Thromboembolic Events Burden in Patients With Solid Tumors and Their Predisposing Factors.

INTRODUCTION: The relationship between cancers and thromboembolic events is well established. In our study, we aim to determine the burden of thromboembolic events in patients with solid tumors and identify the risk factors related to their development. MATERIALS & METHODS: Data on patients with solid tumors and thromboembolism between January 2013 and September 2014 were collected and analyzed. RESULTS: During the study period 174 patients were identified. Of which, 172 (98.9%) had venous thrombus embolism, 137 (79%) were diagnosed with deep vein thromboses, 67 (38.5%) with pulmonary embolism, 84 (48.3%) were symptomatic and 90 (51.7) were incidental at diagnosis. The most common patients and disease characteristics were female sex, high body mass index (BMI), metastatic stage, colorectal and breast primaries, and anti-neoplastic therapy. CONCLUSION:  Our study confirmed the high burden of thromboembolic events in cancer patients and the relevant factors associated with its development.

Survival benefit of surgical resection after first-line triplet chemotherapy and bevacizumab in patients with initially unresectable metastatic colorectal cancer.

BACKGROUND: Surgical resection of metastatic disease in patients with initially non-resectable colorectal cancer (CRC) has improved overall survival. Intensified chemotherapy regimens have increased the probability of converting unresectable metastasis to resectable. Here, we report the result of combining intensive chemotherapy (triplet) and surgical resection of metastatic lesions in patients with metastatic CRC. PATIENTS AND METHODS: Patients with unresectable metastatic CRC were enrolled in phase I/II trial of triplet chemotherapy consisting of capecitabine, oxaliplatin, irinotecan, and bevacizumab. Patients were given 5-8 cycles induction chemotherapy of the above regimen followed by maintenance capecitabine and bevacizumab until disease progression, unacceptable toxicity, or patient request. All patients were assessed at a multidisciplinary conference for possible surgical resection of their metastatic disease at the time of inclusion in the trial and 2 monthly intervals thereafter. Patients who underwent R0 resection of their metastatic disease received adjuvant oxaliplatin and capecitabine to complete a total of 6 months of chemotherapy. RESULTS: Fifty-three patients were enrolled. The median age was 52 years (range 23-74), 29 (55%) were males, ECOG PS 0-1 was 13 (66%), 11 (42%) had a right-sided tumor, 29 (55%) had resection of their primary tumor, 22 (42%) had a single metastatic site, and 8 (15.1%) had a liver-limited disease. Thirteen patients (24.5%) underwent surgical resection of residual metastatic disease +/- the primary tumor with 10 (18.9%) of them were R0. The surgical group had a higher incidence of males compared to the non-surgical group (69.3% vs 47.2%, p = 0.2), equal performance status, lower median number of metastatic sites (1 vs 2, p = 0.09), higher mutant Kras (53.8% vs 34.2%, p = 0.3), and higher response rate (84.6% vs 56.2%, p = 0.3). With a median follow-up duration of 89 months, the median PFS for the whole group was 16.1 months [95% confidence interval (CI) 9.1-20] and the median OS was 28.2 months (95% CI 22.5-53.3). The median PFS for the surgery group was 18.9 months (95% CI 12.6-not reached) compared to 9.6 months (95% CI 7.0-18.3) for the non-surgical group, log-rank p = 0.0165. The median OS for both groups was not reached (95% CI 53.3-not reached) and 23.2 months (95% CI 17.0-28.4) respectively, log-rank p = 0.0006. Five-year PFS and OS for the surgery group were 46.2% and 67.6% respectively. CONCLUSIONS: Patients with unresectable metastatic CRC and fit for triplet chemotherapy should have the benefit of combining this intensified regimen and surgical resection of their metastatic disease if possible. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01311050 , registered March 6, 2011, retrospectively registered.

Efficacy and Prognostic Factors of Sunitinib as First-Line Therapy for Patients With Metastatic Renal Cell Carcinoma in an Arab Population.

PURPOSE: Antiangiogenic tyrosine kinase inhibitors have been the mainstay first-line therapy for metastatic renal cell carcinoma (mRCC). We reviewed the efficacy of first-line therapy with sunitinib in patients with mRCC in an Arab population. METHODS: Medical records of patients with mRCC treated at a tertiary care center in Saudi Arabia, during the period from 2007 to 2016, were reviewed. Demographic data, treatment received, response, and prognostic factors were analyzed. RESULTS: Fifty-five patients who received sunitinib were identified. The median age was 60 years (range, 18 to 78 years), and 42 of the 55 patients were men (76.3%). International Metastatic RCC Diagnostic Consortium prognostic scores for favorable/intermediate/poor were 14.5%/43.6%/38.2%, respectively. The median performance status was 1, and the median Charlson comorbidity index score was 9. Thirty-seven patients (67.2%) had cytoreductive nephrectomy. Thirty-seven patients (67.2%) had clear cell histology. Twenty-two patients (40%) underwent dose reduction. Twenty-seven patients (49%) received second-line therapy, and seven patients (12.7%) received third-line therapy. Response rates were complete response in one patient (1.8%), partial response in 17 (30.9%), stable disease in 10 (18.1), and disease progression in 20 (36.3%). Progression-free survival (PFS) and overall survival (OS) were 6.0 and 24.7 months, respectively. Univariate analysis showed statistically improved PFS for dose reduction (P = .015) and the development of hypothyroidism (P = .03). It also showed statistically improved OS for dose reduction (P = .035), hypothyroidism (P = .0002), and cytoreductive nephrectomy (P = .0052). Multivariate analysis showed statistically improved PFS for dose reduction (P = .01) and OS for development of hypothyroidism (P = .007). CONCLUSION: Our data for sunitinib in mRCC show significantly lower PFS than expected. The absence of prognostic value of the International Metastatic RCC Diagnostic Consortium scoring system and pathologic subtype warrant further investigation and possible inclusion of genetic scoring in this ethnic group of patients.

Surgical and oncological outcome after laparoscopic versus open nephroureterectomy for non-metastatic, upper-tract urothelial carcinoma. A single-centre experience.

OBJECTIVES: We determined the surgical and oncological outcomes of laparoscopic nephroureterectomy (LNU) in comparison to open nephroureterectomy (ONU) and factors predicting bladder recurrence after nephroureterectomy. Methods: We retrospectively reviewed and compared the data of patients who underwent ONU or LNU for non-metastatic, upper-tract urothelial carcinoma from 2000 to 2016. The primary endpoint was to determine bladder cancer recurrence-free survival (BCRFS), cancer-specific survival (CSS), and overall survival (OS). The data were analysed using Student's t-test, Chi-square test, and Kaplan-Meier curve. Results: Total of 50 patients, of which 24 had LNU and 26 had ONU, met the inclusion criteria. Median durations of follow-up were 4.2 and 6.5 years (p=0.1070) in LNU and ONU, respectively. Operative time, blood loss and hospital stay were significantly lower in the LNU group than in the ONU group (p=0.0001, p=0.0001, p=0.0018). Cancer-specific survival rate in the LNU was 75% and ONU was 73.3% (p=0.1902), whereas BCRFS and CSS were not significantly different in both groups (log-rank test; BCRFS: p=0.809 and CSS: p=0.802). Patients who underwent ureteroscopy with biopsy (p=0.001), had multifocality (p=0.001) and previous history of (H/O) bladder cancer (p=0.020) were at significant risk for developing bladder cancer recurrence after nephroureterectomy.  Conclusion: Laparoscopic nephroureterectomy can benefit patients because of its minimal invasiveness, and oncologic outcomes are comparable to ONU. Preoperative ureteroscopy with biopsy, multifocality and previous H/O bladder cancer might be risk factors for bladder cancer recurrence.

rs4889 polymorphism in KISS1 gene, its effect on polycystic ovary syndrome development and anthropometric and hormonal parameters in Saudi women.

BACKGROUND: Kisspeptin is involved in female reproduction. This study was designed to i- estimate kisspeptin levels in women with polycystic ovary syndrome (PCOS), in comparison with controls, ii- study the correlations between kisspeptin and PCOS-related reproductive hormones, and iii- investigate the relation between KISS1 gene polymorphisms and hormone levels in women suffering from PCOS. METHODS: The investigation was a clinically designed study on 28 women with PCOS, and 30 normal, healthy women with no signs of PCOS as controls. Blood samples were collected between day 3 and day 6 of the menstrual cycle in both groups at 8:00 a.m., and circulating levels of LH, FSH and kisspeptin were estimated. DNA was extracted from whole blood and all coding exons of KISS1 gene were sequenced. RESULTS: Women with PCOS had higher LH levels and BMI compared to controls. Plasma kisspeptin levels were positively correlated with LH levels. There was no statistically significant difference between the groups in terms of kisspeptin and FSH levels. The SNP rs4889 C/G, a non-synonymous SNP, was investigated in the PCOS group. The frequency of GG genotype was significantly higher in the PCOS compared to the controls. These patients were more obese, had higher kisspeptin and FSH levels. CONCLUSION: The results of the study show that the genetic variation of KISS1 gene may be a factor contributing to PCOS development. The association between the gene and the gene variation and PCOS need further validation in large-scaled and functional studies.

Prognostic role of KIR genes and HLA-C after hematopoietic stem cell transplantation in a patient cohort with acute myeloid leukemia from a consanguineous community.

NK cell activity is tuned by a balance of activating and inhibitory signals transmitted via their respective receptors, including killer immunoglobulin-like receptors (KIRs). The impact of NK cells on graft-versus-leukemia following hematopoietic stem cell transplantation (HSCT) is well established. These effects sometimes lead to GvHD. The link between KIR/HLA interaction and GvHD remains unclear. Herein, we studied the impact of the KIR/HLA interaction on HSCT outcomes in a longitudinal follow-up study of a highly consanguineous HLA-matched related cohort. Peripheral blood DNA was collected from HSCT donor-recipient pairs (n = 87), including 41 AML pairs. KIR and HLA were genotyped and significant results were only measured when matching KIR (donor) with HLA (recipients). GvHD was observed in 47% of patients. KIR2DL1_C2 and 2DS2_C1 (P = 0.02 and 0.04, respectively) matching was associated with an increased incidence of acute GvHD in AML donor-recipient pairs. The rate of chronic GvHD also rose in AML patients who were matched for KIR2DS1_C2 (P = 0.004) and had either KIR2DL2 or KIR2DS2 (P = 0.03). In conclusion, matching of KIR2DL1, 2DS1, and 2DS2 in donors with their HLA-C ligands in recipients is associated with increased GvHD, and holds potential for selection of HSCT donors.

Incidence of leukopenia and thrombocytopenia with cisplatin plus mitomycin-c versus melphalan in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

INTRODUCTION: Cytopenia after hyperthermic intraperitoneal chemotherapy (HIPEC) with cytoreductive surgery (CRS) has been reported in non-comparative studies with various chemotherapeutic regimens. This study compared the incidence of leukopenia and thrombocytopenia in patients who underwent CRS/HIPEC and received melphalan or cisplatin plus mitomycin-c (CIS + MMC). METHODS: This retrospective study included patients who underwent CRS/HIPEC at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia from March 2011 to March 2017 and received melphalan 60 mg/m2 or CIS 100 mg/m2 combined with MMC 30 mg/m2. Incidences and severity of leukopenia, neutropenia, thrombocytopenia, and anemia were compared between groups. RESULTS: This study included 46 patients who received CIS + MMC and 35 patients who received melphalan. The leukopenia incidence was 25.7% in the melphalan group and 17.3% in the CIS + MMC group (P = 0.362), with one patient (2.8%) in the melphalan group developed grade V leukopenia. The number of days to leukocyte nadir was 32.8 days for CIS + MMC group compared to 9.8 days for melphalan group(P = 0.035). Thrombocytopenia occurred at a similar rate in the melphalan (60%) and CIS + MMC (68.8%) groups (P = 0.4). Grade III thrombocytopenia developed in 3.2% and 5% of patients in the melphalan and the CIS + MMC groups, respectively. Neutropenia did not occur in any patient. In multivariate analysis, leukopenia predictors were female gender (P = 0.047) and baseline leukocyte counts (P = 0.029). Baseline platelet count predicted thrombocytopenia (P < 0.001). CONCLUSIONS: Melphalan and CIS + MMC regimens were associated with comparable incidences of leukopenia and thrombocytopenia. Severe leukopenia and severe thrombocytopenia were rare following CRS/HIPEC using both chemotherapy regimens.

Extramedullary relapses after allogeneic stem cell transplantation for acute myeloid leukemia: clinical characteristics, incidence, risk factors and outcomes.

Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplant (allo-HCT) is challenging. Data on extramedullary relapse (EMR) after allo-HCT are limited. We analyzed 215 patients with AML who underwent allo-HCT in our institution between January 2005 and December 2015. We limited this retrospective review to patients who received a MA conditioning, were in complete remission (CR) at the time of transplant and who received a matched sibling transplant, all other patients were excluded to avoid heterogeneity. Seventy-seven (35.8%) patients experienced disease relapse, 45 had BMR, and 32 had EMR. The only variable that was statistically associated with EMR post allo-HCT was male sex (OR = 3.2 (1.2, 8.2), p-value = 0.01); there was a trend for association between transplant in >CR2 and EMR (OR = 0.38 (0.14, 1.06), p-value = 0.06). The median overall survival (OS) after relapse for all relapses was 10 months (95% CI 4.839-15.161). The median OS for BMR group was 8 months (95% CI 2.850-13.150) and 14 months for the EMR group (95% CI 5.776-22.224); however, this was not statistically significant, p-value = 0.4. Multivariate analysis revealed that gender, treatment modality, and time from allo-HCT to relapse (≥12 vs. <12 months) have significant association with the post-relapse death. Male gender was the only significant factor associated with EMR.

Breast Arterial Calcifications on Mammography Do Not Predict Myocardial Ischemia on Myocardial Perfusion Single-Photon Emission Computed Tomography.

BACKGROUND: The aim of this study was to determine if breast arterial calcification (BAC) on mammography predicts myocardial ischemia (MI) on stress myocardial perfusion single-photon emission computed tomography (MPS). BAC is a type of medial artery calcification that can be seen incidentally on mammography, but the relationship between coronary artery calcification and MI on MPS is yet unknown. METHODS: A total of 435 consecutive women underwent mammography and stress MPS within 1 year of each other. BAC was quantitatively evaluated (0 - 13). Patients with known coronary artery diseases (CADs) such as coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), MI, positive coronary angiogram or positive MPS were excluded from the study. Risk factors for CAD were obtained from a chart review. RESULTS: The mean age was 58 ± 8 years. BAC was found in 258 (59%) of the study population. BAC-positive patients were significantly older than BAC-negative patients (P < 0.0001), there were strong associations between BAC and hypertension (P = 0.0309), chronic kidney disease (CKD) (P = 0.0001), and diabetes (P = 0.0309), but there were significant associations between BACV and hyperlipidemia, family history of CAD, and smoking (P = 0.6856, P = 0.9642, and P = 0.087, respectively). The mean score of BAC was 5 ± 5 in patients with normal MPS and was 6 ± 6 in patients with abnormal MPS. There were no associations between total BAC and MPS results (P = 0.2095), and between BAC categories and MPS result (P = 0.3069). CONCLUSIONS: Based on our study, the presence and severity of BAC on screening or diagnostic mammography do not predict MI on stress MPS, and further cardiac workup based on the presence of BAC is not warranted. BAC is very common in mammography up to 59% and associated with age, diabetes, CKD, and hypertension. In contrast, the prevalence of MI is only 13% in women with BAC and associated with age, diabetes, CKD, hyperlipidemia, and impaired left ventricular function.

Etiology of optic atrophy: a prospective observational study from Saudi Arabia.

BACKGROUND: Optic atrophy (OA) represents permanent retinal ganglion cell loss warranting study to establish etiology. OBJECTIVES: To describe neurogenic causes of OA. DESIGN: Prospective, observational. SETTING: Tertiary care center, Riyadh, Saudi Arabia. PATIENTS AND METHODS: We included consecutive patients of all ages with OA caused by lesions affecting the visual pathways who were referred over a 9-month period (November 2013 to July 2014). Diagnosis was based on visual acuity, ophthalmoscopic features and ancillary tests. Patient demographics, results of a clinical examination, test data and etiology were recorded. For each cause of OA, both gender and age group were analyzed as potential risk factors using simple univariate logistic regression. OA associated with glaucoma and retinal diseases was excluded. MAIN OUTCOME MEASURE: Description of causes of OA. RESULTS: Two hundred and four patients and 353 eyes met inclusion criteria. The median age was 27 years (range 3 months-77 years; interquartile range, 27 years) among 111(54.4%) females and 93(45.6%) males, with no statistically significant difference in age of presentation between the genders. The majority of lesions were bilateral (n=151, 74%). Tumors were the most common cause, accounting for 127 (62.2%) cases. These occurred mostly in adults (72.4%) compared to the pediatric group (OR=3.3, 95% CI: 1.79-6.03; P < .001). Hereditary neoplasia (OR=5.55; 95% CI: 1.67-18.42; P=.005) and metabolic diseases (OR=17.57; 95% CI: 2.15-143.62; P=.007) were more common causes in the pediatric group. There were no significant associations between gender or visual acuity and etiology of OA. In developed nations, OA is frequently the result of ischemia and neuritis. We found many other causes, especially orbital and intracranial tumors. CONCLUSIONS: The frequency of tumors as the cause of OA may represent a higher incidence of aggressive tumors coupled with poor recognition/acknowledgement of symptoms and limited access, resulting in late presentations. LIMITATIONS: These findings may reflect bias from selective referrals to a tertiary center and may not represent all of Saudi Arabia.

Prevalence and severity of pain in cancer patients in an outpatient palliative care setting in Saudi Arabia.

BACKGROUND: The prevalence and severity of cancer pain in the outpatient palliative care (PC) setting have not been explored previously in Saudi Arabia (SA). Exploration of this basic information may help in evaluating pain severity in patients new to PC as compared to those with previous PC exposure. OBJECTIVE: This paper aims to determine the prevalence and severity of cancer pain among new and follow-up patients attending a PC outpatient clinic. METHODS: In a PC outpatient setting in a major tertiary hospital in SA, we interviewed adult patients with cancer during their attendance to the clinic. Patients were requested to score the severity of their pain on a 0 to 10 numerical scale. RESULTS: A total of 124 patients were interviewed, of whom 73 (59%) were females. The majority of patients (82.3%) had metastatic disease. The most common cancers were breast (27.4%) and head and neck (15.3%). The majority of patients (85.5%) reported pain, with a median intensity score of 5 and a mean of 4.6. Of those who reported pain, 54 (51%) scored above 4. The mean pain score did not differ between groups of patients according to various characteristics such as age, sex, performance status, type of cancer or encounter type. CONCLUSION: Pain is a prevalent symptom in new and follow-up cancer patients seen in a PC outpatient setting in SA. Further research on a larger scale is needed to evaluate the magnitude of the problem more comprehensively with emphasis on detailed pain assessment and exploration of the adopted management approaches.

Association between HLA variations and chronic hepatitis B virus infection in Saudi Arabian patients.

Hepatitis B virus (HBV) infection is a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. Human leukocyte antigens (HLAs) play an important role in the regulation of immune response against infectious organisms, including HBV. Recently, several genome-wide association (GWAS) studies have shown that genetic variations in HLA genes influence disease progression in HBV infection. The aim of this study was to investigate the role of HLA genetic polymorphisms and their possible role in HBV infection in Saudi Arabian patients. Variations in HLA genes were screened in 1672 subjects who were divided according to their clinical status into six categories as follows; clearance group, inactive carriers, active carriers, cirrhosis, hepatocellular carcinoma (HCC) patients and uninfected healthy controls. Three single nucleotide polymorphisms (SNPs) belonged to HLA-DQ region (rs2856718, rs7453920 and rs9275572) and two SNPs belonged to HLA-DP (rs3077 and rs9277535) were studied. The SNPs were genotyped by PCR-based DNA sequencing (rs2856718) and allele specific TaqMan genotyping assays (rs3077, rs7453920, rs9277535 and rs9275572). The results showed that rs2856718, rs3077, rs9277535 and rs9275572 were associated with HBV infection (p = 0.0003, OR = 1.351, CI = 1.147-1.591; p = 0.041, OR = 1.20, CI = 1.007-1.43; p = 0.045, OR = 1.198, CI = 1.004-1.43 and p = 0.0018, OR = 0.776, CI = 0.662-0.910, respectively). However, allele frequency of rs2856718, rs7453920 and rs9275572 were found more in chronically infected patients when compared to clearance group infection (p = 0.0001, OR = 1.462, CI = 1.204-1.776; p = 0.0178, OR = 1.267, CI = 1.042-1.540 and p = 0.010, OR = 0.776, CI = 0.639-0.942, respectively). No association was found when polymorphisms in HLA genes were compared in active carriers versus cirrhosis/HCC patients. In conclusion, these results suggest that variations in HLA genes could affect susceptibility to and clearance of HBV infection in Saudi Arabian patients.

Age-specific gene expression signatures for breast tumors and cross-species conserved potential cancer progression markers in young women.

Breast cancer in young women is more aggressive with a poorer prognosis and overall survival compared to older women diagnosed with the disease. Despite recent research, the underlying biology and molecular alterations that drive the aggressive nature of breast tumors associated with breast cancer in young women have yet to be elucidated. In this study, we performed transcriptomic profile and network analyses of breast tumors arising in Middle Eastern women to identify age-specific gene signatures. Moreover, we studied molecular alterations associated with cancer progression in young women using cross-species comparative genomics approach coupled with copy number alterations (CNA) associated with breast cancers from independent studies. We identified 63 genes specific to tumors in young women that showed alterations distinct from two age cohorts of older women. The network analyses revealed potential critical regulatory roles for Myc, PI3K/Akt, NF-κB, and IL-1 in disease characteristics of breast tumors arising in young women. Cross-species comparative genomics analysis of progression from pre-invasive ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) revealed 16 genes with concomitant genomic alterations, CCNB2, UBE2C, TOP2A, CEP55, TPX2, BIRC5, KIAA0101, SHCBP1, UBE2T, PTTG1, NUSAP1, DEPDC1, HELLS, CCNB1, KIF4A, and RRM2, that may be involved in tumorigenesis and in the processes of invasion and progression of disease. Array findings were validated using qRT-PCR, immunohistochemistry, and extensive in silico analyses of independently performed microarray datasets. To our knowledge, this study provides the first comprehensive genomic analysis of breast cancer in Middle Eastern women in age-specific cohorts and potential markers for cancer progression in young women. Our data demonstrate that cancer appearing in young women contain distinct biological characteristics and deregulated signaling pathways. Moreover, our integrative genomic and cross-species analysis may provide robust biomarkers for the detection of disease progression in young women, and lead to more effective treatment strategies.

Nonpain Symptoms of New and Follow-up Cancer Patients Attending a Palliative Care Outpatient Clinic in Saudi Arabia.

BACKGROUND: Epidemiology of cancer-related nonpain symptoms receives less attention in literature as compared with cancer pain. OBJECTIVE: This paper aims at exploring the prevalence and severity of nonpain symptoms in cancer patients attending a palliative care (PC) outpatient clinic. MATERIALS AND METHODS: Over a 5 months period, consecutive adult cancer patients attending PC outpatient clinic at a tertiary hospital were evaluated for the presence and severity of 10 nonpain symptoms. Patients were grouped to new or follow-up cases and were also grouped according to performance status and cancer type. Prevalence and severity of symptoms were compared between groups using t test or analysis of variance as appropriate. RESULTS: Fifty-one males and 73 females were interviewed. The most common cancer is female breast (27.4%) followed by head and neck (15.3%). Majority of patients (67%) were new to PC clinic. Patients had 5.1 nonpain symptoms on average, with most common symptoms being tiredness (79.8%), loss of appetite (71.8%), dry mouth (69.4%), anxiety (60.5%), and depression (50.8%). The least common symptoms were confusion and nausea (22.6% each). The median scores of severity were highest for tiredness, loss of appetite, dry mouth, and insomnia (5 points each). Symptoms were fewer among patients with good performance status (P = 0.002), whereas age, gender, cancer type, and encounter type were not associated with difference in symptom prevalence. Younger patients, females and those with poor performance status have shown a tendency toward higher severity scores for several symptoms. CONCLUSION: The significant prevalence and severity of nonpain symptoms among new and follow-up cancer patients seen in a PC outpatient clinic emphasizes the need for comprehensive assessment and routinely audited symptom management plans.

Toll-like receptor 4 and high-mobility group box 1 are critical mediators of tissue injury and survival in a mouse model for heatstroke.

The molecular mechanisms that initiate the inflammatory response in heatstroke and their relation with tissue injury and lethality are not fully elucidated. We examined whether endogenous ligands released by damaged/stressed cells such as high-mobility group box 1 (HMGB1) signaling through Toll-like receptor 4 (TLR4) may play a pathogenic role in heatstroke. Mutant TLR4-defective (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to heat stress in an environmental chamber pre-warmed at 43.5 °C until their core temperature reached 42.7°C, which was taken as the onset of heatstroke. The animals were then allowed to recover passively at ambient temperature. A sham-heated group served as a control. Mutant mice displayed more histological liver damage and higher mortality compared with wild type mice (73% vs. 27%, respectively, P<0.001). Compared to wild type mice, mutant mice exhibited earlier plasma release of markers of systemic inflammation such as HMGB1 (206 ± 105 vs. 63 ± 21 ng/ml; P = 0.0018 and 209 ± 100 vs. 46 ± 32 ng/ml; P<0.0001), IL-6 (144 ± 40 vs. 46 ± 20 pg/ml; P<0.001 and 184 ± 21 vs. 84 ± 54 pg/ml; P = 0.04), and IL-1ß (27 ± 4 vs. 1.7 ± 2.3 pg/ml; P<0.0001 at 1 hour). Both strains of mice displayed early release of HMGB1 into the circulation upstream of IL-1ß and IL-6 responses which remained elevated up to 24 h. Specific inhibition of HMGB1 activity with DNA-binding A Box (600 µg/mouse) protected the mutant mice against the lethal effect of heat stress (60% A Box vs. 18% GST protein, P = 0.04). These findings suggest a protective role for the TLR4 in the host response to severe heat stress. They also suggest that HMGB1 is an early mediator of inflammation, tissue injury and lethality in heatstroke in the presence of defective TLR4 signaling.

Prevalence and severity of suffering among patients with advanced cancer.

BACKGROUND: Suffering is an expression commonly used to describe distressing experience of cancer patients. Suffering experience among patients with advanced cancer has not been studied before in Saudi Arabia. OBJECTIVE: The objective of this study is to determine the pattern of suffering and the feasibility of measuring its severity on a numerical scale for cancer patients attending a palliative care outpatient clinic. METHODS: This is part of a larger survey studying the pattern of symptomatology in an outpatient palliative care clinic. Over a 5-month period, cancer patients attending an outpatient palliative care clinic were requested to rate their suffering as well as 11 listed symptoms on a 0-10 numerical scale. RESULTS: Of the 124 patients interviewed, 73 (59 %) were females. Only 15 patients (12 %) reported no suffering. For those who were suffering (88 %), the median score is 5. Suffering scores did not differ based on sex, age, or type of cancer. Patients with a Palliative Performance Scale of ≤50 % had significantly higher mean suffering score (6.8) compared to those with better performance status (4.8; P = 0.003). Multivariate analysis resulted in three independent variables showing a significant relationship to suffering score, namely pain (P = 0.018), tiredness (P = 0.022), and depression (P = 0.022). CONCLUSION: Patients with advanced cancer were able to easily rate their suffering on a numerical scale. Pain, tiredness, and depression were associated with the suffering scores. Suffering scores might help in tracing the trend of suffering in the individual patient over time.

Outcome of second allogenic stem cell transplantation in pediatric patients with non-malignant hematological and immune deficiency disorders.

BACKGROUND: Second stem cell transplantation (SCT) is usually associated with high morbidity and mortality and the data on its outcome in pediatric patients with non-malignant disorders are scarce. PATIENTS AND METHODS: We present 30 children with non-malignant conditions who underwent second SCT at our institution for graft failure after the first SCT; 20 had a non-malignant hematological disorder and 10 had an immune deficiency disorder. Median age at the second SCT was 6.1 years (range, 0.4-13 years) and median time from the first SCT to the second SCT was 6.2 months (range, 1.2-96 months). RESULTS: Twenty patients (70%) engrafted; severe acute GVHD developed in four patients (13%), and chronic GVHD developed in two patients of those at risk (10%). Thirteen deaths occurred and nine were considered treatment related. The 5-year overall (OS) and event free survival (EFS) for all patients were 53% and 47% respectively. The interval between the two transplants seemed to affect the outcome; patients who had the second SCT ≥ 6 months from the first SCT had better survival; the 5-year OS for the two groups (<6 months and ≥ 6 months) respectively were 30% and 74% (P = 0.004), and the 5-year EFS were 27% and 66% (P = 0.004). The underlying disease did not affect the outcome nor did the use of radiation in the conditioning regimen for the second SCT. CONCLUSIONS: Second SCT for graft failure should be considered for children with non-malignant hematological and immune deficiency disorders.

TP53 genetic alterations in Arab breast cancer patients: Novel mutations, pattern and distribution.

Breast cancer remains a worldwide public health concern. The incidence and mortality of breast cancer varies significantly in ethnically and geographically distinct populations. In the Kingdom of Saudi Arabia (KSA) breast cancer has shown an increase in incidence and is characterized by early onset and aggressiveness. The tumor suppressor TP53 gene is a crucial genetic factor that plays a significant role in breast carcinogenesis. Furthermore, studies have shown a correlation between certain p53 mutations and response to therapy in breast cancer. In the present study, TP53 mutations were identified by direct sequencing of the gene (exons 4-9) from 119 breast cancer tissues. The prevalence of TP53 mutations in Arab breast cancer patients living in the KSA is among the highest in the world (40%). Notably, 73% of the patients whose tumors harbored p53 mutations were less than 50 years of age. Furthermore, for the first time, we identified 7 novel mutations and 16 mutations in breast cancer tissues. Notably, all the novel point mutations were found in exon 4, wherein 29% of the mutations were localized. Furthermore, an excess of G:C→A:T transitions (49%) at non-CpG sites was noted, suggesting exposure to particular environmental carcinogens such as N-nitroso compounds. The results indicate that the TP53 gene plays a significant role in breast carcinogenesis and the early onset of the disease among Arab female individuals.

Transplant tourism outcome: a single center experience.

BACKGROUND: Transplant tourism is the term used for patients who travel abroad for transplantation. Transplant tourism has always been surrounded with controversy regarding how these organs were obtained, the donor's care after transplantation, and the recipient outcome. Many authors have found that the outcome of the recipients in transplant tourism is inferior to those transplanted in their own countries. However, most these studies were small, with the latest one including only 33 patients. Here, we describe the outcome of 93 patients who were transplanted abroad compared with local transplantation. MATERIAL AND METHODS: All transplant patients who were followed up at our Nephrology Clinic from 1998 until 2008 were identified using our data base system. We selected patients transplanted from 2003 and forward because the computerized system for laboratory and electronic records began operation that year. RESULTS: A total of 165 patients were identified (93 in the tourist group and 72 in the local one). Transplant tourists had a higher rate of acute rejection in the first year compared with local transplantation (27.9% vs. 9.9, P=0.005), higher mean creatinine at 6 months and 1 year (120 vs. 101 micromol/L, P=0.0007, 113 vs. 98 micromol/L, P=0.008). There was no statistical difference in graft or patient survival in 1 or 2 years after transplantation. However, transplant tourist had a higher rate of cytomegalovirus infection (15.1% vs. 5.6%, P=0.05) and hepatitis C seroconversion (7.5% vs. 0%, P=0.02). CONCLUSION: Transplant tourists had a more complex posttransplantation course with higher incidence of acute rejection and infectious complications.

Impact of laparoscopic sleeve gastrectomy on iron indices: 1 year follow-up.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has been recently introduced as a stand-alone, restrictive bariatric surgery. Theoretically, LSG attenuates micronutrients deficiencies and associated complications that typically observed following malabsorptive procedures. The aim of this study was to assess iron indices and the 1-year incidence of iron deficiency in patients undergoing LSG. METHODS: This was a prospective, cohort study; patients who underwent LSG from June 2007 to April 2008 at our institution were screened for inclusion. Preoperative hemoglobin and iron indices including serum iron, transferrin saturation, ferritin, and soluble transferrin receptor were compared to their levels at 6 and 12 months after surgery. Similarly, vitamin B12 and red blood cell (RBC) folate were analyzed as secondary end points. Weight parameters and C-reactive protein (CRP) levels were compared before surgery and 1 year postoperatively. RESULTS: A total of 61 patients were included in the study. One year after surgery, there was a significant decrease in the mean body mass index from 47.5 +/- 9.6 to 30.5 +/- 6.5 (P < 0.001). The incidence of iron deficiency was 4.9% at both follow-up time points. Anemia was evident in 4.9% of patients 1 year postoperatively. Significant decrease in the means of the natural logarithm of vitamin B12 and RBC folate were observed as early as 6 months after surgery (P = 0.014; P < 0.005, respectively). The decrease in mean CRP level 12 months postoperatively was statistically significant compared to its preoperative value (P < 0.0001). CONCLUSION: LSG is an effective procedure for the treatment of morbid obesity and its associated inflammatory state. One year after surgery, development of iron deficiency was insignificant.