The development of a nomogram to determine the frequency of elevated risk for non-medical opioid use in cancer patients.

OBJECTIVE: Non-medical opioid use (NMOU) is a growing crisis. Cancer patients at elevated risk of NMOU (+risk) are frequently underdiagnosed. The aim of this paper was to develop a nomogram to predict the probability of +risk among cancer patients receiving outpatient supportive care consultation at a comprehensive cancer center. METHOD: 3,588 consecutive patients referred to a supportive care clinic were reviewed. All patients had a diagnosis of cancer and were on opioids for pain. All patients were assessed using the Edmonton Symptom Assessment Scale (ESAS), Screener and Opioid Assessment for Patients with Pain (SOAPP-14), and CAGE-AID (Cut Down-Annoyed-Guilty-Eye Opener) questionnaires. "+risk" was defined as an SOAPP-14 score of ≥7. A nomogram was devised based on the risk factors determined by the multivariate logistic regression model to estimate the probability of +risk. RESULTS: 731/3,588 consults were +risk. +risk was significantly associated with gender, race, marital status, smoking status, depression, anxiety, financial distress, MEDD (morphine equivalent daily dose), and CAGE-AID score. The C-index was 0.8. A nomogram was developed and can be accessed at https://is.gd/soappnomogram. For example, for a male Hispanic patient, married, never smoked, with ESAS scores for depression = 3, anxiety = 3, financial distress = 7, a CAGE score of 0, and an MEDD score of 20, the total score is 9 + 9+0 + 0+6 + 10 + 23 + 0+1 = 58. A nomogram score of 58 indicates the probability of +risk of 0.1. SIGNIFICANCE OF RESULTS: We established a practical nomogram to assess the +risk. The application of a nomogram based on routinely collected clinical data can help clinicians establish patients with +risk and positively impact care planning.

Paraoxonase 1 (PON1) Q192R and L55M polymorphisms, lipid profile, lipid peroxidation and lipoprotein-a levels in Turkish patients with pregnancy-related disorders.

The aim of this study was to investigate the role of PON1Q192R and L55M single nucleotide polymorphisms(SNPs) and its association with the maternal levels of lipid parameters in gestational diabetes mellitus(GDM) and preeclampsia(PE). Ninety-nine pregnant with GDM, 97 pregnant with PE and 98 healthy pregnant were included in the study. No statistically significant difference was observed in the alleles or in the genotypes frequencies of SNPs between groups. In GDM patients, total cholesterol was higher in MM genotype of L55M gene (p < .05); Lp(a) were lower in LM genotype of the gene compared to their respective control (p < .05). In PE, HDL-C levels were higher in LM genotype (p < .05); LDL-C levels were lower in MM genotype of the gene compared to their respective control (p < .05). In PE patients, malondialdehyde(MDA) were higher in QQ genotype compared to their respective control (p < .05). Triglyceride levels were higher in PE patients with QR genotype compared with GDM patients with QR genotype (p < .05). Our results indicated that lipid profiles, Lp(a) and MDA levels showed significant differences in GDM and PE pregnants. These findings support the importance of the lipid profile, oxidized lipid and Lp(a) in different genotypes of L55M and Q192R in Turkish pregnant women with PE/GDM suggesting their roles in etiopathogenesis in these pregnancy-related disorders.

Scheduled and Breakthrough Opioid Use for Cancer Pain in an Inpatient Setting at a Tertiary Cancer Hospital.

Background: Our aim was to examine the frequency and prescription pattern of breakthrough (BTO) and scheduled (SCH) opioids and their ratio (BTO/SCH ratio) of use, prior to and after referral to an inpatient supportive care consult (SCC) for cancer pain management (CPM). Methods and Materials: Patients admitted at the MD Anderson Cancer Center and referred to a SCC were retrospectively reviewed. Cancer patients receiving SCH and BTO opioids for ≥24 h were eligible for inclusion. Patient demographics and clinical characteristics, including the type and route of SCH and BTO opioids, daily opioid doses (MEDDs) of SCH and BTO, and BTO/SCH ratios were reviewed in patients seen prior to a SCC (pre-SCC) and during a SCC. A normal BTO ratio was defined as 0.5-0.2. Results: A total of 665/728 (91%) patients were evaluable. Median pain scores (p < 0.001), BTO MEDDs (p < 0.001), scheduled opioid MEDDs (p < 0.0001), and total MEDDs (p < 0.0001) were higher, but the median number of BTO doses was fewer (2 vs. 4, p < 0.001), among patients seen at SCC compared to pre-SCC. A BTO/SCH ratio over the recommended ratio (>0.2) was seen in 37.5% of patients. The BTO/SCH ratios in the pre-SCC and SCC groups were 0.10 (0.04, 0.21) and 0.17 (0.10, 0.30), respectively, p < 0.001. Hydromorphone and Morphine were the most common BTO and SCH opioids prescribed, respectively. Patients in the early supportive care group had higher pain scores and MEDDs. Conclusions: BTO/SCH ratios are frequently prescribed higher than the recommended dose. Daily pain scores, BTO MEDDs, scheduled opioid MEDDs, and total MEDDs were higher among the SCC group than the pre-SCC group, but the number of BTO doses/day was lower.

Frequency of and Factors Associated With Nonmedical Opioid Use Behavior Among Patients With Cancer Receiving Opioids for Cancer Pain.

IMPORTANCE: One of the main aims of research on nonmedical opioid use (NMOU) is to reduce the frequency of NMOU behaviors through interventions such as universal screening, reduced opioid exposure, and more intense follow-up of patients with elevated risk. The absence of data on the frequency of NMOU behavior is the major barrier to conducting research on NMOU. OBJECTIVE: To determine the overall frequency of and the independent predictors for NMOU behavior. DESIGN, SETTING, AND PARTICIPANTS: In this prognostic study, 3615 patients with cancer were referred to the supportive care center at MD Anderson Cancer Center from March 18, 2016, to June 6, 2018. Patients were eligible for inclusion if they had cancer and were taking opioids for cancer pain for at least 1 week. Patients were excluded if they had no follow-up within 3 months of initial consultation, did not complete the appropriate questionnaire, or did not have scheduled opioid treatments. After exclusion, a total of 1554 consecutive patients were assessed for NMOU behavior using established diagnostic criteria. All patients were assessed using the Edmonton Symptom Assessment Scale, the Screener and Opioid Assessment for Patients with Pain (SOAPP), and the Cut Down, Annoyed, Guilty, Eye Opener-Adapted to Include Drugs (CAGE-AID) survey. Data were analyzed from January 6 to September 25, 2020. RESULTS: A total of 1554 patients (median [interquartile range (IQR)] age, 61 [IQR, 52-69] years; 816 women [52.5%]; 1124 White patients [72.3%]) were evaluable for the study, and 299 patients (19.2%) had 1 or more NMOU behaviors. The median (IQR) number of NMOU behaviors per patient was 1 (IQR, 1-3). A total of 576 of 745 NMOU behaviors (77%) occurred by the first 2 follow-up visits. The most frequent NMOU behavior was unscheduled clinic visits for inappropriate refills (218 of 745 [29%]). Eighty-eight of 299 patients (29.4%) scored 7 or higher on SOAPP, and 48 (16.6%) scored at least 2 out of 4 points on the CAGE-AID survey. Results from the multivariate model suggest that marital status (single, hazard ratio [HR], 1.58; 95% CI, 1.15-2.18; P = .005; divorced, HR, 1.43; 95% CI, 1.01-2.03; P = .04), SOAPP score (positive vs negative, HR, 1.35; 95% CI, 1.04-1.74; P = .02), morphine equivalent daily dose (MEDD) (HR, 1.003; 95% CI, 1.002-1.004; P < .001), and Edmonton Symptom Assessment Scale pain level (HR, 1.11; 95% CI, 1.06-1.16; P < .001) were independently associated with the presence of NMOU behavior. In recursive partition analysis, single marital status, MEDD greater than 50 mg, and SOAPP scores greater than 7 were associated with a higher risk (56%) for the presence of NMOU behavior. CONCLUSIONS AND RELEVANCE: This prognostic study of patients with cancer taking opioids for cancer pain found that 19% of patients developed NMOU behavior within a median duration of 8 weeks after initial supportive care clinic consultation. Marital status (single or divorced), SOAPP score greater than 7, higher levels of pain severity, and MEDD level were independently associated with NMOU behavior. This information will assist clinicians and investigators designing clinical and research programs in this important field.

Sedation Practices and Preferences of Turkish Intensive Care Physicians: A National Survey.

OBJECTIVE: Sedation is one of the most common practices applied in the intensive care units (ICUs), and the management of sedation, analgesia and delirium is a quality measure in the ICUs. Several guidelines on sedation had been published, and many surveys investigated the practices of sedation in the ICUs, but knowledge on the sedation practices in Turkey is lacking. The aim of the present study was to provide baseline knowledge on the sedation practices and preferences of Turkish intensive care physicians and to establish some points to be improved. METHODS: An electronic survey form consisting of 34 questions was generated and posted to email addresses. The survey included questions about demographics and practices on sedation, analgesia, neuromuscular blockage and delirium. RESULTS: Of 1700 email addresses, 429 (25.0%) were returned. Sedation was practised by 98.0% of the respondents, and mechanical ventilation was indicated as the primary indication (94.0%) for sedation. The presence of a written sedation protocol was 37.0%. For drug choices for sedation, midazolam was the most preferred agent (90.0%). With regard to pain questions, the most commonly used evaluation tool was Visual Analogue Scale (69.0%), and the most preferred drug was tramadol. Nearly half of the participants routinely evaluated delirium and used the confusion assessment method in the ICU. CONCLUSION: The results of this survey have indicated some areas to be improved, and a national guideline should be prepared taking pain, agitation and delirium in focus. ClinicalTrials.gov ID: NCT03488069.

Factors associated with acute and chronic pain after inguinal herniorraphy.

OBJECTIVES: The aim of this study was to analyse the relationship between types of anaesthesia, patients' demographic variables, preoperative emotional states and the prevalence of postoperative pain. METHOD: In this randomized prospective study, postoperative pain was assessed in 100 patients, who were ASA (American Society of Anaesthesiologist) I-II and between 18-65 years old, undergoing inguinal herniorrhaphy with either general or spinal anaesthesia. In addition, postoperative pain compared with patients' demographic properties and psychological conditions in each group was also considered. Acute pain was evaluated at 1, 2, 4, 6, 12 and 24th hours with the Numerical Rating Scale (NRS) and chronic neuropathic pain was at 1, 2 and 3rd months with Douleur Neuropathique 4 Questions (DN4). All patients were treated with the same analgesics after operation. RESULTS: Group spinal anaesthesia had lower acute pain at 1 and 2nd hours but they felt more severe pain at the 24th hour. Also patients' anxieties were correlated with acute and chronic postoperative pain. Ten patients complained about postoperative chronic pain after 3 months and there was no significant difference between groups. CONCLUSION: Spinal anaesthesia decreased acute pain intensity at the first postoperative hours. Patients with anxiety felt high pain levels and they had an increased chronic pain prevalence.

A novel combination treatment for breast cancer cells involving BAPTA-AM and proteasome inhibitor bortezomib.

Glucose-regulated protein 78 kDa/binding immunoglobulin protein (GRP78/BIP) is a well-known endoplasmic reticulum (ER) chaperone protein regulating ER stress by facilitating protein folding, assembly and Ca2+ binding. GRP78 is also a member of the heat shock protein 70 gene family and induces tumor cell survival and resistance to chemotherapeutics. Bortezomib is a highly specific 26S proteasome inhibitor that has been approved as treatment for patients with multiple myeloma. The present study first examined the dose- and time-dependent effects of bortezomib on GRP78 expression levels in the highly metastatic mouse breast cancer 4T1 cell line using western blot analysis. The analysis results revealed that GRP78 levels were significantly increased by bortezomib at a dose as low as 10 nM. Time-dependent experiments indicated that the accumulation of GRP78 was initiated after a 24 h incubation period following the addition of 10 nM bortezomib. Subsequently, the present study determined the half maximal inhibitory concentration of intracellular calcium chelator BAPTA-AM (13.6 µM) on 4T1 cells. The combination effect of BAPTA-AM and bortezomib on the 4T1 cells was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and WST-1 assays and an iCELLigence system. The results revealed that the combination of 10 nM bortezomib + 5 µM BAPTA-AM is more cytotoxic compared with monotherapies, including 10 nM bortezomib, 1 µM BAPTA-AM and 5 µM BAPTA-AM. In addition, the present results revealed that bortezomib + BAPTA-AM combination causes cell death through the induction of apoptosis. The present results also revealed that bortezomib + BAPTA-AM combination-induced apoptosis is associated with a clear increase in the phosphorylation of stress-activated protein kinase/Jun amino-terminal kinase SAPK/JNK. Overall, the present results suggest that bortezomib and BAPTA-AM combination therapy may be a novel therapeutic strategy for breast cancer treatment.

Anticancer agent ukrain and bortezomib combination is synergistic in 4T1 breast cancer cells.

The identification and in-depth understanding of intracellular signalling pathways led to the synthesis and discovery of many agents targeting cancer cells. In this study, we investigated for the first time the effect of anticancer agent ukrain as a single agent or in combination with cisplatin, etoposide, 5-fluorouracil, quercetin and bortezomib in 4T1 breast cancer and B16F10 melanoma cells. It was found that ukrain is cytotoxic and apoptotic in 4T1 breast carcinoma and B16F10 melanoma cells when given alone. The IC50 value of ukrain in 4T1 cells was found as 40 ± 6.8 µM and that in B16F10 cells as 76 ± 10 µM. It was then found that apoptosis can be induced in 4T1 breast cancer cells in a dose-dependent manner in response to ukrain treatment, based on DNA fragmentation evidence. The induction of apoptosis was corroborated by the analysis of cleavage products of caspase-3 in 4T1 cells using Western blot technique. When ukrain was tested in combination with cisplatin and etoposide, no significant enhancement of cytotoxicity was detected as compared with single agent treatments. Similarly, 5-fluorouracil and quercetin also did not potentiate the cytotoxic effects of ukrain in 4T1 cells. Finally, we examined the effect of various concentrations of ukrain in combination with 10 nM bortezomib in 4T1 cells. Determination of combination index values showed that bortezomib potentiated the effect of ukrain. And the combination was found to cause synergistic cell death. The lowest combination index detected was 0.57 which was obtained when the cells were treated with 10 nM bortezomib + 100 µM ukrain. Likewise, when cells were treated with different doses of bortezomib in the presence of 25 µM ukrain, synergism was similarly detected between the two drugs in a dose-dependent manner. Altogether, the results presented here suggest that the combination of ukrain + bortezomib may be further evaluated and tested in clinical settings.

Chemical composition and in vitro cytotoxic activity of the essential oils of Stachys rupestris and Salvia heldreichiana, two endemic plants of Turkey.

The chemical composition of the essential oils of two endemic plants of Turkey, Stachys rupestris Montbret et Aucher ex Benth. and Salvia heldreichiana Boiss. ex Benth., were obtained by hydrodistillation and studied by GC and GC-MS. In all, 46 compounds were identified, 22 for S. rupestris accounting for 94.6% of the total oil and 30 for S. heldreichiana, accounting for 91.9% of the total oil. The presence of diterpenoids (50.7%) characterized the oil from S. rupestris, while S. heldreichiana oil was rich in oxygenated sesquiterpenes (78.9%).The essential oils were evaluated for their in vitro potential cytotoxic activity on three human cancer cell lines. The oil of S. rupestris showed the higher antiproliferative activity against PC-3 and MCF-7 cancer cell lines.