Nevin Manimala

RMD Open. 2023 Aug;9(3):e003268. doi: 10.1136/rmdopen-2023-003268.

ABSTRACT

OBJECTIVES: To evaluate the efficacy and safety of ustekinumab (UST) in a multicentre, randomised, double-blind, placebo-controlled trial in adult Japanese patients with active polymyositis (PM) and dermatomyositis (DM).

METHODS: Fifty-one Japanese adults diagnosed with active PM/DM who did not respond adequately to one or more standard-of-care treatments were randomised 1:1 to receive UST (n=25) or placebo (n=26). Participants received body weight-range based intravenous administration of UST (6 mg/kg) or placebo at week 0 followed by 90 mg subcutaneous (SC) administration of UST or placebo every 8 weeks from week 8 to week 24. At week 24, placebo group crossed over to receive body weight-range based intravenous administration of UST, and thereafter, all participants received/were to receive SC administration of UST 90 mg every 8 weeks (week 32 through to week 72). The primary efficacy endpoint was the proportion of participants who achieved minimal improvement (≥20) in the International Myositis Assessment and Clinical Studies Total Improvement Score (IMACS TIS) at week 24.

RESULTS: No statistically significant difference was seen in the proportion of participants who achieved minimal improvement (≥20) in IMACS TIS at week 24 between the treatment groups (UST 64.0% vs placebo 61.5%, p=0.94) based on the primary estimand of the primary endpoint analysis.

CONCLUSIONS: UST was safe and well tolerated but did not meet the primary efficacy endpoint in adult Japanese participants with active PM/DM based on the primary analysis at week 24 in the study.

TRIAL REGISTRATION NUMBER: NCT03981744.

PMID:37652554 | DOI:10.1136/rmdopen-2023-003268

J Nucl Med. 2023 Aug 31:jnumed.123.265642. doi: 10.2967/jnumed.123.265642. Online ahead of print.

ABSTRACT

Molecular markers are of increasing importance for classifying, treating, and determining the prognosis for central nervous system tumors. Isocitrate dehydrogenase (IDH) is a critical regulator of glucose and amino acid metabolism. Our objective was to investigate metabolic reprogramming of glioma using compartmental uptake (CU) characteristics in O-(2-¹⁸F-fluoroethyl)-l-tyrosine (FET) PET and to evaluate its diagnostic potential for IDH genotyping. Methods: Between 2017 and 2022, patients with confirmed glioma were preoperatively investigated using static ¹⁸F-FET PET. Metabolic tumor volume (MTV), MTV for 60%-100% uptake (MTV₆₀), and T2-weighted and contrast-enhancing lesion volumes were automatically segmented using U-Net neural architecture and isocontouring. Volume intersections were determined using the Dice coefficient. Uptake characteristics were determined for metabolically defined compartments (central [80%-100%] and peripheral [60%-75%] areas of ¹⁸F-FET uptake). CU ratio was defined as the fraction between the peripheral and central compartments. Mean target-to-background ratio was calculated. Comparisons were performed using parametric and nonparametric tests. Receiver-operating-characteristic curves, regression, and correlation were used for statistical analysis. Results: In total, 52 participants (male, 27, female, 25; mean age ± SD, 51 ± 16 y) were evaluated. MTV₆₀ was greater and distinct from contrast-enhancing lesion volume (P = 0.046). IDH-mutated tumors presented a greater volumetric CU ratio and SUV CU ratio than IDH wild-type tumors (P < 0.05). Volumetric CU ratio determined IDH genotype with excellent diagnostic performance (area under the curve [AUC], 0.88; P < 0.001) at more than 5.49 (sensitivity, 86%, specificity, 90%), because IDH-mutated tumors presented a greater peripheral metabolic compartment than IDH wild-type tumors (P = 0.045). MTV₆₀ and MTV were not suitable for IDH classification (P > 0.05). SUV CU ratio (AUC, 0.72; P = 0.005) and target-to-background ratio (AUC, 0.68; P = 0.016) achieved modest diagnostic performance-inferior to the volumetric CU ratio. Furthermore, the classification of loss of heterozygosity of chromosomes 1p and 19q (AUC, 0.75; P = 0.019), MGMT promoter methylation (AUC, 0.70; P = 0.011), and ATRX loss (AUC, 0.73; P = 0.004) by amino acid PET was evaluated. Conclusion: We proposed parametric ¹⁸F-FET PET as a noninvasive metabolic biomarker for the evaluation of CU characteristics, which differentiated IDH genotype with excellent diagnostic performance, establishing a critical association between spatial metabolic heterogeneity, mitochondrial tricarboxylic acid cycle, and genomic features with critical implications for clinical management and the diagnostic workup of patients with central nervous system cancer.

PMID:37652542 | DOI:10.2967/jnumed.123.265642

J Nucl Med. 2023 Aug 31:jnumed.123.265853. doi: 10.2967/jnumed.123.265853. Online ahead of print.

ABSTRACT

Predictive biomarkers of response to human epidermal growth factor receptor 2 (HER2)-directed therapy are essential to inform treatment decisions. The TBCRC026 trial reported that early declines in tumor SUVs corrected for lean body mass (SUL_max) on ¹⁸F-FDG PET/CT predicted a pathologic complete response (pCR) to HER2 therapy with neoadjuvant trastuzumab and pertuzumab (HP) without chemotherapy in estrogen receptor (ER)-negative, HER2-positive breast cancer. We hypothesized that ¹⁸F-FDG PET/CT SUL_max parameters would predict recurrence-free survival (RFS) and overall survival (OS). Methods: Patients with stage II/III ER-negative, HER2-positive breast cancer received neoadjuvant HP (n = 88). pCR after HP alone was 22% (18/83), additional nonstudy neoadjuvant therapy was administered in 28% (25/88), and the majority received adjuvant therapy per physician discretion. ¹⁸F-FDG PET/CT was performed at baseline and at cycle 1, day 15 (C1D15). RFS and OS were summarized using the Kaplan-Meier method and compared between subgroups using logrank tests. Associations between ¹⁸F-FDG PET/CT (≥40% decline in SUL_max between baseline and C1D15, or C1D15 SUL_max ≤ 3) and pCR were evaluated using Cox regressions, where likelihood ratio CIs were reported because of the small numbers of events. Results: Median follow-up was 53.7 mo (83/88 evaluable), with 6 deaths and 14 RFS events. Estimated RFS and OS at 3 y was 84% (95% CI, 76%-92%) and 92% (95% CI, 87%-98%), respectively. A C1D15 SUL_max of 3 or less was associated with improved RFS (hazard ratio [HR], 0.36; 95% CI, 0.11-1.05; P = 0.06) and OS (HR, 0.14; 95% CI, 0.01-0.85; P = 0.03), the latter statistically significant. The association of an SUL_max decline of at least 40% (achieved in 59%) with RFS and OS did not reach statistical significance. pCR was associated with improved RFS (HR, 0.25; 95% CI, 0.01-1.24; P = 0.10) but did not reach statistical significance. Conclusion: For the first time, we report a potential association between a C1D15 SUL_max of 3 or less on ¹⁸F-FDG PET/CT and RFS and OS outcomes in patients with ER-negative, HER2-positive breast cancer receiving neoadjuvant HP alone. If confirmed in future studies, this imaging-based biomarker may facilitate early individualization of therapy.

PMID:37652539 | DOI:10.2967/jnumed.123.265853

Int J Gynecol Cancer. 2023 Aug 31:ijgc-2023-004621. doi: 10.1136/ijgc-2023-004621. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the safety and the effectiveness of thoracic epidural analgesia as part of the enhanced recovery after surgery (ERAS) multimodal analgesic protocol in patients with gynecologic oncology who have undergone laparotomy for suspected or confirmed malignancy.

METHODS: We conducted a prospective cohort study, following an enhanced recovery after surgery pathway, among patients who had undergone laparotomy for confirmed or suspected gynecological malignancy between January 2020 and September 2021. All patients who underwent laparotomy at the gynecologic oncology department for the aforementioned reason during that time were considered eligible. Patients (n=217) were divided into two groups: epidural (n=118) and non-epidural (n=99) group. Both groups were treated with the standard ERAS departmental analgesic protocol. The primary outcomes were length of hospital stay, complications, and readmission rates.

RESULTS: Data from 217 patients (epidural group, n=118 vs non-epidural group, n=99) with median age of 61 years (IQR 53-68) were analyzed. The most common type of cancer was of ovarian origin (85/217, 39.2%, p=0.055) and median (Aletti) surgical complexity score was 3 (p=0.42). No differences were observed in the patients’ demographics, clinical, and surgical characteristics. Primarily, median length of stay was 4 days in both groups with statistically significant lower IQR in the epidural group (3-5 vs 4-5, p=0.021). Complication rates were more common in the non-epidural group (38/99, 38.3% vs 36/118, 30.5%, p<0.001) with similar rates of grade III (p=0.51) and IV (0%) complications and readmission rates (p=0.51) between the two groups. Secondarily, the epidural group showed lower pain scores (p<0.001) on the day of surgery and in the first post-operative day (p<0.001), higher mobilization rates on the day of surgery (94.1% vs 57.6%, p<0.001), faster removal of urinary catheter (p<0.001), shorter time to flatus (p<0.001), and less nausea on the day of surgery (p<0.001).

CONCLUSION: In this study we showed that thoracic epidural analgesia, when used as part of an ERAS protocol, is safe and offers more favorable pain relief along with a number of additional benefits, improving the peri-operative experience of patients with gynecologic cancer.

PMID:37652530 | DOI:10.1136/ijgc-2023-004621

In Vivo. 2023 Sep-Oct;37(5):2244-2252. doi: 10.21873/invivo.13326.

ABSTRACT

BACKGROUND/AIM: The aim of this study was to evaluate patient preferences regarding cervical dysplasia clinics. Specifically, preferences in terms of diagnostic and therapeutic pathways as well as logistical and structural aspects were addressed to recognize unmet needs and improve existing structures of cervical dysplasia care.

PATIENTS AND METHODS: This questionnaire-based study was conducted between June and December 2022 at an academic medical center in Southwestern Germany. A total of 226 patients who had an appointment at the certified dysplasia clinic were included.

RESULTS: The vast majority of patients (74.8%) preferred counseling at the certified dysplasia clinic in the case of an abnormal finding of the cervix or labia. A prompt appointment (within a maximum of 4 weeks), a timely notification about test results (within a maximum of 2 weeks), a travel time <60 minutes and seeing the same doctor during follow-up appointments were recognized as important aspects. While about half of the patients (53.5%) were indifferent to the sex of the gynecologist, almost all of the remaining patients stated they would prefer to be seen by a female doctor (44.3% female doctor vs. 2.2% male doctor).

CONCLUSION: Most women expect very timely appointments and result notifications. Moreover, they favor short travel times and continuity of care. The identified patient preferences should be considered to increase patient satisfaction and quality of care when developing and optimizing management at specialized dysplasia clinics.

PMID:37652527 | DOI:10.21873/invivo.13326

In Vivo. 2023 Sep-Oct;37(5):2219-2223. doi: 10.21873/invivo.13322.

ABSTRACT

BACKGROUND/AIM: To investigate the possible association of kisspeptin levels with the ovarian reserves of women of reproductive age.

PATIENTS AND METHODS: Eighty women aged 19-40 participated after signing an informed consent. Of these, 74 were finally included as in 6 women the blood samples were considered inappropriate due to hemolysis. They were divided into three main groups according to their ovarian reserve patterns: women with adequate ovarian reserves (Group A – AOR) (n=30), women with increased ovarian reserves (Group B – PCOS) (n=31), and women with diminished ovarian reserves (Group C – DOR) (n=13).

RESULTS: Women with diminished ovarian reserves had statistically significantly increased age and FSH compared to the other two groups. No statistically significant difference was found between the three groups for estradiol and thyroid stimulating hormone. Moreover, body mass index, luteinizing hormone, total testosterone, 17-hydroxyprogesterone, dehydroepiandrosterone, anti-Mullerian hormone (AMH), and antral follicle count (AFC) were increased in group B compared to the other two groups. AMH and AFC were decreased in women with diminished ovarian reserves compared to the other two groups, as expected. The comparison of kisspeptin levels between the three groups showed that kisspeptin levels were increased in women with diminished ovarian reserves, compared to the other two groups, but without a statistically significant difference. However, kisspeptin levels in group C were statistically significantly higher than those in group A.

CONCLUSION: There are no strong indications that kisspeptin levels are associated with the ovarian reserve in women of reproductive age.

PMID:37652519 | DOI:10.21873/invivo.13322

In Vivo. 2023 Sep-Oct;37(5):2371-2380. doi: 10.21873/invivo.13342.

ABSTRACT

BACKGROUND/AIM: Osteoarthritis is one of the most common degenerative conditions that causes pain, stiffness, and decreased functionality. The management of knee osteoarthritis necessitates collaboration among specialists from different disciplines, considering the primary clinical manifestations and functional level of the disease. The aim of this study was to highlight the disparities in postoperative outcomes between knee arthroplasty procedures with and without non-steroidal anti-inflammatory drugs (NSAIDs). The study specifically focuses on the immediate advantages and outcomes observed at the 6-month milestone.

PATIENTS AND METHODS: This study followed 713 patients who were randomly divided into two groups: a group that did not receive non-steroidal anti-inflammatory drugs (N-NSAIDs) consisting of 394 patients, and a group that received non-steroidal anti-inflammatory drugs (NSAIDs) comprising 319 patients. The study spanned a duration of 5 years (2018-2022), with patients being followed and evaluated for up to 6 months after the surgery.

RESULTS: It was observed that, from a therapeutic standpoint, the use of injectable treatments decreased. Significantly better differences were recorded in the N-NSAIDs group regarding return to pre-osteoarthritis activities at 6 months and reduced or absent night pain at 3 months (p<0.05).

CONCLUSION: Statistically significant improvements were observed in the N-NSAIDs group concerning the ability to resume pre-osteoarthritis activities within 6 months, as well as a reduction or absence of nighttime pain within 3 months.

PMID:37652499 | DOI:10.21873/invivo.13342

In Vivo. 2023 Sep-Oct;37(5):2365-2370. doi: 10.21873/invivo.13341.

ABSTRACT

BACKGROUND/AIM: Studies have suggested that benefits of definitive radiotherapy might be limited to specific patients in clinically lymph node positive (cN1) prostate cancer (PC). However, the beneficial subgroup remains to be elucidated. This study aimed to analyze survival outcomes and prognostic factors after definitive radiotherapy and androgen deprivation therapy (definitive RT+ADT) in these patients and to define subgroups of patients who would benefit from definitive RT+ADT the most.

PATIENTS AND METHODS: A total of 60 patients with cN1 PC treated with definitive RT+ADT in a single tertiary hospital were accrued. Their clinicopathological variables were analyzed and a new subgroup was identified based on statistically significant variables.

RESULTS: At a median follow-up of 31 months, ADT duration ≥24 months (p=0.043, HR=0.26) and positive biopsy core ≥75% (p=0.044, HR=5.29) showed significant relationships with distant metastasis-free survival. Overall survival showed significant relationships with ADT duration ≥24 months (p=0.002, HR=0.06) and number of lymph node (LN) metastases ≥4 (p=0.019, HR=7.17). For prognostic subgroup analysis, patients were divided into three risk groups: low-risk group (LN metastases <4 and ADT ≥24 months), high-risk group (LN metastases ≥4 and ADT <24 months), and intermediate-risk group (all remaining cases). Three-year actuarial overall survival rates for the low-, intermediate-, and high-risk groups were 100%, 93.3%, and 45.7%.

CONCLUSION: ADT duration and number of LN metastases were important prognostic factors in patients with cN1 PC receiving definitive RT+ADT, with low-risk cN1 PC patients showing better outcomes than others.

PMID:37652494 | DOI:10.21873/invivo.13341

Age Ageing. 2023 Aug 1;52(8):afad159. doi: 10.1093/ageing/afad159.

ABSTRACT

OBJECTIVE: To develop a prognostic model of 1-year mortality for individuals aged 65+ presenting at the emergency department (ED) with a fall based on health care spending patterns to guide clinical decision-making.

DESIGN: Population-based cohort study (n = 35,997) included with a fall in 2013 and followed 1 year.

METHODS: Health care spending indicators (dynamical indicators of resilience, DIORs) 2 years before admission were evaluated as potential predictors, along with age, sex and other clinical and sociodemographic covariates. Multivariable logistic regression models were developed and internally validated (10-fold cross-validation). Performance was assessed via discrimination (area under the receiver operating characteristic curve, AUC), Brier scores, calibration and decision curve analysis.

RESULTS: The AUC of age and sex for mortality was 72.5% [95% confidence interval 71.8 to 73.2]. The best model included age, sex, number of medications and health care spending DIORs. It exhibited high discrimination (AUC: 81.1 [80.5 to 81.6]), good calibration and potential clinical benefit for various threshold probabilities. Overall, health care spending patterns improved predictive accuracy the most while also exhibiting superior performance and clinical benefit.

CONCLUSIONS: Patterns of health care spending have the potential to significantly improve assessments on who is at high risk of dying following admission to the ED with a fall. The proposed methodology can assist in predicting the prognosis of fallers, emphasising the added predictive value of longitudinal health-related information next to clinical and sociodemographic predictors.

PMID:37651750 | DOI:10.1093/ageing/afad159

SAR QSAR Environ Res. 2023 Jul-Sep;34(8):639-659. doi: 10.1080/1062936X.2023.2247326.

ABSTRACT

2,4-Disubstituted quinoline derivatives were designed based on a 3D-QSAR study, synthesized and evaluated for antimalarial activity. A large dataset of 178 quinoline derivatives was used to perform a 3D-QSAR study using CoMFA and CoMSIA models. PLS analysis provided statistically validated results for CoMFA (r²_ncv = 0.969, q² = 0.677, r²_cv = 0.682) and CoMSIA (r²_ncv = 0.962, q² = 0.741, r²_cv = 0.683) models. Two series of a total of 40 2,4-disubstituted quinoline derivatives were designed with amide (quinoline-4-carboxamide) and secondary amine (4-aminoquinoline) linkers at the -C4 position of the quinoline ring. For the purpose of selecting better compounds for synthesis with good pEC₅₀ values, activity prediction was carried out using CoMFA and CoMSIA models. Finally, a total of 10 2,4-disubstituted quinoline derivatives were synthesized, and screened for their antimalarial activity based on the reduction of parasitaemia. Compound #5 with amide linker and compound #19 with secondary amine linkers at the -C4 position of the quinoline ring showed maximum reductions of 64% and 57%, respectively, in the level of parasitaemia. In vivo screening assay confirmed and validated the findings of the 3D-QSAR study for the design of quinoline derivatives.

PMID:37651746 | DOI:10.1080/1062936X.2023.2247326