Unfavorable Patients Research Articles

The expression of ERAP1 is favorable for the prognosis and immunotherapy in colorectal cancer: a study based on the bioinformatic and immunohistochemical analysis.

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an emerging pharmacological target in cancer immunotherapy. This study was set out to examine the expression profiles and implications for prognosis and immunotherapy of ERAP1 in CRC. Based on bioinformatics and immunohistochemical analysis, we analyzed ERAP1 for potential diagnostic and prognostic significance in CRC. Functional enrichment analysis was conducted to detect the pathways associated with ERAP1, thus determining possible mechanisms. ESTIMATE, TIMER, and CIBESORT probed the links between ERAP1 and tumor-infiltrating immune cells. Lastly, we examined how ERAP1 expression correlated with the sensitivity to immunotherapy. Tumor tissues had decreased levels of ERAP1 expression relative to normal tissues. Patients whose ERAP1 expression was low suffered a worse chance of survival. Besides, it was shown that ERAP1 expression was associated with the advanced M stage and pathologic stage. Survival analysis revealed that low ERAP1 expression, age, pathologic stage, T stage, and M stage were independent indicators for unfavorable CRC patients' prognoses. The 1-, 3-, and 5-year OS calibration curves all fit well with the ideal model, suggesting that the age-ERAP1-T-stage-M-stage nomogram is a reliable predictor of OS. Additionally, we discovered that ERAP1 expression was associated with immune response and infiltration of various immune cells, such as down-regulated inhibitory immune cells and up-regulated stimulating immune cells. Sensitivity to PD-1 and CTLA4 inhibitors was associated with high ERAP1 levels. In summary, ERAP1 has potential as a diagnostic and prognostic biological marker, highlighting new insights into the study of CRC and the design of effective therapies.

Hematological Parameters in Patients with Pulmonary Tuberculosis and its Presentation among Favorable and Unfavorable Treatment Outcomes.

Tuberculosis (TB) management continues to be a challenge globally; weakened immunity plays a significant role in the reactivation of TB. There is limited information on hematological parameters in patients with pulmonary TB and its association with outcome. We present hematological parameters of newly diagnosed sputum-positive pulmonary TB patients enrolled in a randomized, clinical trial that assessed the efficacy and safety of 3 and 4 regimens using moxifloxacin. Blood hematological parameters at baseline, comparison of the baseline and end of treatment values, including the monocytes by lymphocytes ratio (M/L), neutrophil lymphocyte ratio (N/L), and platelet lymphocyte ratio (P/L) between the patients with favorable and unfavorable TB treatment outcome, and among different age group and sex presented in this paper. Among the total 1059 patients, 782 were males, the mean hemoglobin (HB) ± standard deviation (SD) was 11.5 g/dL ± 2.0, the mean white blood cell (WBC) count ± SD was 9800 ± 3009 and the mean platelet count (in lakhs) ± SD was 4.24 ± 1.42 cells/uL. There was an increase from baseline in the mean hemoglobin, eosinophil, and lymphocyte count and a decrease in mean neutrophil, monocyte counts to the end of treatment. There was a decrease in baseline mean total WBC count posttreatment, both in favorable (10,271 cells/uL ± 3007 SD to 6689 cells/uL ± 1837 SD, [P ≤ 0.001]), and unfavorable TB outcome patients. An increase in HB, and a decrease in WBC count, M/L, N/L, and P/L ratio is possible at the end of TB treatment and future studies to correlate blood hematology parameters with TB treatment outcome.

Association of Postarrest Hypotension Burden With Unfavorable Neurologic Outcome After Pediatric Cardiac Arrest.

Quantify hypotension burden using high-resolution continuous arterial blood pressure (ABP) data and determine its association with outcome after pediatric cardiac arrest. Retrospective observational study. Academic PICU. Children 18 years old or younger admitted with in-of-hospital or out-of-hospital cardiac arrest who had invasive ABP monitoring during postcardiac arrest care. None. High-resolution continuous ABP was analyzed up to 24 hours after the return of circulation (ROC). Hypotension burden was the time-normalized integral area between mean arterial pressure (MAP) and fifth percentile MAP for age. The primary outcome was unfavorable neurologic status (pediatric cerebral performance category ≥ 3 with change from baseline) at hospital discharge. Mann-Whitney U tests compared hypotension burden, duration, and magnitude between favorable and unfavorable patients. Multivariable logistic regression determined the association of unfavorable outcomes with hypotension burden, duration, and magnitude at various percentile thresholds from the 5th through 50th percentile for age. Of 140 patients (median age 53 [interquartile range 11-146] mo, 61% male); 63% had unfavorable outcomes. Monitoring duration was 21 (7-24) hours. Using a MAP threshold at the fifth percentile for age, the median hypotension burden was 0.01 (0-0.11) mm Hg-hours per hour, greater for patients with unfavorable compared with favorable outcomes (0 [0-0.02] vs. 0.02 [0-0.27] mm Hg-hr per hour, p < 0.001). Hypotension duration and magnitude were greater for unfavorable compared with favorable patients (0.03 [0-0.77] vs. 0.71 [0-5.01]%, p = 0.003; and 0.16 [0-1.99] vs. 2 [0-4.02] mm Hg, p = 0.001). On logistic regression, a 1-point increase in hypotension burden below the fifth percentile for age (equivalent to 1 mm Hg-hr of burden per hour of recording) was associated with increased odds of unfavorable outcome (adjusted odds ratio [aOR] 14.8; 95% CI, 1.1-200; p = 0.040). At MAP thresholds of 10th-50th percentiles for age, MAP burden below the threshold was greater in unfavorable compared with favorable patients in a dose-dependent manner. High-resolution continuous ABP data can be used to quantify hypotension burden after pediatric cardiac arrest. The burden, duration, and magnitude of hypotension are associated with unfavorable neurologic outcomes.

Abstract CT127: A macrophages-based immunotherapy of solid tumors microenvironment: Preliminary results of the TEM-GBM_01 study

Abstract Glioblastoma multiforme (GBM) is an incurable tumor affecting the central nervous system. The reported median survival in the unfavorable patients′ subgroup with unmethylated MGMT promoter is 12.7 months with less than the 15% of patient surviving up to 2–years. Despite immunotherapies being able to slow or eradicate numerous tumors, none so far have extended survival in GBM. Using genetically modified autologous CD34+ HSPCs, we developed an advance medicinal product, (Temferon) designed to deliver interferon–α2 within the TME by Tie–2 expressing macrophages (TEMs). Temferon is currently in the clinic in a Phase 1/2a dose-escalation non-randomized open label study in newly diagnosed GBM with unmethylated MGMT. The study aims to evaluate the short– (up to 90 days) and long– (up to 2 years) term tolerability and safety of 5 escalating doses in up to 27 GBM patients. Following a sub–myeloablative conditioning regimen (Thiotepa + BCNU or Thiotepa + Busulfan or Busulfan alone), up to 3 million Temferon cells/kg are administered with a fixed dose of non–manipulated CD34+ supporter cells As of 27th July 2023, 21 GBM patients in 7 cohorts received incremental Temferon doses and 5 patients were still alive with a 17 months median OS and a 8.3 months median PFS (95% CI) post surgery. To date, no DLTs have been identified. In all patients, rapid engraftment and fast hematological recovery have been observed within 2 weeks from the transplantation. Grade 4 or 5 serious adverse events (n=7 patients), were mostly attributed to the conditioning chemotherapy, but steroid usage or disease progression were also listed. 1 SUSAR (persistent GGT elevation) occurred. The higher transduced cells proportion in the BM was observed 30 days after Temferon with a chimerism for the highest dose tested up to 40%, still detectable in the long–term. Very low IFNα concentrations were detected in the plasma, indicating a tight vector expression regulation. 7 patients underwent second surgery and genetically engineered cells were detected (in 85%) within the bulk tumor lesion (&amp;gt;3% in 3 patients). IFN–responsive genes (IGS) were up–regulated, suggesting a local IFNα release by TEMs. In 1 patient, a stable lesion, compared to a synchronous, progressing lesion, had a higher proportion of T cells &amp; TEMs, an increased IGS e and myeloid re–programming. TCR blood and tumor sample sequencing showed a post–treatment increase of peripherally expanded clones frequency in the tumor samples, as evidence of a crosstalk between peripheral and tumor T cell repertoires . These data corroborate the initial evidence on safety and tolerability of Temferon and suggest that Temferon has potential to counteract disease progression in patients affected by unmethylated MGMT GBM. Clinical Trial Registry (if applicable): NCT03866109 Citation Format: Francesca Farina, Bernhard Gentner, Gaetano Finocchiaro, Marica Eoli, Alessia Capotondo, Elena Anghileri, Matteo Barcella, Valentina Brambilla, Matteo Carrabba, Valeria Cuccarini, Quintino Giorgio D'alessandris, Francesco DiMeco, Valeria Ferla, Paolo Ferroli, Filippo Gagliardi, Federico Legnani, Stefania Mazzoleni, Alessandro Olivi, Roberto Pallini, Marco Saini, Luigi Naldini, Carlo Russo, Fabio Ciceri. A macrophages-based immunotherapy of solid tumors microenvironment: Preliminary results of the TEM-GBM_01 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT127.

Lack of awareness of systemic lupus erythematosus and its consequences in a cohort of moderate and severe patients in Spain: The LupusVoice study.

Systemic lupus erythematosus (SLE) is an autoimmune condition that can highly impact patients' quality of life (QoL). However, there is a lack of knowledge about SLE, affecting the general population and health care professionals (HCPs) alike. This lack of knowledge has negative implications for patients and the healthcare system, worsening prognosis, negatively impacting QoL, and increasing healthcare utilization. The aim of this paper is to draw attention, according to the perspective of the participants of this study, to the lack of awareness of SLE and its consequences in Spain, and to suggest improvements. This qualitative, descriptive, observational, multicenter, and cross-sectional study included 40 patients with moderate or severe SLE, recruited during their routine visits in six university hospitals in Spain. The study also included 11 caregivers and 9 HCPs. All participants were individually interviewed. Data from the interviews were coded and analyzed thematically by two anthropologists following a phenomenological perspective. Our study identified a lack of disease awareness among primary care physicians, emergency medicine doctors, and other specialists treating SLE symptomatology. This led to diagnostic delays, which had a clinical and emotional impact on patients. Furthermore, symptom awareness was found to be context dependent. Differences in symptom awareness between HCPs and patients led to a mismatch between the severity evaluation made by doctors and patients. Some HCPs did not consider the limitations of the current severity evaluation of SLE, and therefore attributed symptoms potentially caused by SLE to the unfavorable socioeconomic conditions patients lived in. Finally, a lack of social awareness among friends, family members, and romantic partners led to lower social support, increased isolation, and negative physical and emotional impact for patients. Gender differences in the provision of support were identified. This study highlights the need to increase SLE awareness among patients, HCPs, and the broader public in order to improve patient QoL. Being aware of the clinical and emotional impact of such lack of awareness, as well as the role played by context on the patient experience of SLE, is a crucial step towards achieving this goal.

Clinical Characteristics of m.11778G>A Leber Hereditary Optic Neuropathy with Favorable Outcomes

ABSTRACT The prognosis of 11,778 mitochondrial mutations in Leber hereditary optic neuropathy (LHON) is poor. Patients with favorable outcomes (visual acuity better than 20/100) who could be observed for more than 6 months were analyzed. Among 74 patients (57 male, 17 female), 6 (8.1%) showed improvement in visual acuity of 20/100 or higher. The patients with favorable outcomes have better visual acuity at nadir (logMAR 0.98 ± 0.69 in the favorable patients and logMAR 2.32 ± 0.93 in the unfavorable patients, p = .003). Among the favorable group, four patients (36, 32, 19, and 7 years of age at onset) took idebenone within 6 months of onset. However, fifty-one percent of the patients with unfavorable outcomes took idebenone (p = .008). Although the age at onset in the favorable patients is relatively younger than that of the unfavorable patients (20.3 ± 10.8 versus 28.8 ± 12.8 years), a significant difference was not found (p = .138). In conclusion, better visual acuity in nadir and administration of idebenone may affect vision recovery.

Identification of At-Risk Patients That Need More Intensive Treatment Following mTBI: Post-Hoc Insights From the UPFRONT-Study.

To investigate which factors within an at-risk group make patients less likely to benefit from preventive treatment following mild traumatic brain injury (mTBI). Inclusion in 3 level I trauma centers in the Netherlands. Data collection through surveys as outpatients. mTBI patients (18-66 years), reporting 3 or more complaints 2 weeks postinjury (at-risk status). Eighty-four patients included and randomized (39 patients cognitive behavioral therapy, 45 patients telephonic counseling). Eighty patients filled out the questionnaires 12 months postinjury. Post hoc analysis investigating 80 patients as 1 at-risk group receiving psychological treatment. Post hoc study of a randomized controlled trial (RCT). Binomial logistic regression performed determining which variables 2 weeks postinjury contributed strongly to unsuccessful return to work/study (RTW) and unfavorable outcome at 12 months. RTW and functional outcome as measured with the Glasgow Outcome Scale-Extended (GOSE) at 12 months postinjury. Out of 80 patients, 43 (53.8%) showed a favorable functional outcome at 12 months, and 56 (70%) patients had a full RTW. Patients with unfavorable outcome had a higher age and higher reports of anxiety, depression at 2 weeks and 12 months postinjury. Patients with an unsuccessful RTW had a higher age and higher reports of depression, and posttraumatic stress disorder at 2 weeks and 12 months postinjury. A logistic regression model for functional outcome (GOSE) was statistically significant (χ² 7 = 40.30, P < .0001). Of 6 predictor variables, 3 were significant: anxiety, depression, and treatment condition. For RTW, logistic regression was also statistically significant (χ² 7 = 19.15, P = .008), with only 1 out of 6 predictor variables (ie, age) being significant. Main findings comprise differences in demographic and psychological measures between patients with favorable and unfavorable outcomes and patients with RTW versus no RTW. Prediction models of outcome and RTW showed several psychological measures at 2 weeks greatly determining patients' likelihood benefitting from the preventive treatment. Results suggest that from the beginning there are some patients for whom a short preventive treatment is not sufficient. Selection and treatment of at-risk patients might be better based on psychological symptoms instead of posttraumatic complaints.

The roles of phosphorylation of signaling proteins in the prognosis of acute myeloid leukemia.

Signaling pathways of Retinoblastoma (Rb) protein, Akt-kinase, and Erk-kinase (extracellular signal-regulated kinase) have an important role in the pathogenesis of acute myeloid leukemia. Constitutive activation of these proteins by phosphorylation contributes to cell survival by regulation of cell cycle, proliferation and proapoptotic signaling processes. According to previous data phosphorylated forms of these proteins represent a worse outcome for cancer patients. We investigated the presence of phosphorylated Rb (P-Rb), Akt (P-Akt) and Erk (P-Erk) proteins by Western blot technique using phospho-specific antibodies in bone marrow or peripheral blood samples of 69 AML patients, 36 patients with myelodysplastic syndrome (MDS) and 10 healthy volunteers. Expression level of PTEN (Phosphatase and tensin homolog) and PHLPP (PH domain and leucine-rich repeat Protein Phosphatase) phosphatases, the negative regulators of Akt kinase pathway were also examined. We tested the effect of these proteins on survival and on the correlation with known prognostic features in AML. We found 46.3% of AML patients had detectable P-Rb, 34.7% had P-Akt and 28.9% had P-Erk protein. 66.1% of patients expressing PTEN, 38.9% PHLPP, 37.2% both PTEN and PHLPP and 32.2% neither PTEN nor PHLPP phosphatases. Compared to nucleophosmin mutation (NPMc) negative samples P-Erk was significantly less in nucleophosmin mutated patients, P-Rb was significantly less in patients' group with more than 30G/L peripheral leukocyte count by diagnosis. PHLPP was significantly present in FAB type M5. The expression of P-Rb represented significant better overall survival (OS), while P-Akt represented significantly worse event-free survival (EFS) in unfavorable cytogenetics patients. The presence of both PHLPP and PTEN phosphatases contributes to better OS and EFS, although the differences were not statistically significant. We confirmed significant positive correlation between P-Akt and PHLPP. Assessing the phosphorylation of Rb, Akt and Erk may define a subgroup of AML patients who would benefit especially from new targeted treatment options complemented the standard chemotherapy, and it may contribute to monitoring remission, relapse or progression of AML.

Development and internal validation of a nomogram predicting 3-year chronic kidney disease upstaging following robot-assisted partial nephrectomy.

Aim of the present study was to develop and validate a nomogram to accurately predict the risk of chronic kidney disease (CKD) upstaging at 3years in patients undergoing robot-assisted partial nephrectomy (RAPN). A multi-institutional database was queried to identify patients treated with RAPN for localized renal tumor (cT1-cT2, cN0, cM0). Significant CKD upstaging (sCKD-upstaging) was defined as development of newly onset CKD stage 3a, 3b, and 4/5. Model accuracy was calculated according to Harrell C-index. Subsequently, internal validation using bootstrapping and calibration was performed. Then nomogram was depicted to graphically calculate the 3-year sCKD-upstaging risk. Finally, regression tree analysis identified potential cut-offs in nomogram-derived probability. Based on this cut-off, four risk classes were derived with Kaplan-Meier analysis tested this classification. Overall, 965 patients were identified. At Kaplan-Meier analysis, 3-year sCKD-upstaging rate was 21.4%. The model included baseline (estimated glomerular filtration rate) eGFR, solitary kidney status, multiple lesions, R.E.N.A.L. nephrometry score, clamping technique, and postoperative acute kidney injury (AKI). The model accurately predicted 3-year sCKD-upstaging (C-index 84%). Based on identified nomogram cut-offs (7 vs 16 vs 26%), a statistically significant increase in sCKD-upstaging rates between low vs intermediate favorable vs intermediate unfavorable vs high-risk patients (1.3 vs 9.2 vs 22 vs 54.2%, respectively, p < 0.001) was observed. Herein we introduce a novel nomogram that can accurately predict the risk of sCKD-upstaging at 3years. Based on this nomogram, it is possible to identify four risk categories. If externally validated, this nomogram may represent a useful tool to improve patient counseling and management.

Marginless 5-Fraction Robotic Radiosurgery for Unfavorable Nonfunctioning Pituitary Macroadenoma: 5-year Outcomes from a Single Institution Protocol

Nonfunctioning macroadenoma is a commonly diagnosed pituitary tumor. Resection is the favored treatment, with radiosurgery often utilized for residual or progressing disease. Long-term outcomes are established for single-session radiosurgery, but mature outcomes are lacking for multisession radiosurgery. We report our institution's 5-year efficacy and safety results for unfavorable nonfunctioning pituitary macroadenoma patients treated with marginless 5-fraction robotic radiosurgery. Between 2010-2020, patients who completed marginless 5-fraction radiosurgery for the treatment of unfavorable nonfunctioning pituitary macroadenomas were included. A tumor was considered unfavorable if the gross tumor volume (GTV) was larger than 5 cc or if it closely approached a critical structure (optic apparatus, brainstem or pituitary gland). Local control was calculated using the Kaplan-Meier Method. Twenty predominately female patients (60%), age from 21-77 (median: 53 years) were included in this study. All underwent primary resection. Indications for radiosurgery included unresectable recurrence (85%) and residual disease progression (70%). Median tumor volume was 3.4 cm3 (range: 0.3-20.8 cm3) and 40% of the tumors were suprasellar. A mean dose of 28.8 Gy (range: 25 Gy-30 Gy), was delivered to a median isodose line of 80% (range: 75%-89%). The median optic chiasm maximum point dose was 21.8 Gy (range: 12.0-25.9 Gy). Toxicity was minimal with 12 patients (40%) developing acute short-lived headaches and 1 patient (5%) developing a brief ipsilateral 6th nerve palsy. There was no radiation induced optic or pituitary dysfunction identified in this cohort. At a median follow up of 5 years local control was 95%. There was 1 in-field failure pathologically confirmed following surgery for pituitary tumor hemorrhage and 2 radiographically confirmed out-of-field failures in patients with large tumors (>20 cc). The treatment of unfavorable nonfunctioning pituitary macroadenoma with marginless 5-fraction robotic radiosurgery provides excellent local control to date, with minimal toxicity. However, tumors with GTV's greater than 20 cc may require conventionally fractionated treatment with a margin to optimize local control.

Comparison of Standard vs. Relative Risk Models to Define Candidates for Deintensification in Locoregionally Advanced P16+ Oropharyngeal Cancer

Various methods to identify candidates for treatment deintensification with p16+ oropharyngeal squamous cell carcinoma (OPSCC) have been used, but the optimal approach is unknown. Multi-institutional cohort study of 385 patients with previously untreated p16+ OPSCC undergoing definitive radiotherapy (RT) with or without systemic therapy between 2009-2020. Chemotherapy intensity was categorized as high (bolus cisplatin and/or induction chemotherapy), medium (weekly cisplatin), or low (non-cisplatin or RT alone). Standard favorable vs. unfavorable risk was defined using NRG HN005 eligibility criteria. High vs. low relative risk (RR) group was defined using the HNCIG omega score (≥ 0.80 vs. < 0.80), which quantifies the proportion of a patient's overall event risk due to cancer. We used multivariable ordinal logistic regression to estimate effects of age (yrs), sex, performance status (PS), Charlson comorbidity index (CCI), T/N (AJCC 8th), current smoking, and pack-years (> 10 vs. ≤ 10) on treatment allocation. Effects on relative event hazards were estimated using generalized competing event regression. Median follow-up time was 44.2 months. Chemotherapy intensity was high in 206 (54%), medium in 108 (28%), and low in 71 (18%). 280 patients (73%) were unfavorable risk and 197 (51%) were high RR. 178 patients (46%) had discordant risk classification. On univariable analysis, significant predictors of higher intensity chemotherapy (normalized odds ratio (OR)) were CCI 0-1 (OR 1.49, 95% CI: 1.23-1.79), high omega score (OR 1.46; 1.20-1.77), decreased age (OR 1.43; 1.18-1.74), and PS 0 (OR 1.22; 1.01-1.48). Controlling for CCI, higher omega score was associated with significantly higher odds of intensive chemotherapy (OR 1.35; 1.10-1.65, but unfavorable risk (HN005 ineligibility) was not (OR 1.19; 0.98-1.44). Higher omega score was also associated with significantly higher RR for cancer recurrence (Rec) vs. competing mortality (CM) events (relative HR (rHR) 1.76; 1.12-2.75), but unfavorable risk was not (rHR 1.05; 0.63-1.75). Among patients receiving cisplatin, 50 favorable risk patients (58%) had high RR; all of their event risk was due to cancer recurrence (Table). The 110 unfavorable risk patients (48%) with low omega score had significantly lower RR for cancer events compared to the high omega score group (rHR 0.49; 0.29-0.84). Many patients with favorable risk p16+ OPSCC have high relative risk for cancer events, which correlates with a benefit of intensive treatment. The HNCIG omega score is a strong predictor of allocation to intensive chemotherapy and may help identify candidates for deintensification.

LDR-Brachytherapy monotherapy appears unsuited for NCCN unfavorable intermediate-risk prostate cancer patients

BackgroundTo validate the subdivision of intermediate-risk (IR) prostate cancer (PCa) into favorable intermediate-risk (FIR) and unfavorable intermediate-risk (UIR) PCa in a historical patient cohort and to compare 2 different radiotherapy regimens. MethodsPatients with intermediate-risk (IR) PCa, treated either by 125J-LDR-brachytherapy monotherapy (BT) or by combined-modality radiation therapy (CRT), were retrospectively subclassified into FIR and UIR and reanalyzed with regard to biochemical recurrence-free survival (BRFS), metastasis-free survival (MFS), and prostate cancer-specific survival (CSS). Kaplan-Meier product-limit method and log-rank tests were applied to estimate survival probabilities and compare survival, respectively. Uni- and multivariable analyses were performed using Cox proportional hazard regression. ResultsOf 490 IR patients, 252 had received BT (86.5% FIR, 13.5% UIR), and 238 had received CRT (30% FIR, 70% UIR). Retrospective analysis revealed that BRFS at 10 years was 81% for BT, and 94% for CRT in FIR patients. For UIR patients, BRFS at 10 years was 37% for BT, and 89% for CRT. MFS at 10 years for FIR patients was 87% for BT, and 94% for CRT. For UIR patients MFS at 10 years was 78% for BT, and 95% for CRT. In multivariable analysis treatment (BT vs. CRT) was the single associated factor for biochemical recurrence, and for metastases in the UIR group (BFRS, P < 0.001, HR 16.07 (CI 4.23–61.10); MFS, P = 0.011, HR 8.43 (CI 1.62–43.9). ConclusionsSubclassification of IR prostate cancer into FIR and UIR subcategories appears mandatory. For FIR patients, outcomes after BT monotherapy were acceptable. However, clinical failure after 125J-LDR-BT in UIR patients was notably increased, suggesting that BT monotherapy was less successful in this risk group. In contrast, the outcome in UIR patients after CRT was excellent.

Prognostic value of baseline metabolic tumor volume (MTV) for forecasting chemotherapy outcome in early-stage unfavorable Hodgkin lymphoma: Data from the phase III HD17 trial.

The prognostic relevance of metabolic tumor volume (MTV) having recently been demonstrated in patients with early-stage favorable and advanced-stage Hodgkin lymphoma. The current study aimed to assess the potential prognostic value of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in early-stage unfavorable Hodgkin lymphoma patients treated within the German Hodgkin Study Group HD17 trial. 18 F-FDG PET/CT images were available for MTV analysis in 154 cases. We used three different threshold methods (SUV2.5 , SUV4.0 , and SUV41% ) to calculate MTV. Receiver-operating-characteristic analysis was performed to describe the value of these parameters in predicting an adequate therapy response. Therapy response was evaluated as PET negativity after 2 cycles of eBEACOPP followed by 2 cycles of ABVD. All three threshold methods analyzed for MTV showed a positive correlation with the PET response after chemotherapy. Areas under the curve (AUC) were 0.70 (95% CI 0.53-0.87) and 0.65 (0.50-0.80) using the fixed thresholds of SUV4.0 and SUV2.5 , respectively, for MTV- calculation. The calculation of MTV using a relative threshold of SUV41% showed an AUC of 0.63 (0.47-0.79). MTV does have predictive value after chemotherapy in early-stage unfavorable Hodgkin lymphoma, particularly when the fixed threshold of SUV4.0 is used for MTV calculation. ClinicalTrials.gov NCT01356680.

The combination of NDUFS1 with CD4+ T cell infiltration predicts favorable prognosis in kidney renal clear cell carcinoma.

Background: Kidney renal clear cell carcinoma (KIRC) is an immunogenic tumor, and immune infiltrates are relevant to patients' therapeutic response and prognosis. NDUFS1, the core subunit of mitochondrial complex I, has been reported to be associated with KIRC patients' prognosis. However, the upstream regulator for NDUFS1 and their correlations with immune infiltration remain unclear. Methods: The expression of NDUFS genes in KIRC and their influences on patients' survival were investigated by UALCAN, ENCORI, Oncomine, TIMER as well as Kaplan-Meier Plotter. miRNAs regulating NDUFS1 were predicted and analyzed by TargetScan and ENCORI. The correlations between NDUFS1 expression and immune cell infiltration or gene marker sets of immune infiltrates were analyzed via TIMER. The overall survival in high/low NDUFS1 or hsa-miR-320b expressed KIRC patients with or without immune infiltrates were analyzed via Kaplan-Meier Plotter. The combined NDUFS1 expression and/or CD4+ T cell infiltration on KIRC patients' overall survival were validated by multiplexed immunofluorescence (mIF) staining in tissue microarray (TMA). Furthermore, the influences of NDUFS1 expression on the chemotaxis of CD4+ T cells to KIRC cells were performed by transwell migration assays. Results: We found that the low expression of NDUFS1 mRNA and protein in KIRC was correlated with unfavorable patients' survival and poor infiltration of CD4+ T cells. In patients with decreased CD4+ T cell infiltration whose pathological grade less than III, TMA mIF staining showed that low expression of NDUFS1 had significantly poor OS than that with high expression of NDUFS1 did. Furthermore, hsa-miR-320b, a possible negative regulator of NDUFS1, was highly expressed in KIRC. And, low NDUFS1 or high hsa-miR-320b consistently correlated to unfavorable outcomes in KIRC patients with decreased CD4+ T cell infiltration. In vitro, NDUFS1 overexpression significantly increased the chemotaxis of CD4+ T cell to KIRC cells. Conclusion: Together, NDUFS1, upregulated by decreased hsa-miR-320b expression in KIRC patients, might act as a biomarker for CD4+ T cell infiltration. And, the combination of NDUFS1 with CD4+ T cell infiltration predicts favorable prognosis in KIRC.

Neuroinflammation-associated miR-106a-5p serves as a biomarker for the diagnosis and prognosis of acute cerebral infarction

BackgroundAcute cerebral infarction (ACI) is a common cerebrovascular disease. Previous studies have shown that some abnormally expressed microRNAs (miRNAs) play important roles in ACI. This study aimed to investigate the role of miR-106a-5p in the diagnosis and prognosis of ACI patients, and analyze the regulatory potential of miR-106a-5p on the inflammation of BV-2 microglial cells.MethodSerum and cerebrospinal fluid (CSF) samples were collected from 98 ACI patients, and the expression of serum miR-106a-5p was analyzed using qRT-PCR. A receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic value of miR-106a-5p. The association of miR-106a-5p with ACI prognosis was evaluated using the logistic analysis. In vitro experiments were performed in BV-2 cells by oxygen glucose deprivation (OGD) treatment, and the effects of miR-106a-5p on BV-2 inflammation were assessed using an enzyme linked immunosorbent assay (ELISA).ResultIt was observed that miR-106a-5p was significantly upregulated in the serum and CSF of ACI patients (all P < 0.001), and had considerable diagnostic accuracy. The highest serum miR-106a-5p was observed in severe ACI cases, and miR-106a-5p expression was significantly increased in unfavorable prognosis patients. Serum and CSF expression of miR-106a-5p was positively correlated with proinflammatory cytokines in ACI patients, and the inflammation of OGD-induced BV-2 cells was suppressed by miR-106a-5p reduction.ConclusionMiR-106a-5p is overexpressed in ACI patients and may serve as a diagnostic and prognostic biomarker for ACI. Furthermore, miR-106a-5p may be involved in ACI progression by regulating neuroinflammation.

Comment on "Surgical Outcomes in Patients With Low-Risk Papillary Thyroid Microcarcinoma from MAeSTro Study: Immediate Operation Versus Delayed Operation Following Active Surveillance A Multicenter Prospective Cohort Study".

The overdiagnosis and overtreatment of patients with low-risk papillary thyroid microcarcinoma (PTMC) led to the initiation of active surveillance studies in many institutions. We read the recent study by Hwang et al1 in which the authors conducted a multicenter prospective cohort study and evaluated the results of surgical and clinical outcomes in patients with low-risk PTMC who chose delayed operation following active surveillance. This study is clinically relevant and novel, and we would like to raise several concerns. Although the authors demonstrated that the extent of thyroidectomy and postoperative complications did not differ between delayed operation (DOP) and immediate operation (IOP), we would like to clarify that surgical decision-making for low-risk PTMC is a complex process that must consider multiple aspects.2 In this multicenter cohort study, multi-surgeon chose the surgical extent according to their experience, skill level, own and patient preference. In this context, there is a direct relationship between surgeon experience and postoperative complications. The postoperative complication rates are low in experienced hands. This study did not standardize this factor. Therefore, the relationship between unfavorable events and patients who underwent DOP was not causal but just an association affected by confounders. Another area of considerable variation surrounds patients’ preferences. Decision-making presenting the hemithyroidectomy or total thyroidectomy (TT) should inform the patient of their downstream risk, as it could significantly impact choices. Socioeconomic differences in medical centers worldwide can also significantly affect the surgical extent between different countries, as demonstrated in Japan where hemithyroidectomy was adopted as the standard therapy over TT earlier than in other countries.3 In addition, there was a significant difference in the proportion of multifocality between patients who underwent DOP and patients who underwent IOP. Multifocality as an indicator of tumor aggressiveness manifests a higher propensity of lymphatic invasion.4 Since multifocal tumors comprised 40.9% of cases in the DOP group, will such a high proportion affect the unfavorable pathological features? Additionally, the results indicated that 109 patients were known to be multifocal papillary thyroid cancer and 109 patients underwent TT in the IOP group. There was no detailed information on how many multifocal papillary thyroid cancer patients have been identified before the operation. Multifocality is an important factor for surgeons to consider the surgical extent,5 which can further affect the incidence of postoperative complications. We believe the results should be interpreted cautiously. Last but not least, disease progression was initially defined in this study to include a size increase of ≥3 mm in at least 1 dimension, or ≥2 mm in at least 2 dimensions. But with recent advances, the researchers also found significant differences in the rate of the extent of thyroidectomy when tumor volume changes were taken into account. We want to see the data of this part of patients and the difference with the IOP group and wonder if the research team would adjust the timing of surgery for those patients in the DOP group. Therefore, we have several questions that we would appreciate having answered.

Unfavorable early-stage Hodgkin lymphoma: assessment of patient characteristics in a real-world setting.

Aim: Unfavorable prognostic factors among classical Hodgkin lymphoma (cHL) patients in the real-world setting have yet to be fully characterized. Methods: In this retrospective study using the ConcertAI Oncology Dataset, patient characteristics, unfavorable prognostic factorsand treatment patterns were evaluated among patients diagnosed with cHL. Results: Among 324 adult cHL patients diagnosed 2016-2021, 16.1% were classified as early favorable, 32.7% early unfavorableand 51.2% advanced disease. Early unfavorable patients were younger and had a larger nodal mass. The prognostic factor B symptoms was most frequently documented in early unfavorable patients (59.4%), followed by bulky disease (46.2%), >3 involved lymph node regions (31.1%), and erythrocyte sedimentation rate ≥50 (25.5%). Conclusion: In this analysis of real-world data, we found that nearly a third of newly diagnosed cHL patients had early unfavorable disease. Our analysis also showed differences in the proportion of patients for each unfavorable factor among patients with early-stage unfavorable cHL.

58: HYPOTENSION MAGNITUDE VIA HIGH-RESOLUTION ABP IS ASSOCIATED WITH OUTCOME AFTER PEDIATRIC ARREST

Introduction: Early post-arrest hypotension may impact outcomes after pediatric cardiac arrest. Our aim was to utilize high-resolution continuous arterial blood pressure (ABP) data to quantify hypotension burden and determine its association with outcome after pediatric cardiac arrest. We hypothesized that a greater calculated hypotension burden would be associated with unfavorable outcome. Methods: This is a single-center retrospective observational study of patients who suffered cardiac arrest and had invasive ABP monitoring during post-arrest care. We collected high-resolution (100Hz) continuous ABP waveforms in the first 24 hours after return of spontaneous circulation (ROSC). ABP was percentile adjusted for age, and the lower quartile of mean arterial pressure (MAP) was set as threshold. Outcome was unfavorable neurologic status at hospital discharge (Pediatric Cerebral Performance Score, PCPC, of ≥3 with change ≥1 from pre-arrest baseline). We determined the association of outcome with magnitude and duration of MAP below threshold, and with below-threshold burden (area between MAP and threshold MAP) normalized by monitoring duration. Data reported as median and IQR. Mann-Whitney tests compared favorable and unfavorable outcome. Results: Of the 102 patients (age 4.8 [1.3,12.4] years, 64% male, 47% in-hospital cardiac arrest) analyzed, 66% had unfavorable outcome. Time from ROSC to ABP monitoring was 91 [58,157] minutes. Monitoring duration was 21 [7,24] hours. MAP percentile for age was 64th [46th,86th]. Threshold was set at 40th percentile. Magnitude of MAP below threshold was greater for unfavorable vs. favorable patients, (5.61 [2.91,9.00] vs. 3.99 [2.00,5.96] mmHg, p=0.048). Neither percent duration nor burden below threshold MAP differed between unfavorable and favorable patients, respectively (26 [4,50] vs 25 [3,48] percent, p=0.90; 1.51 [0.16,4.56] vs 0.92 [0.13,2.98] mmHg, p=0.32). Conclusions: High-resolution continuous ABP data can be utilized to quantify hypotension burden after pediatric cardiac arrest. Magnitude of MAP below the 40th percentile for age, but not duration or burden, was associated with unfavorable outcome in the first 24 hours after ROSC.

Nivolumab and AVD in Early-Stage Unfavorable Hodgkin Lymphoma: Follow-up Analysis of the Randomized GHSG Phase II Nivahl Trial

Background Anti-PD1 inhibition is increasingly investigated as first-line treatment of classical Hodgkin lymphoma (HL), usually either in sequential or concomitant combination with other therapeutics. While impressive response rates and short-term progression-free survival are observed, long-term efficacy and safety as well as quality-of-life (QoL) remain unknown. Herein we present the preplanned 3-year follow-up (FU) analysis of the GHSG phase II NIVAHL trial in early-stage unfavorable HL. Methods NIVAHL is an investigator-sponsored randomized phase II trial (NCT03004833) financially supported by Bristol-Myers Squibb which was conducted at 28 GHSG trial centers and enrolled 109 patients aged 18-60 years with centrally confirmed first diagnosis of early-stage unfavorable HL. Patients received either fully concomitant (4xnivo-AVD; arm A) or sequential (4xnivolumab, 2xnivo-AVD, 2xAVD; arm B) nivolumab-based 1st-line treatment, each followed by 30Gy involved-site radiotherapy (IS-RT). The primary analysis showed feasibility with a favorable safety profile and outstanding 1-year efficacy (Bröckelmann JAMA Oncol 2020). During FU, patients were monitored regularly for signs of HL relapse, persisting or late toxicities and QoL by the EORTC QLQ-C30 questionnaire. This FU analysis of key secondary endpoints including progression-free (PFS) and overall survival (OS), long-term safety and QoL was preplanned at three years after the registration of the last patient. Results With a median FU of 40 months, no PFS or OS events were observed since the NIVAHL primary analysis. Importantly, no patient with a partial remission by central response assessment required further treatment and all 7 patients converted to a complete remission during FU. With no deaths recorded, 3-year OS is 100% in both arms and 3-year PFS estimates are 98% and 100% in arm A and B, respectively (Figure 1). No second primary malignancies were reported and overall, no new safety signals were identified: While any treatment for potentially treatment-associated morbidities was required in 13% of patients, no patient required long-term corticosteroid treatment at last FU. Mean forced expiratory pressure in one second (FEV1) at baseline and 3 years after enrollment was 91.1% (standard deviation (SD) 13.6%) and 94.7% (SD 13%), respectively. Mean diffusion capacity for carbon monoxide adjusted for hemoglobin (DLCOc) at baseline and 3 years after enrollment was 86.2% (SD 16.5%) and 81.0% (SD 22.6%), respectively. No cardiac events >°1 were reported during FU and left ventricular ejection fraction (LVEF) was in the normal range in 93% of patients at last FU. The median global health score and global QoL by EORTC QLQ-C30 improved over time and were 64 (SD 22) and 80 (SD 16) at baseline, 76 (SD 17) and 87 (SD 15) 1 year after enrollment and 82 (SD 15) and 92 (SD 11) 3 years after enrollment, respectively. Relevant fatigue existed prior to treatment (mean fatigue score difference from age- and sex-adjusted German population reference value: 22 (SD 30)), briefly worsened on-treatment (after chemotherapy: 38 (SD 27), after radiotherapy: 27 (SD 23)) but resolved over time (1 year after enrollment: 10 (SD23), 3 years after enrollment: -3 (SD 18); Figure 2). Conclusion This preplanned FU analysis of the largest anti-PD1 HL first-line trial to date confirms the outstanding efficacy and favorable safety profile of this therapeutic approach. Additionally, QoL and fatigue appear relevantly improved compared to baseline during prolonged FU. Building on NIVAHL, the upcoming GHSG phase II INDIE trial (NCT04837859) will investigate an individualized immunotherapy with tislelizumab in early-stage unfavorable HL patients. Since likely not all patients require the full course of chemoimmunotherapy and consolidative IS-RT, INDIE will be the first trial investigating a chemo- and radiotherapy-free 1st-line HL treatment in optimally responding patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

NCOG-30. MULTISESSION RADIOSURGERY FOR UNFAVORABLE NONFUNCTIONING PITUITARY MACROADENOMA: 5-YEAR OUTCOMES FROM A SINGLE INSTITUTION PROTOCOL

Abstract Nonfunctioning macroadenoma is a commonly diagnosed pituitary tumor. Resection is the favored treatment, with radiosurgery often utilized for residual or progressing disease. Long-term outcomes are established for single-session radiosurgery, but mature outcomes are lacking for multisession radiosurgery. We report our institution’s 5-year efficacy and safety results for unfavorable nonfunctioning pituitary macroadenoma patients treated with 5-fraction robotic radiosurgery. Between 2010-2020, patients who completed 5-fraction radiosurgery for the treatment of unfavorable nonfunctioning pituitary macroadenomas were included. A tumor was considered unfavorable if the gross tumor volume (GTV) was larger than 5 cc or if it closely approached a critical structure (optic apparatus, brainstem or pituitary gland). Local control was calculated using the Kaplan-Meier Method. RESULTS Twenty predominately female patients (60%), age from 21-77 (median: 53 years) were included in this study. All underwent primary resection. Indications for radiosurgery included unresectable recurrence (85%) and residual disease progression (70%). Median tumor volume was 3.4 cm3 (range: 0.3-20.8 cm3) and 40% of the tumors were suprasellar. A mean dose of 30 Gy (range: 25Gy-30Gy), was delivered to a median isodose line of 80% (range: 75%-89%). Toxicity was minimal with 12 patients (40%) developing acute short-lived headaches and 1 patient (5%) developing a brief ipsilateral 6th nerve palsy. There was no radiation induced optic or pituitary dysfunction identified in this cohort. At a median follow up of 5 years local control at 5 years was 95%. There was 1 in-field failure pathologically confirmed following surgery for pituitary tumor hemorrhage and 2 radiographically confirmed out-of-field failures in patients with large tumors (&amp;gt; 20 cc) treated with lower doses (25 Gy). CONCLUSIONS The treatment of unfavorable nonfunctioning pituitary macroadenoma with 5-fraction robotic radiosurgery provides excellent local control to date, with minimal toxicity. Continued follow-up for the long term optic and pituitary function preservation and tumor control is needed.