This is true in the context of a country with little availability of palliative care resources, where health policies should be more focused on incorporating palliative medicine in all medical strategies.

EARLY INCREASE of CA 19-9 in ADVANCED PANCREATIC CANCER RECEIVING FOLFIRINOX. Is it a sign of efficacy?.

INTRODUCTION: Advanced pancreatic cancer (APC), one of the most aggressive tunors, was considered to be resistant to chemotherapy for decades. FOLFIRINOX (5-FU, leucovorin, iNinotecah and oxaliplatin) regimen showed an improvement of quality of life and overall sUrvival.ir APb patients with good performance status (ECOG < 2). MATERIAL AND METHODS: Seven patients diagnosed with APO, during a six-month period, received FOLFIRINOX as first line treat- ment. Tumor measurement Was assesed every two months and CA 19-9, tHe specific tumor marker of pahcteatid can6er, was assessed every two wedks at every cycle. RESULTS: Three patients ouf of seven receiving FOLFiRINOX dtpe- riented an early And transitory increase of CA 19-9 after th6 first two cybles resulting ih a considerable response with a median survival of 15 mnths and suggesting a fhdel of fdmor release syndrome. CONCLUSION: This phenoMenon of early and transitory increase of CA 19-9 in APC could reflect the high efficacy of FOLFIRINOX and could predict better out- come in these patients.

Cyclosporine protects the heart during aortic valve surgery.

BACKGROUND: Part of the myocardial damage occurring during cardiac surgery is a consequence of reperfusion injury. Cyclosporine, a potent inhibitor of the opening of the mitochondrial permeability transition pore, attenuates reperfusion injury in patients with acute ST-segment elevation myocardial infarction. This study investigated whether the administration of cyclosporine just before the aortic cross-unclamping would reduce myocardial injury in patients undergoing aortic valve surgery. METHODS: This study was a monocentric, prospective, randomized, single-blinded, controlled trial. Sixty-one patients, scheduled for elective aortic valve surgery, were randomly assigned (computer-generated randomization sequence) to receive either an intravenous bolus of cyclosporine (2.5 mg/kg, cyclosporine group, n = 30) or normal saline (control group, n = 31) 10 min before aortic cross-unclamping. The primary endpoint was the 72-h area under the curve for cardiac troponin I. RESULTS: Both groups were similar with respect to baseline characteristics and aortic cross-clamping duration. A significant 35% reduction of area under the curve for cardiac troponin I was observed in the cyclosporine group compared with the control group (242 ± 225 vs. 155 ± 71 arbitrary units, mean ± SD; mean difference, -86.2 ± 42.5; 95% CI, -172.3 to -0.1; P = 0.03). Cyclosporine beneficial effect remained significant after adjustment for aortic cross-clamping duration in each group (mean difference, -88 ± 34, 95% CI, -157 to -19; P = 0.01). None of the treated patients had significant side effects (odds ratio, 0.64; 95% CI, 0.16 to 2.55; P = 0.52). CONCLUSIONS: Cyclosporine administration at the time of reperfusion protects against reperfusion injury in patients undergoing aortic valve surgery. The clinical benefit of this protection requires confirmation in a larger clinical trial.

Is a severe preoperative condition a contraindication for aortic valve-sparing reimplantation in type A aortic dissection?

BACKGROUND: Type A aortic dissection (TAAD) surgical management is still under debate. The purpose of this study was to demonstrate the feasibility and safety of the aortic valve-sparing root reconstruction (AVSR) procedure in 92 consecutive patients operated for TAAD, even when preoperative condition was severe (malperfusion, shock or both). METHODS: Our hospital database was reviewed to identify all patients who underwent an AVSR procedure for TAAD over 14 years. From May 2000 to June 2014, 92 consecutive patients were studied regarding to their preoperative condition. RESULTS: Age (61±13 years) and logistic Euroscore (23.4±15.3%) as well as cross-clamping (113±39 min), cardiopulmonary bypass (142±49 min) and circulatory arrest (22±13 min) times were collected. Hospital mortality was 16.3%. Mean follow-up was complete for a mean period of 27.6 months. One patient had early reoperation for aortic insufficiency. Actuarial survival at 1 year was 82.5%. The analysis of each group showed comparable mortality and morbidity in between patients. CONCLUSIONS: Based upon our experience in the management of TAAD, a reimplantation procedure could be performed regardless preoperative malperfusion or shock, with an acceptable postoperative over mortality or morbidity. A word of caution should be brought to patients over 70 years old.

Liquid biopsy as a tool for KRAS/NRAS/BRAF baseline testing in metastatic colorectal cancer.

BACKGROUND: The absence of KRAS and NRAS gene mutations (RAS wild type) in metastatic colorectal cancer (mCRC), is associated with a good response to targeted therapy with anti-EGFR receptor antibodies. The current gold standard for RAS mutational status identification is genetic testing on tissue biopsy samples. OBJECTIVE: This study aimed to assess the relevance of liquid biopsy as a less invasive alternative to tissue biopsy for detecting KRAS/NRAS and BRAF mutations in patients with metastatic colorectal cancer (mCRC). The study also aimed to determine the concordance between liquid biopsy and tissue biopsy. METHODS: This is a phase IV, observational, uncontrolled, non-comparative, non-randomized, open label study. RAS/BRAF status will be tested at baseline using tissue and liquid biopsy using the Idylla/Biocartis PCR-based device. The primary endpoint is the comparison of the RAS status based on liquid biopsy with the RAS status based on tissue biopsy. RESULTS: 100 patients with mCRC were included in the study. 75% of patients showed concordant results between liquid biopsy and tissue biopsy, while 25% had discordant results. Liquid biopsy demonstrated a sensitivity of 62% and a specificity of 93%. The accuracy of liquid biopsy was 75%, with a moderate agreement between the two tests. The most frequent mutations in concordant cases were in KRAS (41%), followed by NRAS (4%) and BRAF (3%). Mutations were not detected in 42% of tissue biopsy samples and 60% of liquid biopsy samples. The presence of hepatic metastases did not significantly affect the concordance between the biopsy methods. CONCLUSION: Liquid biopsy using the Idylla™ system showed a relatively low sensitivity but high specificity for detecting KRAS/NRAS and BRAF mutations in mCRC patients. Despite some discordant cases, liquid biopsy remains a promising alternative to tissue biopsy due to its non-invasiveness, ability to provide multiple samples, and better representation of tumor heterogeneity.

High-dose calcitriol, docetaxel and zoledronic acid in patients with castration-resistant prostate cancer: a phase II study.

INTRODUCTION: Docetaxel has become the standard chemotherapy for patients with castration-resistant prostate cancer (CRPC). We wanted to assess the efficacy and safety of a weekly high-dose calcitriol, docetaxel and zoledronic acid combination in CRPC. PATIENTS AND METHODS: Thirty patients were enrolled to receive calcitriol 0.5 µg/kg orally in 4 divided doses over 4 h on day 1 of each treatment week, docetaxel 36 mg/m(2) i.v. infusion on day 2 of each treatment week and zoledronic acid 4 mg i.v. on day 2 of the first and fifth week of each cycle. Treatment was administered weekly for 6 consecutive weeks on an 8-week cycle. RESULTS: Out of 23 evaluable patients, there was a response of prostate-specific antigen (PSA) in 11 patients (47.8%); 6 (26.1%) had a stable PSA level for a median of 4.2 months. The median survival time was 15 months (95% confidence interval 13.9-16.1 months). The regimen was generally tolerated; anemia was the only grade 3/4 hematological toxicity in 2 patients. CONCLUSIONS: This regimen was tolerated, and half of the patients had a PSA response. Although our response rates are inferior to some studies using docetaxel, we believe our response rates are acceptable knowing that we are treating CRPC, which still has variable outcomes.