Negative Prognostic Factor For Overall Survival Research Articles

Abstract PO4-04-05: HER2 immunohistochemistry (IHC) expression in HER2-positive (HER2-pos) metastatic breast cancer (mBC): clinical and prognostic differences between IHC 2+ and IHC 3+ populations

Abstract Background: The exploration of heterogeneity in mBC has gained significant interest in optimizing therapeutic strategies. While the impact of differential HER2 IHC staining has been extensively studied in HER2-low neoplasms, limited data is available regarding IHC 2+ and IHC 3+ categories in HER2-pos mBC. The aim of our study is to compare, the clinical variables, metastatic patterns, and prognosis between patients classified as IHC 2+ and IHC 3+ in HER2-pos mBC. Methods: Pts with HER2 pos mBC, determined by HER2 IHC staining of 3+ or 2+ with amplification at the in situ hybridization assay, were selected from the GIM14 study database for analysis. Associations among variables were assessed by conducting logistic regression analyses. Additionally, prognostic factors for overall survival (OS) and time to treatment failure (TTF) were evaluated using both uni- and multi-variable Cox regression models. Results: A total of 766 HER2-pos mBC pts were included in the analysis. Among them, 302 (39%) had IHC score of 2+ and 464 (61%) had a IHC score of 3+. Central nervous system (CSN) metastases (mts) were observed in 68 (9%) pts (32% IHC 2+; 68% IHC 3+), lymph node (LN) mts in 330 (43%) pts (46% IHC 2+; 54% IHC 3+), lung (LU) mts in 182 (24%) pts (46% IHC 2+; 54% IHC 3+), liver (LI) mts in 227 (30%) pts (45% IHC 2+, 55% IHC 3+), skin (SK) mts in 68 (9%) pts (28% IHC 2+; 72% IHC 3+) and pleural (PL) mts in 40 (5%) pts (47% IHC 2+, 53% IHC 3+). In univariable (uni) analysis, IHC 3+ compared to IHC 2+ was significantly associated with SK mts (OR 1.76, P=0.043) and less likely to be associated with LI (OR 0.71, P=0.031), LU (OR 0.70, P =0.036), and LN (OR 0.63, P=0.002) mts. In multivariable (multi) analysis, LN mts maintained statistical significance (OR 0.62, P=0.004). In subgroup analysis, among IHC 3+ patients, factors associated with worse OS pts were neo Tx (HR 1.55, P=0.032), adjuvant radiotherapy (HR 1.34, P=0.042), neo ChT (HR 1.63, P=0.002), CNS mts (HR 1.98, P=0.002), and LI mts (HR 1.68, P< 0.0001). In multi analysis, CNS mts (HR 1.73, P=0.028) and LI mts (HR 1.47, P=0.017) remained prognostic for IHC 3+ subgroup. The only factor associated with worse OS in IHC 2+ pts was LI mts (HR 1.67, P=0.005). Multi analysis in the overall HER2-pos population identified neo chemotherapy (ChT) (HR 1.49, P=0.009), CNS mts (HR 1.53, P=0.003) and PL mts (HR 1.50, P=0.036) as negative prognostic factors for OS, while PL mts (HR 1.74, P=0.048) were associated with a shorter time to treatment failure (TTF). Conclusions: Our exploratory data revealed that HER2-pos mBC with a IHC score of 3+ is less likely to be associated with LN mts and with visceral mts. The site of mts has prognostic significance, as CNS mts are associated with worse OS in pts with an IHC score of 3+ pts, while LI mts are associated with worse OS in both IHC 2+ and 3+ subgroups. However, the IHC score itself (2+ or 3+) does not have independent prognostic value. The relationship between HER2 IHC staining and treatment outcomes requires further investigation to better understand its potential impact on clinical practice. Citation Format: Arianna Dri, Eva Blondeaux, Claudia Bighin, Simona Gasparro, Stefania Russo, Lorenzo Foffano, Palma Pugliese, Andrea Fontana, Enrico Cortesi, Antonella Ferzi, Ferdinando Riccardi, Valentina Sini, Luca Boni, Alessandra Fabi, Filippo Montemurro, Michelino De Laurentiis, Grazia Arpino, Lucia Del Mastro, Lorenzo Gerratana, Fabio Puglisi. HER2 immunohistochemistry (IHC) expression in HER2-positive (HER2-pos) metastatic breast cancer (mBC): clinical and prognostic differences between IHC 2+ and IHC 3+ populations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-05.

Cancer cachexia as a predictor of adverse outcomes in patients with non-small cell lung cancer: A meta-analysis

IntroductionCancer cachexia is a complex problem characterized by weight loss due to skeletal muscle and adipose tissue reduction. The purpose of this meta-analysis is to examine the association between cancer cachexia and adverse outcomes in patients with non-small cell lung cancer (NSCLC). MethodsA comprehensive search was conducted in the PubMed, Web of Science, and Embase databases from their inception to January 15, 2024. Retrospective or prospective studies that investigated the cancer cachexia as a predictor of overall survival (OS), progression-free survival (PFS), overall response rate (ORR), or disease control rate (DCR) in NSCLC patients were included in this analysis. ResultsSixteen studies, comprising 5,919 NSCLC patients, were identified. The pooled prevalence of cachexia in NSCLC patients was 39%, with individual studies reporting rates ranging from 19% to 63.8%. A meta-analysis using a random effects model showed that cachexia was associated with reduced OS (hazard ratio [HR] 1.84; 95% confidence interval [CI] 1.54-2.21) and PFS (HR 1.49; 95% CI 1.27-1.73).Subgroup analysis indicated that cancer cachexia significantly predicted OS, regardless of study design, NSCLC subtypes, cancer stage, definitions of cachexia, or follow-up duration. However, there was no clear association between cancer cachexia and ORR or DCR. ConclusionsCancer cachexia emerges is a negative prognostic factor for OS and PFS in NSCLC patients. Assessing cancer cachexia can improve risk classification for survival outcomes in this patient population.

Lymph node volume predicts survival in esophageal squamous cell carcinoma treated with neoadjuvant chemoradiotherapy and surgery.

Large primary tumor volume has been identified as a poor prognostic factor of esophageal squamous cell carcinoma (ESCC) treated with definitive concurrent chemoradiotherapy (CCRT). However, when neoadjuvant CCRT and surgery are adopted, the prognostic impact of primary tumor and lymph node (LN) volume on clinical outcomes in ESCC remains to be elucidated. This study included 107 patients who received neoadjuvant CCRT and surgery for ESCC. The volume of the primary tumor and LN was measured using radiotherapy planning computed tomography scans, and was correlated with overall survival (OS), disease-free survival (DFS), and cancer failure pattern. The median OS was 24.2 months (IQR, 11.1-93.9) after a median follow-up of 18.4 months (IQR, 8.1-40.7). The patients with a baseline LN volume > 7.7 ml had a significantly worse median OS compared to those with smaller LN volume (18.8 vs. 46.9 months, p = 0.049), as did those with tumor regression grade (TRG) 3-5 after CCRT (13.9 vs. 86.7 months, p < 0.001). However, there was no association between OS and esophageal tumor volume (p = 0.363). Multivariate analysis indicated that large LN volume (HR 1.753, 95% CI 1.015-3.029, p = 0.044) and high TRG (HR 3.276, 95% CI 1.556-6.898, p = 0.002) were negative prognostic factors for OS. Furthermore, large LN volume was linked to increased locoregional failure (p = 0.033) and decreased DFS (p = 0.041). In conclusion, this study demonstrated that large LN volume is correlated with poor OS, DFS, and locoregional control in ESCC treated with neoadjuvant CCRT and esophagectomy.

Application of the Second Revision of the International Staging System (R2-ISS) in the prognostic assessment of newly diagnosed multiple myeloma

Objective: To investigate the prognostic value of the Second Revision of the International Staging System (R2-ISS) in patients with newly diagnosed multiple myeloma (NDMM) . Methods: The retrospective study was performed in 326 NDMM patients with immunomodulatory drugs and/or proteasome inhibitors as the first-line treatment attending the Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China, from December 2012 to March 2022. The Kaplan-Meier method was used for the survival analysis, with the Log-rank test comparing the between-group differences and Cox proportional risk regression modeling A multifactorial analysis was performed. Results: ①326 patients were included in the study, 190 of whom were males. The median age was 63 years, and the median followup time was 37 months. R2-ISS can effectively predict prognosis, particularly for R-ISS Ⅱ patients. The median progression-free survival (PFS) time of R2-ISS Ⅰ, R2-ISS Ⅱ, R2-ISS Ⅲ, and R2-ISS Ⅳ was 52, 29, 20, and 15 months (P<0.001), while the median overall survival (OS) time was 91, 60, 44, and 36 months (P<0.001). Multifactor analysis revealed that ISS Ⅱ, ISS Ⅲ, del (17p), t (4;14), 1q+, LDH increased, and age >65 years old were independent negative prognostic factors for OS. ISS Ⅱ, ISS Ⅲ, del (17p), t (4;14), 1q+, and LDH were independent negative prognostic factors for PFS. ②The C-index score of R2-ISS was 0.724, higher than that of R-ISS (0.678), indicating high prediction efficiency. ③The median PFS for 1q+-related double-hit in R2-ISS Ⅲ and Ⅳ were 20, 15 months (P=0.084) and the median OS were 35, 36 months (P=0.786), respectively. In R2-ISS Ⅲ, there were twenty-seven cases of 1q+-related double-hit, sixty-one cases of 1q+ single abnormality, and sixty-eight cases with no 1q+. The median PFS for the three groups were 20, 18, and 21 months (P=0.974), while the median OS was 35, 47, and 56 months (P=0.042), respectively. Adjusting the assignment of 1q+ to 1, the median PFS and OS of different R2-ISS stages differed significantly after regrouping (P<0.001) . Conclusions: The prognostic stratification value of R2-ISS is higher than R-ISS, particularly in the highly heterogeneous R-ISS Ⅱ population. Adjusting the assignment of the 1q+-related double-hit can improve R2-ISS, which should be validated in future studies with multi-center and expanded cases.

Efficacy, safety, and predictors of fruquintinib plus anti-programmed death receptor-1 (PD-1) antibody in refractory microsatellite stable metastatic colorectal cancer in a real-world setting: a retrospective cohort study.

Patients with microsatellite stable (MSS) advanced colorectal cancer (CRC) have few alternatives for salvage therapy and a large unmet clinical need. Preclinical studies demonstrate that fruquintinib combined with anti-programmed death protein 1 (PD-1) has a synergistic anti-tumor effect. But a few phase 2 clinical studies show inconsistent efficacy of this combination therapy in CRC. The aim of this study was to investigate the efficacy, safety, and predictors of fruquintinib plus PD-1 antibodies in refractory MSS metastatic CRC (mCRC) in a real-world setting. We performed a retrospective single-center analysis to assess the outcomes of patients with MSS mCRC who were treated with fruquintinib plus anti-PD-1 antibodies subsequent to the failure of standard therapies at the Hunan Cancer Hospital. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity were reviewed and evaluated. The primary endpoint was OS. The impact on OS and PFS was examined using the Cox regression model. Between 1 January 2019 and 30 June 2022, we enrolled 70 eligible patients. The median follow-up was 17.2 months (range, 5.3-32.9 months). The median OS (mOS) and median PFS (mPFS) were 19.48 and 5.5 months respectively. The ORR was 11.43% and the DCR was 84.29%. Multivariate Cox regression analysis reveals liver metastasis (LM) without local treatment was a risk factor for OS [hazard ratio (HR) =5.31, P=0.0184], whereas that with local treatment (HR =2.19, P=0.263) was not. The most common adverse events were hand-foot syndrome (37.14%), hypertension (34.29%), mucositis oral (32.86%). No serious adverse effects or adverse effect-related deaths were reported. There were no instances of severe adverse effects or deaths related to adverse effects reported. Our study indicates that the combination of fruquintinib and anti-PD-1 antibodies can improve the OS and PFS with a tolerable toxicity profile for Chinese patients with refractory MSS mCRC. LM without local therapy is a negative prognostic factor for OS, but those with local treatment can significantly prolong survival. We require additional well-structured, prospective, and extensive studies to confirm and validate these findings.

Long-Term Outcomes from the Phase 3 OCEAN (OP-103) Study: Melflufen and Dexamethasone (Dex) Versus Pomalidomide (Pom) and Dex in Relapsed Refractory Multiple Myeloma (RRMM)

Background/Introduction: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases resulting in rapid release of alkylating agents inside tumor cells. Based on the phase 2 HORIZON study and supported by the phase 3, randomized, controlled OCEAN study, melflufen was approved in Europe for use in patients (pts) with triple-class refractory RRMM with ≥3 prior lines of therapy (LoTs) and without prior autologous stem cell transplantation (ASCT) or with a time to progression (TTP) &amp;gt;36 mo after prior ASCT. In the OCEAN study (NCT03151811), melflufen + dex showed superior progression-free survival (PFS) compared with pom + dex (6.8 vs 4.9 mo; hazard ratio [HR]: 0.79; P=0.032); PFS benefit in the melflufen + dex group was mainly driven by pts who had not received prior ASCT. Overall survival (OS) trended in favor of melflufen + dex in pts without prior ASCT and favored pom + dex in pts with prior ASCT (Schjesvold et al. Lancet Haematol. 2022;9:e98). Post-hoc analyses of OCEAN and HORIZON demonstrated that a TTP &amp;lt;36 mo after prior ASCT was a negative prognostic factor for OS with melflufen + dex (Sonneveld et al. Clin Lymphoma Myeloma Leuk. 2023;S2152). Here, we present long-term OS and safety data from the final analysis of the OCEAN study. Methods: Pts with RRMM (2-4 prior LoTs including lenalidomide [len] and a proteasome inhibitor) refractory to len and last LoT were randomized 1:1 (stratified by age, no. of prior LoTs, and International Staging System score) to receive 28-day (d) cycles of melflufen 40 mg intravenously on d1 or pom 4 mg orally (PO) daily on d1 to 21. All pts received dex 40 mg (20 mg for pts ≥75 y) PO on d1, 8, 15, and 22. Pts received therapy until disease progression or unacceptable toxicity. The primary endpoint was PFS, as assessed by independent review committee per IMWG Uniform Response Criteria, and key secondary endpoints were overall response rate, OS, and safety. Results: As of 3 Feb 2023, 495 pts were randomized (246 to melflufen; 249 to pom); median age was 68 y (range, 39-91) and median prior LoTs was 3. In the intent-to-treat (ITT) melflufen and pom populations, median OS was 20.2 mo vs 24.0 mo (HR, 1.09 [95% CI, 0.88-1.35]), at a median follow-up of 40.3 mo and 38.1 mo, respectively. In the target subgroup of the melflufen and pom groups (pts without a prior ASCT or TTP &amp;gt;36 mo after an ASCT), median OS was 23.6 mo vs 19.1 mo (HR, 0.88 [95% CI, 0.67-1.16]); in the non-target population (pts with TTP &amp;lt;36 mo after ASCT), median OS was 15.7 mo vs 27.5 mo (HR, 1.60 [95% CI, 1.15-2.21]), respectively. While any grade hematologic toxicities were more common with melflufen, the occurrence of non-hematologic toxicities was similar in the 2 groups. Grade 3/4 (G3/4) treatment-emergent adverse events (TEAEs) in the safety population (melflufen [n=228] and pom [n=246]) occurred in 90% vs 76% of pts, respectively; most commonly thrombocytopenia (78% vs 13%; occurring with G3/4 hemorrhage in 1% vs 0%), neutropenia (64% vs 50%; occurring with G3/4 infections in 4% vs 7%), anemia (43% vs 19%), and infection and infestations (14% vs 24%). Serious AEs occurred in 43% vs 50% of pts (including pneumonia [6% vs 9%], COVID-19 pneumonia [5% vs 6%], and anemia [4% vs 2%]), and fatal AEs in 14% vs 15% (including COVID-19 pneumonia [4% vs 2%] and pneumonia [2% vs 2%]) in the melflufen and pom groups, respectively. With melflufen and pom, TEAEs led to dose reductions in 52% vs 28% of pts (most frequently thrombocytopenia [32% vs 2%] and neutropenia [12% vs 8%]), and discontinuations in 30% vs 24% of pts, respectively. Deaths occurred in 74% vs 68% of pts in the melflufen and pom groups, with AEs being the primary cause of death ≤30 d after last dose in 8% and 11%, respectively. Conclusion: Long-term results were consistent with those of previous analyses (Schjesvold, et al. Lancet Haematol. 2022;9:e98-e110). While OS trended in favor of pom in the ITT population, OS outcomes continued to be more favorable with melflufen in pts with no prior ASCT or with TTP &amp;gt;36 mo after ASCT. No new safety signals were reported, and AEs were manageable with dose modifications, consistent with previous reports. This long-term follow-up of OCEAN confirms the favorable safety and OS outcomes of melflufen + dex in the target population and supports its continued use as an alternative treatment choice for pts with RRMM who have received ≥2 prior LoT and who have not received ASCT.

Melflufen in relapsed/refractory multiple myeloma refractory to prior alkylators: A subgroup analysis from the OCEAN study.

Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP ≥ 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators.

Primary adult choroid plexus carcinomas: a single-center experience with a systematic review.

Primary adult choroid plexus carcinomas (PACPCs) are extremely rare brain tumors. The existing literature primarily comprises case reports, which limits our understanding of this uncommon disease. This study aims to describe the clinical characteristics and prognosis of PACPCs, as well as to identify optimal treatment strategies. We conducted a comprehensive analysis of clinical data from 7 patients with PACPCs who underwent surgical treatment at the Department of Neurosurgery, Beijing Tiantan Hospital, between March 2011 and March 2023. Additionally, a thorough search of the PubMed database was performed using the keywords "choroid plexus carcinoma" or "choroid plexus carcinomas" within the time frame of August 1975 to April 2023, which yielded a total of 28 identified cases. Subsequently, we evaluated risk factors for progression-free survival (PFS) and overall survival (OS) based on the pooled cases. The pooled cohort, consisting of 7 cases from our institution and 28 cases from the literature, included 20 males and 15 females with a mean age of 44.3 ± 14.7 years (range: 21-73 years). Gross-total resection (GTR) and non-GTR were achieved in 22 (62.9%) and 13 (37.1%) patients, respectively. Radiotherapy and chemotherapy were administered to 29 (90.6%) and 13 (40.6%) patients, respectively. After a mean follow-up of 21.0 ± 26.7 months (range: 2-132 months), 18 patients were alive, and 11 patients had died. The multivariate Cox regression model demonstrated that non-GTR (HR 5.262, 95% CI 1.350-20.516, p=0.017) was a negative prognostic factor for OS. However, we did not find any risk factors for PFS. Complete surgical resection should be considered as the primary treatment approach for this rare disease. Chemotherapy and radiotherapy appear to have limited effectiveness in treating this condition. Further research with large cohorts is needed to validate our conclusions.

High Infiltration of CD163-Positive Macrophages in Intratumor Compartment Predicts Poor Prognosis in Patients With Upper Urinary Tract Urothelial Carcinoma and Radical Nephroureterectomy.

To investigate the prognostic value of CD68- and CD163-positive macrophages in patients with upper urinary tract urothelial carcinoma (UTUC). This retrospective study enrolled 50 patients (34 men and 16 women) with UTUC who received radical nephroureterectomy (RNU). We evaluated the expression of CD68 and CD163 in the intratumor compartment by immunohistochemistry. The Kaplan-Meier method and Cox proportional hazards regression model were used to evaluate overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and bladder recurrence-free survival (BRFS). High infiltration of CD163-positive macrophages in patients with UTUC was significantly correlated with worse OS, CSS, and RFS (P < .05 for all). Multivariate analysis showed that high infiltration of CD163-positive macrophages was an independent negative prognostic factor of OS and CSS in patients with UTUC who received RNU. Lymphovascular invasion was an independent negative prognostic factor of RFS, and high infiltration of CD68-positive macrophages was an independent positive prognostic factor of BRFS. This study indicated that high infiltration of CD163-positive macrophages in the intratumor compartment might be a useful prognostic marker for survival in patients with UTUC who receive RNU. Further, high infiltration of CD68-positive macrophages in the intratumoral compartment might be a useful prognostic marker for bladder recurrence in these patients.

Adenosquamous cell carcinoma of the head and neck: a retrospective single institution series.

Head and neck adenosquamous cell carcinoma (HN-ASCC) is a rare, aggressive neoplasm, with limited data reported in the literature. The aim of this study was to assess tumour behaviour and prognostic factors impacting overall survival (OS) in a retrospective, single institution series. A retrospective study on patients affected by HN-ASCC who were treated surgically between 2002 and 2019 at the Department of Otorhinolaryngology - Head and Neck Surgery of the University of Brescia was conducted. Demographics, clinical data, OS, and relative prognostic factors were analysed. The study included 32 patients, with a median age of 66 years, mostly males (84.4%) and untreated (68.8%). Adjuvant treatments followed surgery in 28.1% of patients. Compared to conventional SCC, ASCC showed a higher proportion of cases arising in the larynx (40.6%); no difference was found in other features. Advanced (pT3-4) local stage at presentation (p = 0.023), perineural invasion (PNI, p = 0.01), and positive margins (p = 0.007) were independent negative prognostic factors for OS. HN-ASCC is a rare, aggressive cancer, most frequently arising in the larynx of elderly males, usually diagnosed in an advanced local stage. OS is generally poor, affected by local advanced stage, PNI, and positive resection margins.

Risk factors and prognostic models of lymph node metastatic hypopharyngeal squamous cell carcinoma.

To explore the risk factors for lymph node metastasis (LNM) and establish nomograms for predicting survival outcomes and assessing individual risk in patients with LNM and hypopharyngeal squamous carcinoma (HSCC). Clinical data of patients with HSCC were retrospectively reviewed. The study's primary endpoints were overall survival (OS) and disease-specific survival (DSS). Nomograms were established based on Cox regression analyses. The accuracy and calibration ability of the nomograms were evaluated using the C-index, area under the curve, calibration curves, and decision curve analysis. Overall, 2888 patients were enrolled, and the LNM rate was 74.2%. Age ≤ 60 years, male sex, unmarried status, pyriform sinus location, grade III-IV, tumor larger than 4 cm, and advanced T stage increased the risk of LNM. In addition, LNM was a negative prognostic factor for OS and DSS. Ten variables were identified and incorporated into nomograms to estimate OS and DSS. Our nomograms outperformed the traditional staging system in training and validation cohorts. Patients were stratified into risk subgroups based on the OS- and DSS-nomogram scores. Patients in the high-risk subgroup had a higher risk of death and disease-specific mortality than those in the low- and intermediate-risk subgroups. LNM worsens the prognosis of HSCC. This study identified the independent prognostic factors for HSCC with LNM and developed satisfactory OS- and DSS-monogram to provide individual prediction and risk classification for patients with this diagnosis.

Targeted Next-Generation Sequencing Improves the Prognostication of Patients with Disseminated Appendiceal Mucinous Neoplasms (Pseudomyxoma Peritonei).

Appendiceal mucinous neoplasms (AMNs) with disseminated disease (pseudomyxoma peritonei) are heterogeneous tumors with variable clinicopathologic behavior. Despite the development of prognostic systems, objective biomarkers are needed to stratify patients. With the advent of next-generation sequencing (NGS), it remains unclear if molecular testing can improve the evaluation of disseminated AMN patients. Targeted NGS was performed for 183 patients and correlated with clinicopathologic features to include American Joint Committee on Cancer/World Health Organization (AJCC/WHO) histologic grade, peritoneal cancer index (PCI), completeness of cytoreduction (CC) score, and overall survival (OS). Genomic alterations were identified for 179 (98%) disseminated AMNs. Excluding mitogen-activated protein kinase genes and GNAS due to their ubiquitous nature, collective genomic alterations in TP53, SMAD4, CDKN2A, and the mTOR genes were associated with older mean age, higher AJCC/WHO histologic grade, lymphovascular invasion, perineural invasion, regional lymph node metastasis, and lower mean PCI (p < 0.040). Patients harboring TP53, SMAD4, ATM, CDKN2A, and/or mTOR gene alterations were found to have lower OS rates of 55% at 5 years and 14% at 10 years, compared with 88% at 5 years and 88% at 10 years for patients without the aforementioned alterations (p < 0.001). Based on univariate and multivariate analyses, genomic alterations in TP53, SMAD4, ATM, CDKN2A, and/or the mTOR genes in disseminated AMNs were a negative prognostic factor for OS and independent of AJCC/WHO histologic grade, PCI, CC score, and hyperthermic intraperitoneal chemotherapy treatment (p = 0.006). Targeted NGS improves the prognostic assessment of patients with disseminated AMNs and identifies patients who may require increased surveillance and/or aggressive management.

High visceral fat attenuation and long-term mortality in a health check-up population.

The prognostic role of increased visceral fat attenuation (VFA) remains underexplored. We investigated the long-term prognostic implications of computed tomography (CT)-derived VFA in a health check-up population. This study included consecutive individuals who had positron-emission tomography/CT scans for health check-ups between January 2004 and December 2010. The primary outcome was overall survival (OS), and the secondary outcomes were cancer-specific survival (CSS) and non-cancer-specific survival (NCS). Commercially available body composition analysis software was used to obtain abdominal waist VFA, visceral fat volume index (VFI) and skeletal muscle index (SMI) at the L3 level. Sarcopenia was determined using sex-specific SMI references. VFA and VFI were dichotomized using the thresholds for the highest quartiles. The relationship between CT-derived body composition parameters and body mass index (BMI) was evaluated with Pearson correlation coefficients. The prognostic implications of VFA and sarcopenic obesity (SO) defined by VFA were assessed by multivariable Cox regression analysis and Kaplan-Meier plots with log-rank tests. A total of 2720 individuals (1530 men [56.3%] and 1190 women [43.7%]; median age: 53years, inter-quartile range: 47-60years) were included. During the median follow-up of 138months, 128 individuals (5%) died (cancer mortality: 2%; non-cancer mortality: 3%), with 0.2% (5 of 2720) and 1.1% (30 of 2720) of 1- and 5-year mortality rates. VFA was negatively correlated with BMI (r=-0.62; P<0.001) and VFI (r=-0.69; P<0.001). After adjusting for clinical variables, sarcopenia and VFI, high VFA was a negative prognostic factor for OS (hazard ratio [HR]: 1.05 per Hounsfield unit; 95% confidence interval [CI]: 1.02, 1.08; P=0.001), CSS (HR: 1.07 per Hounsfield unit; 95% CI: 1.02, 1.12; P=0.006) and NCS (HR: 1.03 per Hounsfield unit; 95% CI: 1.01, 1.06; P=0.009). Individuals with high VFA had higher high-sensitivity C-reactive protein levels than those with low VFA (0.11 vs. 0.03mg/dL; P<0.001). Individuals with SO defined by VFA had worse OS (9% vs. 4%; P<0.001), CSS (3% vs. 2%; P=0.02) and NCS (6% vs. 3%; P<0.001) than those without SO, even in the same BMI (underweight-to-normal BMI, OS: 8% vs. 4%; overweight-to-obese BMI, OS: 38% vs. 4%; P<0.001 in both) or VFI category (high VFI, OS: 43% vs. 6%; low VFI, OS: 8% vs. 3%; P<0.001 in both). High VFA was associated with long-term mortality and low-grade inflammation. VFA can further stratify the current SO by BMI or VFI, and SO defined by VFA can identify individuals who are most vulnerable to long-term mortality.

Prognostic factors for pulmonary carcinoid with positive lymph node after surgical resection: a SEER database study.

Prognostic factors and role with chemotherapy (CT) and radiotherapy (RT) remain unclear for patients of pulmonary carcinoid (PC) with positive lymph node after surgery. PC patients who underwent surgery and with positive lymph node between 2000 and 2016 were identified from the SEER database. Univariate and multivariate cox regression analysis were used to identify independent risk factors for overall survival (OS). A total of 552 patients were identified. Multivariate analysis indicated that age (≤ 70/ > 70) (HR = 0.32, 95% CI 0.21-0.50; P < 0.001), histologic type (typical carcinoid [TC]/atypical carcinoid [AC]) (HR = 0.53, 95% CI 0.36-0.78, P = 0.001), number of positive lymph nodes (n ≥ 3/n = 1-2) (HR = 1.91, 95% CI 1.26-2.90; P = 0.002), and treatment mode (surgery + RT/surgery alone) (HR = 1.75, 95% CI 1.09-2.81; P 0.02) were independent prognostic factors for OS. In subgroup analysis according to histological type, prognostic factors were similar between AC and TC, except surgery + RT being negative prognostic factor for TC but AC. No significant difference in OS was observed between the surgery alone and surgery + CT in any subgroup of patients. Age > 70, histological type of AC, positive lymph nodes ≥ 3, and surgery + RT were likely to be negative prognostic factors for OS. Addition CT to surgery did not appear to provide additional OS benefit.

Old age and intense chemotherapy exacerbate negative prognostic impact of postoperative complication on survival in patients with esophageal cancer who received neoadjuvant therapy: a nationwide study from 85 Japanese esophageal centers.

The prognostic impact of docetaxel, cisplatin, and 5-FU (DCF) reported in JCOG1109 was successfully validated using real-world data in patients < 75years old. However, DCF was not reported to be beneficial in elderly patients with a relatively higher postoperative complication incidence. This study aimed to clarify the impact of postoperative complications on the prognosis of ESCC and the difference in the magnitude of the impact by age and regimen. Patients with esophageal squamous cell carcinoma (ESCC) who underwent subtotal esophagectomy at 85 authorized institutes were retrospectively reviewed from 2010 to 2015. The prognostic impact of postoperative anastomotic leakage (AL) and pneumonia on survival was evaluated. The prognostic value of the postoperative complications was assessed by stratifying patients according to age and neoadjuvant chemotherapy regimen. Patients with AL, pneumonia, and infectious complications (ICs: a combination of pneumonia and AL) showed significantly worse overall survival (OS). IC served as a negative prognostic factor of OS and recurrence-free survival, and its negative prognostic impact was more evident in patients aged > 75years. When the patients were further stratified by chemotherapeutic regimens, using the CF/IC(-) group as a reference, the DCF/IC (+) group showed significantly shorter OS in patients aged > 75years with a hazard ratio (HR) of 2.551. The HR of the CF/IC (+) group was 1.503. The negative impact of postoperative complications on survival was confirmed in this nationwide study. Furthermore, its magnitude was higher in elderly patients who received triplet chemotherapy.

Clinical Outcomes After Progression on First-Line Therapies in IDH1 Mutated Versus Wild-Type Intrahepatic Cholangiocarcinoma Patients.

Isocitrate dehydrogenase-1 (IDH1) mutations occur in a significant proportion of intrahepatic cholangiocarcinomas (iCCAs). No data are available regarding the prognostic impact of IDH1 mutations in advanced iCCA patients after progression on first-line therapies. We investigated the role of IDH1 mutation in advanced iCCA after progression on first-line therapies. After progression on first-line therapies for advanced iCCA, consecutive patients were retrospectively collected. The IDH1 status was tested at baseline. This analysis aimed to examine the association between the presence of IDH1 missense mutations and survival outcomes in patients with advanced iCCA treated with a second-line therapy. The analysis included 119 patients; 56/119 (47%) were IDH1 mutated (IDH1m) and 63/119 (53%) were IDH1 wild type (IDH1 WT). At univariate analysis for overall survival (OS), the presence of IDH1 mutation was associated with a worse median OS (mOS; 8.2 vs. 14.1 months; hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2-3.0, p=0.0047). Patients harboring IDH1 mutations showed a worse objective response rate (ORR) compared with patients without IDH1 mutation, whereas no significant differences in disease control rate (DCR) were found. Multivariate analysis confirmed IDH1 mutations as an independent negative prognostic factor for OS (HR 1.7, 95% CI 1.1-2.7, p=0.0256). By evaluating only patients receiving FOLFOX as second-line therapy, no statistically significant differences were found in terms of both OS and PFS between IDH1m and IDH1WT patients. In this subset of patients, those harboring an IDH1 mutation showed a worse ORR and DCR compared with those without. Finally, at univariate analysis for OS from third-line treatment, the presence of an IDH1 mutation was associated with a trend toward a worse mOS (6.0 vs. 11.9 months; HR 1.6, 95% CI 0.8-3.2, p=0.25). The present analysis constitutes the first evidence of a negative prognostic impact of IDH1 mutations in a cohort of patients treated after progression on first-line therapies in contrast to IDH1 inhibitors.

Interventional Antibiotic Treatment Replacing Antibiotic Prophylaxis during Allogeneic Hematopoietic Stem Cell Transplantation Is Safe and Feasible: A Single-Center Analysis

Background: Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk of infection-related mortality during the pre-engraftment period. Systemic antibiotic prophylaxis (SAP) is widely used during the period of neutropenia but is associated with disruption of the intestinal microbiome, an increased risk of Clostridium difficile infection (CDI) and colonization with multi-drug resistant (MDR) bacteria. Aims: We retrospectively assessed the safety and efficacy of a change in our center policy from SAP to an exclusively interventional antibiotic treatment (IAT) in adult patients undergoing allogeneic HSCT. Outcome measures were overall survival (OS) and non-relapse mortality (NRM) at 3 years, antibiotic administration, incidence of blood-stream infections (BSI) and incidence and severity of acute and chronic graft-versus-host disease (GVHD). Methods: Cefotaxime was used as standard of care prophylaxis during neutropenia after HSCT prior to January 2018. After a 12 months transition time during which both strategies were employed in parallel, SAP was replaced by an IAT strategy with meropenem being administered immediately by nursing staff in case of neutropenic fever or any other signs of infection, and subsequently deescalated to piperacillin/tazobactam (pip/taz) when appropriate. We compared 67 consecutive patients undergoing HSCT in 2017, all of whom received antibiotic prophylaxis (SAP cohort) with all patients in 2019 comprising the IAT cohort (n=68). Use of antibiotics is reported as number of daily doses per 100 care days (DDD/100CD) until discharge after HSCT. Results: Patient characteristics are summarized in table 1. Median age was 56 years, 82% of patients were grafted with peripheral blood stem cells (PBSC) for acute leukemia (74%) from a matched unrelated or related donor (MUD, 61%; MRD 17%). Patient characteristics were well balanced between the SAP and IAT cohorts, except those patients transplanted in 2019 were more likely to have an HCT-CI ≥ 3 (56% vs 36%, p=0.025) and receive reduced-intensity conditioning (62% vs 40%, p=0.025). In the SAP and IAT cohort, neutropenic fever was observed in 46% and 62% of patients (p=0.085). However, the cumulative incidence (CI) of BSI by day +100 post-HSCT was significantly higher in the IAT vs SAP cohort (40% vs 13%, p<0.001), which did not result in more patients admitted to the intensive care unit (13% vs 6%, p=ns) and did not translate into a higher CI of NRM at 3 years (10% vs 9%, p=ns). With a median follow-up of 1052 days, 3-year OS was 70% and 69% for the SAP and IAT cohort, resp. (p=ns, figure 1). CI of acute GVHD grade II-IV or chronic GVHD of any grade at 3 years was 34% (p=ns) and 45% (p=ns), resp., resulting in identical survival free of acute GVHD grade III-IV, chronic GVHD requiring systemic immunosuppressive therapy and relapse-free survival (GRFS) of 36% (p=ns) in both groups. We observed a tendency to a higher CI of severe chronic GVHD in the SAP cohort (27% vs 13%, p=0.08). There was no significant difference between the two cohorts in terms of newly detected colonization with MDR bacteria during conditioning and after HSCT (VRE 17%; ESBL 5%; 3/4 MRGN 5%; MRSA 0%) and the incidence of CDI was likewise equal in both cohorts (13%, p=ns). Compared to SAP, IAT resulted in significantly fewer days of antibiotic therapy (24 vs 18, p<0.001) and accordingly less administration of cefotaxime (12.8 vs 3.8 DDD/100CD), teicoplanin (26.2 vs 6.3 DDD/100CD), vancomycin (11.5 vs 8.3 DDD/100CD) and meropenem (23.1 vs 16.7 DDD/100CD). Solely use of pip/taz increased (14.3 vs 23.6 DDD/100CD), while the amount of imipenem remained unchanged (7.6 versus 7.8 DDD/100CD). Thus, we observed a significant 40% reduction of the median antibiotic consumption (p=0.0312) in 2019. In the multivariate analysis, only age > 60 years and a high or very high disease risk index were identified as negative prognostic factor for OS. Conclusion/Summary: Our single center experience in conducting HSCT without antibiotic prophylaxis but with strict guidelines for prompt antibiotic intervention demonstrated no disadvantage in OS and NRM, despite a higher CI of BSI. IAT resulted in considerably less consumption of cefotaxime, but also carbapenem and glycopeptide antibiotics. We conclude that the proposed procedure of IAT replacing SAP is safe and feasible. Larger patient numbers are needed to confirm a possible benefit of IAT on GVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic values of the gross volume of metastatic lymph nodes in patients with esophageal squamous cell carcinoma treated with definitive concurrent chemoradiotherapy.

We aim to explore whether the gross volume of metastatic lymph nodes (GTVnd) and the gross volume of primary tumor (GTVp) could be prognostic factors for esophageal squamous cell carcinoma (ESCC) patients treated with definitive concurrent chemoradiotherapy (dCCRT). We retrospectively analyzed 252 ESCC patients treated with dCCRT in the eraofintensity-modulatedradiation therapy (IMRT) at our institution. The cut-off value for the GTVnd derived from the restricted cubic splines (RCS) was determined. Univariate and multivariate Cox proportional hazard models were performed to determine the association between GTVnd and prognosis. we performed recursive partitioning analysis (RPA) method using GTVnd to develop a new risk stratification (TGTVndM). Moreover, the linear trend χ2, likelihood ratio χ2, and akaike information criterion (AIC) were used to determine the prognostic value between the TNM and TGTVndM staging systems. The five-year overall survival (OS) rate was 30.6%, with a median follow-up of 38 months. The cut-off value of GTVnd determined by the RCS was 4.35 cm3. GTVnd≥4.35 cm3 was an independent and significant negative prognostic factor for OS (HR=1.949, P<0.001), progression free survival (PFS) (HR=1.425, P=0.048), and distance metastasis free survival (DMFS) (HR=2.548, P=0.001). In multivariable analysis, gender, clinical T stage, and GTVnd were independently associated with OS. RPA segregated patients into 3 prognostic groups: high risk (T1-4 GTVnd≥4.35, n=126, III stage), intermediate risk (T4 GTVnd<4.35,n=38,II stage), and low risk(T1-3GTVnd<4.35, n=88, I stage). The 5-year OS(P<0.001), PFS (P=0.002), and DMFS (P=0.001) were significantly worse in high-risk group in comparison with the intermediate and low risk groups. Compared with the TNM staging system, the clinical T stage combined with GTVnd (TGTVndM) had a higher linear trend χ2 (26.38 versus 25.77), higher likelihood ratio χ2 (24.39 versus 20.69), and lower AIC (1255.07 versus 1260.06). GTVnd may serve as a good prognostic factor in predicting distant metastasis and death for ESCC patients treated with dCCRT. The TGTVndM staging system demonstrated superior accuracy for predicting OS and could serve as a more effective prognostic guidance for unresectable ESCC patients.

Carotid space involvement is a prognostic factor and marker for induction chemotherapy in patients with nasopharyngeal carcinoma

ObjectivesThe carotid space is an integral part of the parapharyngeal space, with ambiguous prognostic value for patients with nasopharyngeal carcinoma (NPC). This study aimed to investigate the prognostic significance of carotid space involvement (CSI) and propose a treatment strategy. Materials and methodsThis retrospective study enrolled 792 patients with biopsy-confirmed, non-distant metastatic NPC staged by magnetic resonance imaging before treatment. We used multivariable Cox regression models and Kaplan–Meier methods to assess the association between the variables and survival outcomes. A matched-pair method (1:1) was used to compare the survival differences between the patients with CSI treated with induction chemotherapy (ICT)and that of those who were not. ResultsThe incidence rate of CSI was 21.7 % (172/792). Multivariate analysis revealed that CSI was not an independent prognostic factor for survival outcomes in the 792 patients with NPC; however, the Chi-square test showed a different distribution of treatment strategies with ICT for patients with and without CSI. After stratification by ICT, CSI was an independent prognostic factor for overall survival (OS) (p = 0.049) in patients without ICT, but not for distant metastasis-free, local recurrence-free, or progression-free survival (p˃0.05). Additionally, ICT improved OS in patients with CSI (hazard ratio, 0.42; p = 0.019). Matched pair analysis showed that patients with CSI gained prolonged OS from ICT compared with the non-ICT group (88.4 % vs 69.4 %, p = 0.028). ConclusionCSI was an independent negative prognostic factor for OS in patients with NPC without ICT and might be an imaging marker for identifying eligible candidates for ICT.

OR12-5 | LBSAT57 Long-term Follow-Up of Pheochromocytoma/Paraganglioma (PPGL) after first diagnosis: a retrospective single-center study of 173 patients

Abstract Background Pheochromocytoma (Pheo)/Paraganglioma (PGL), together PPGL, are rare but life-threatening tumors, with tumor relapse (TR) rates after initial surgery of 16.5%, and genetic mutations in about 30-40% of patients. Long-term follow-up (FU) and genetic testing in all patients are recommended. Questions remain, however, as to the most suitable duration of FU, the prognostic value of genetic diagnoses and of clinical, biochemical or radiological findings during FU, of the incidence of TR after recommended 10 years FU of low-risk sporadic Pheos, or of TR on morbidity and mortality. Objective, patients, and methods: We retrospectively determined the overall survival (OAS), progression-free survival (PFS) and tumor-recurrence (TR) in 173 patients with PPGL initially operated and followed-up at a single tertiary referral center from 1988 to 2020 by Kaplan-Meier Estimates, and assessed age, sex, hormonal activity, tumor size, and metastatic spread at first diagnosis, pathohistological PASS score, mutation-positive PPGLs (MP-PPGL), TR, and comorbidities (associated with increased cardiovascular risk) as to independent prognostic markers thereof by multivariate Cox-regression. Certificats of the Austrian death registry were also obtained. Results In 8 (5%) PPGLs there was no FU in the charts, but death certified occurring 65±28 (mean±SD, median 2.7) months after first diagnosis. Mean (±SD) age of the remaining 165 (43.9% female) patients (94.5 Pheos, 3.0% multiple PGLs, 2.5% head-and-neck PGLs) was 49(±16) years, mean (range) FU 90(3-537) months. 93 (54%) patients underwent genetic testing, 37 (40%, 21% of entire cohort) had MP-PPGL (mean±SD age 33.8±13.2 yrs, OAS 391 months). 5 of these 37 (13.5%), and 7 of 57 (12%) mutation-negative (MN-PPGL, mean±SD age 53.3±14.8 years, p&amp;lt;0.01 vs. MP-PPGL, OAS 190 months) died during FU (p=0.03). Male sex, higher age, presence of comorbidities, and primary metastatic disease were independent negative prognostic factors for OAS by univariate, but only age and metastatic disease remained significant by multivariate analysis. As to PFS, higher age and no hormonal activity were negatively associated by univariate, but not by multivariate analysis, as were all other tested parameters. Conclusions The cohort of our study is the third-largest original report on long-term FU and prognostic markers in PPGL. While others (Ayola-Ramirez et al, JECM 2011) in 371 patients found tumor size and sympathetic PGL independently associated with OAS, we did not. Patients may have harbored more aggressive tumors in that study, as higher primary metastatic spread (25% of Pheos, 60% of sympathetic PGL) was identified. We identified only age and metastatic disease as independent predictors of OAS, in line with data from Korea (Kim J H, et al., Endocrinol Metab. [Seoul]) in 1048 patients (9% with primary metastatis) and with a metaanalysis comprising 703 PPGLs (Crona J, Endocr Relat Cancer, 2019). Presentation: Sunday, June 12, 2022 12:00 p.m. - 12:15 p.m.