Poor Prognostic Group Research Articles

Efficacy of the combination of lenvatinib with pembrolizumab in patients with advanced renal cell carcinoma

Objective: to re-evaluate the efficacy and safety of lenvatinib with pembrolizumab in unselected Russian renal cell carcinoma (RCC) patients, included in the phase IV study, in a median follow-up extended to 17.1 months. The primary end point was progression-free survival (PFS), secondary end points were overall survival (OS), objective response rate (ORR) and duration of response (DOR), disease control rate (DCR) and its duration, as well as safety.Materials and methods. The study included medical data of 165 patients with verified advanced RCC who received lenvatinib with pembrolizumab in 36 centers of the Russian Federation from 05.02.2018 to 25.07.2024. The median age was 60 (20–76) years, the male to female ratio was 2.3:1. The majority of patients had Karnofsky performance status ³80 % (74.6 %), clear cell RCC (93.3 %) without sarcomatoid differentiation (93.3 %), metachronous metastases (50.9 %) localized in >1 organ (75.2 %), were nephrectomized (63.0 %) and did not receive antitumor therapy (91.0 %). At the time of lenvatinib with pembrolizumab therapy start 40 patients (24.2 %) were classified into International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable prognostic group, 92 (55.8 %) in the intermediate prognostic group, and 33 (20.0 %) in the poor prognostic group. The median follow-up was 17.1 (1.5–72.9) months.Results. The median PFS achieved 24.0 (18.7–29.3) months, 17-month PFS 60.5 %. The median OS was 48.9 (18.5– 79.2) months, 17-month OS – 76.1 %. Objective response was registered in 46.0 % of patients including 2.4 % complete responders; the DCR was 92.1 %. The median DOR was 16.6 (2.1–72.9) months, duration of disease control –14.3 (2.1–72.9) months. Confirmed dynamics of change in the sum of tumor foci diameters was recorded in 152 patients, while the median change was –25 % (from –100 % to +29 %). Any decrease in the sum of tumor foci diameters occurred in 69.1 % of cases. The incidence of any adverse events (AE) was 78.2 %, severe AE – 24.2 %, and serious AE – 9.7 %. Immune-mediated AEs developed in 17.0 % of cases and AE grades 3–4 in 6.7 % of cases. Mortality from AEs was 1.2 %.Conclusion. Compared with the registration study, in real-world clinical practice in patients with advanced RCC the lenvatinib with pembrolizumab provides a lower ORR with comparable PFS and OS rates and demonstrates a satisfactory safety profile.

Comparative analysis of efficacy and safety of combined immunotherapy and immune targeted therapy in the first-line treatment of advanced renal cell carcinoma: a real-world study

Aim. To compare of efficacy and safety of combined immune therapy (dual immune-oncology – IO combination therapies, IO-IO) and immune targeted therapy (ITT) in the first line treatment of patients with advanced renal cell carcinoma (RCC) treated in real world clinical practice. Materials and methods. The ambispective study enrolled patients with metastatic RCC aged ≥18 years, with measurable neoplastic lesions, who were treated with first-line IO-IO therapy or ITT. The primary endpoint was progression-free survival (PFS). Results. The study included data from 126 patients treated with IO-IO [46 (36.5%) patients of the IMDC intermediate and poor prognostic groups] or ITT [80 (63.5%) patients of all IMDC prognostic groups]. In a median follow-up of all patients of 16.1 (0.1–44.9) months, the median PFS was 16.1 (10.9–21.3) months, the median overall survival (OS) was not reached; one-year OS was 83.0%; the objective response rate on the first line of therapy was 44.4% with a complete response rate of 3.2%. The rate of tumor control was 88.1%. In the overall population, ITT versus IO-IO provided a significant benefit in terms of ORR (51.2% vs 32.6%; p=0.032), PFS (median 22.9 months vs 8.0 months; p=0.004) and one-year OS (87.5% vs 65.2%; p=0.042). In the IPTW population, multivariate analysis confirmed the independent prognostic significance of the treatment regimen for PFS (hazard ratio, 2.3; 95% confidence interval, 1.1–4.8; p=0.037) and OS (hazard ratio, 2.3; 95% confidence interval 1.1–4.8; p=0.037). No difference in the safety profile of IO-IO and ITT was identified. Conclusion. The results support the hypothesis that ITT is more effective than IO-IO in the first-line treatment of advanced RCC in patients of IMDC intermediate and poor prognostic groups.

The FLARE Score and Circulating Neutrophils in Patients with Cancer and COVID-19 Disease.

Inflammation and neutrophils play a central role in both COVID-19 disease and cancer. We aimed to assess the impact of pre-existing tumor-related inflammation on COVID-19 outcomes in patients with cancer and to elucidate the role of circulating neutrophil subpopulations. We conducted a multicenter retrospective analysis of 524 patients with cancer and SARS-CoV-2 infection, assessing the relationship between clinical outcomes and circulating inflammatory biomarkers collected before and during COVID-19 infection. Additionally, a single-center prospective cohort study provided data for an exploratory analysis, assessing the immunophenotype of circulating neutrophils and inflammatory cytokines. The primary endpoints were 30-day mortality and the severity of COVID-19 disease. Prior to COVID-19, 25% of patients with cancer exhibited elevated dNLR, which increased to 55% at the time of COVID-19 diagnosis. We developed the FLARE score, incorporating both tumor- and infection-induced inflammation, which categorized patients into four prognostic groups. The poor prognostic group had a 30-day mortality rate of 68%, significantly higher than the 23% in the favorable group (p < 0.0001). This score proved to be an independent predictor of early mortality. This prospective analysis revealed a shift towards immature forms of neutrophils and higher IL-6 levels in patients with cancer and severe COVID-19 infection. A pre-existing tumor-induced pro-inflammatory state significantly impacts COVID-19 outcomes in patients with cancer. The FLARE score, derived from circulating inflammatory markers, emerges as an easy-to-use, globally accessible, effective tool for clinicians to identify patients with cancer at heightened risk of severe COVID-19 complications and early mortality who might benefit most from immediate and intensive treatment strategies. Furthermore, our findings underscore the significance of immature neutrophils in the progression of COVID-19 in patients with cancer, advocating for further investigation into how these cells contribute to both cancer and COVID-19 disease.

Decision making for health-related research outcomes that alter diagnosis: A model from paediatric brain tumours.

The question of how to handle clinically actionable outcomes from retrospective research studies is poorly explored. In neuropathology, this problem is exacerbated by ongoing refinement in tumour classification. We sought to establish a disclosure threshold for potential revised diagnoses as determined by the neuro-oncology speciality. As part of a previous research study, the diagnoses of 73 archival paediatric brain tumour samples were reclassified according to the WHO 2016 guidelines. To determine the disclosure threshold and clinical actionability of pathology-related findings, we conducted a result-evaluation approach within the ethical framework of BRAIN UK using a surrogate clinical multidisciplinary team (MDT) of neuro-oncology specialists. The MDT identified key determinants impacting decision-making, including anticipated changes to patient management, time elapsed since initial diagnosis, likelihood of the patient being alive and absence of additional samples since cohort inception. Ultimately, none of our research findings were considered clinically actionable, largely due to the cohort's historic archival and high-risk nature. From this experience, we developed a decision-making framework to determine if research findings indicating a change in diagnosis require reporting to the relevant clinical teams. Ethical issues relating to the use of archival tissue for research and the potential to identify actionable findings must be carefully considered. We have established a structured framework to assess the actionability of research data relating to patient diagnosis. While our specific findings are most applicable to the pathology of poor prognostic brain tumour groups in children, the model can be adapted to a range of disease settings, for example, other diseases where research is dependent on retrospective tissue cohorts, and research findings may have implications for patients and families, such as other tumour types, epilepsy-related pathology, genetic disorders and degenerative diseases.

Sarcopenia in colorectal cancer is related to socio-economic deprivation and Body Mass Index alone misrepresents underlying muscle loss in the deprived

Background & AimsPatients with colorectal cancer who are more socio-economically deprived have worse outcomes; deprivation is also associated with higher obesity rates, defined as a body mass index (BMI) of greater than thirty. Body composition (BC) factors such as sarcopenia and myosteatosis are also known to predispose to poorer outcomes following colorectal cancer surgery. There is limited evidence to date to relate the effect of deprivation upon these host characteristics that are linked to prognosis. We aimed to examine the relationship between deprivation and body composition in colorectal cancer. MethodsAnalysis was performed on a prospectively collected database of preoperative primary colorectal cancer patients at St Mark’s – The National Bowel Hospital, UK. Body composition characteristics were identified by analysing the L3 axial slices of Computer Tomogram (CT) slices of preoperative staging using Slice-O-Matic software with Automatic Body composition Analyser using Computed tomography image Segmentation (ABACS) L3 plug-in. Deprivation status for each patient was determined using their postal code which was linked to the Index of Multiple Deprivation (IMD). Each domain of the IMD was examined individually in relation to BC characteristics. Binary logistic regression analysis was performed on the data using a model developed from previous published analyses of this dataset. Results419 patients were included in the final analysis, the median age was 69 years and 57% of the patient population was male. Patients who were more deprived were significantly more likely to be sarcopenic [OR 1.56 (95% CI 1.01-2.41, p=0.045)] and myosteatotic [OR 1.69 (95% CI 1.019-2.81, p=0.042)]. More deprived patients were also more likely to have a lower BMI [OR 0.60 (95% CI 0.38-0.94, p=0.026)] despite no significant difference in visceral obesity between the most and least deprived. ConclusionsDeprivation is an important independent determinant of sarcopenia in the colorectal cancer population. Identifying these patients early and addressing reversible factors may help improve post-operative surgical outcomes in this poor prognostic group. Sarcopenia may be a premorbid state in the deprived colorectal cancer patient that may not be wholly driven by tumour characteristics.

Bone Metastases in Non-Seminomatous Germ Cell Tumors: A 20-Year Retrospective Analysis.

Background: Non-seminomatous germ cell tumors (NSGCTs) represent a rare yet the most prevalent malignancy among young men. Bone metastases (BMs) are exceedingly uncommon in this neoplasm, and available data regarding the initial disease presentation, survival outcomes, and prognostic significance of BMs are limited. Methods: We conducted a retrospective analysis of 40 NSGCT patients with BMs treated between 2001 and 2021 in our tertiary care center. The cohort was stratified into synchronous (n = 29) and metachronous (n = 11) groups based on the presence of BM at diagnosis or only at relapse, respectively. We assessed overall survival (OS), progression-free survival (PFS), disease presentation, and treatments. Results: After a median follow-up of 93 months, the 5-year PFS and OS rates were 37.6% and 53.9% in the synchronous group and 18.2% and 36.4% in the metachronous group, respectively. At the initial diagnosis, most patients were classified into the IGCCCG poor prognostic group (n = 34, 85%). BMs were mostly asymptomatic (n = 23, 57.5%), involved the spine (n = 37, 92.5%), and could become visible only after disease response (n = 4, 10%). A pathological examination of resected bone lesions after first-line treatment revealed necrosis (n = 5, 71.4%), teratoma, or seminoma (both n = 1, 14.3%). At first relapse, eight patients in the synchronous group did not experience bone recurrence, while eight patients experienced recurrence at the initial affected bone site. Conclusions: In NSGCT patients, BMs often present asymptomatically and may initially be unnoticed. However, these patients may have a poorer prognosis compared to those in the IGCCCG poor prognostic group. Further studies including control groups are needed to assess the independent prognostic significance of BMs.

Survival by first-line therapy and prognostic group among men with metastatic castration-resistant prostate cancer.

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with prognoses varying from months to years at time of castration-resistant diagnosis. Optimal first-line therapy for those with different prognoses is unknown. We conducted a retrospective cohort study of men in a national healthcare delivery system receiving first-line therapy for mCRPC (abiraterone, enzalutamide, docetaxel, or ketoconazole) from 2010 to 2017, with follow-up through 2019. Using commonly drawn prognostic labs at start of mCRPC therapy (hemoglobin, albumin, and alkaline phosphatase), we categorized men into favorable, intermediate, or poor prognostic groups depending on whether they had none, one to two, or all three laboratory values worse than designated laboratory cutoffs. We used Kaplan-Meier methods to examine prostate specific antigen (PSA) progression-free and overall survival (OS) according to prognostic group and first-line therapy, and multivariable cox regression to determine variables associated with survival outcomes. Among 4135 patients, median PSA progression-free survival (PFS) was 6.9 months (95% confidence interval [CI] 6.6-7.3), and median OS 18.8 months (95% CI 18.0-19.6), ranging from 5.7 months (95% CI 4.8-7.0) in the poor prognosis group to 31.3 months (95% CI 29.7-32.9) in the favorable group. OS was similar regardless of initial treatment received for favorable and intermediate groups, but worse for those in the poor prognostic group who received ketoconazole (adjusted hazard ratio 2.07, 95% CI 1.2-3.6). PSA PFS was worse for those who received ketoconazole compared to abiraterone across all prognostic groups (favorable HR 1.76, 95% CI 1.34-2.31; intermediate HR 1.78, 95% CI 1.41-2.25; poor HR 8.01, 95% CI 2.93-21.9). Commonly drawn labs at mCRPC treatment start may aid in predicting survival and response to therapies, potentially informing discussions with care teams. First-line treatment selection impacts disease progression for all men with mCRPC regardless of prognostic group, but impacted OS only for men with poor prognosis at treatment start.

A new prognostic tool for metastatic colorectal cancer patients receiving anti-angiogenic treatment, the PALM score: A single-center experience.

e15575 Background: Even if anti-angiogenic agents are crucial for metastatic colorectal cancer (mCRC) patients (pts) treatment, to date, no validated prognostic biomarkers are available. We conducted at our Centre a retrospective research to identify a prognostic tool to be applied in clinical practice in this population. Methods: We retrospectively collected laboratory, radiological and clinical data of mCRC pts treated with anti-angiogenic agents at the Medical Oncology Unit of Cagliari University Hospital (2018- 02/2024) in order to identify a potential prognostic tool. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; cut-off: ROC curves; differences among variables: Chi-square test). Results: Globally, 33 mCRC pts were evaluated in our study (19 male, 14 female; 13 RAS wild-type, 22 left-sided primary). 10 were treated with anti-angiogenic drugs in the 1st-line, 13 in the 2nd-line (bevacizumab and aflibercept) and 10 in 1st-2nd line. Median OS was 39.5 months (m) (95%CI:28.2-41.3), median Progression Free Survival (PFS) was 14.9 m (95%CI:9.5-18.5). Pts with lower platelet to lymphocyte ratio (P; ≤253; p &lt; 0.0001, HR = 0,00000048; 95%CI 24.7-39.5 versus [vs] 95% CI 8.2-10.5), alkaline phosphatase (A; &lt; 136 U/l; p = 0.0001, HR = 0.0001; 95%CI 12-39.5 vs 95% CI 8.2-10.5) and lactate dehydrogenasis (L; &lt; 365 U/l; p &lt; 0.0001, HR = 0.0000004; 95%CI 24.7-39.5 vs 95% CI 8.2-10.5) and higher monocyte count (M; &gt; 0.3x103/μL; p = 0.0093, HR 0.01; 95%CI 26.5-39.5 vs 95%CI 8.2-24.7), showed a statistically improved OS. We created the “PALM score” and separated pts in two prognostic groups: good prognostic group (0 unfavorable variables: PALM = 0) and poor prognostic group (≥1 unfavorable variable, PALM = 1). OS was significantly improved in the good prognostic group (PALM = 0): 31.5 m (95%CI:24.7-39.5) vs 10.5 m (PALM = 1) (p = 0.0031, HR = 0.00006). Chi-square test revealed also a statistically significant correlation of upfront resection of primary tumor with the PALM score (73.9% of patients belonging to the PALM = 0 group had undergone surgery for primary tumor and all patients with resected primary belonged to the PALM = 0 group (p = 0.0352). Conclusions: Our research showed a promising prognostic role of easy-to-use PALM score tool in mCRC patients treated with anti-angiogenic drugs in a limited population at our center. Further prospective studies with larger sample size are needed to confirm our findings.

Emerging Treatment Options for Neuroendocrine Neoplasms of Unknown Primary Origin: Current Evidence and Future Perspectives.

Among neuroendocrine neoplasms (NENs), a non-negligible proportion (9-22%) is represented by sufferers of NENs of unknown primary origin (UPO), a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, current guidelines suggest that the treatment of UPO-NENs should be based on tumor clinical-pathological characteristics, disease burden, and patient conditions. Chemotherapy represents the backbone for the treatment of high-grade poorly differentiated UPO-NENs, usually providing deep but short-lasting responses. Conversely, the spectrum of available systemic therapy options for well-differentiated UPO-NENs may range from somatostatin analogs in indolent low-grade tumors, to peptide receptor radioligand therapy, tyrosine kinase inhibitors (TKIs), or chemotherapy for more aggressive tumors or in case of high disease burden. In recent years, molecular profiling has provided deep insights into the molecular landscape of UPO-NENs, with both diagnostic and therapeutic implications. Although preliminary, interesting activity data have been provided about upfront chemoimmunotherapy, the use of immune checkpoint inhibitors (ICIs), and the combination of ICIs plus TKIs in this setting. Here, we review the literature from the last 30 years to examine the available evidence about the treatment of UPO-NENs, with a particular focus on future perspectives, including the expanding scenario of targeted agents in this setting.

Predictors of Immunotherapy Efficacy in Metastatic Non-Small Cell Lung Cancer: Lung Immune Prognostic Index and Immune-Related Toxicity.

Immune checkpoint inhibitors (ICIs) have been proposed as the standard first-line and subsequent treatment for metastatic non-small cell lung cancer (NSCLC). This study analyzed whether patients with good lung immune prognostic index (LIPI) have a better response to ICIs and the relationship between immune-related adverse events (irAEs) and response in clinical practice. This was an observational, retrospective, single-center study. Patients with stage IV NSCLC between 2016 and 2021 were included in the study. Toxicity was assessed according to The Common Terminology Criteria for Adverse Events. Response assessment was performed according to RECIST 2.0 and immuno-related criteria. Descriptive and survival analyses were conducted. Degree of toxicity and response to treatment (based on treatment and histology) were assessed. LIPI and response were assessed. LIPI included dNLR (absolute neutrophil count/(white blood cell count - absolute neutrophil count)) ≥ 3 and lactate dehydrogenase (LDH) greater than the upper limit of normal. Patients were stratified into good (G), intermediate (I), and poor (P) prognostic groups. A total of 168 patients were included (130 men and 38 women, mean age 64.3 years). ICI use in the first- or second-line treatment was 65% and 35%, respectively. Fifteen (9%) patients showed complete response (CR), 50 (30%) showed partial response (PR), 39 (22%) had stable disease (SD), 45 (28%) had progressive disease (PD), and 19 (11%) were not evaluated (NE). Patients with good prognostic LIPI (dNLR < 3 and normal LDH levels) showed a better response. Progression-free survival (PFS) was 19 months in G, 6 months in I, and 2 months in P. Overall survival (OS) was 27 months in G, 8 months in I, and 3 months in P. One hundred fourteen patients died (56% G, 76% I, 93% P). Patients with adenocarcinoma were 116 (77 with irAEs G1-4 (13 CR, 31 PR, 21 SD, eight PD, and four NE)), and without were 39 (three PR, six SD, 21 PD, and nine NE). Fifty-two patients had squamous carcinoma (27 with irAEs G1-4 (two CR, 12 PR, nine SD, and four PD)), and 25 did not (four PR, three SD, 12 PD, and six NE)). IrAEs appearance was observed in longer PFS (19 vs. 2 months) and OS (27 vs. 4 months; P < 0.0001). LIPI was a positive predictor of response to ICI. The presence of irAEs is associated with a better immune response. In contrast, the absence of toxicity predicted a worse prognosis.

Impact of teratoma on survival probabilities of patients with metastatic non-seminomatous germ cell cancer: Results from the IGCCCG Update Consortium

AimsTo resolve the ongoing controversy surrounding the impact of teratoma (TER) in the primary among patients with metastatic testicular non-seminomatous germ-cell tumours (NSGCT). Patients and methodsUsing the International Germ Cell Cancer Collaborative Group (IGCCCG) Update Consortium database, we compared the survival probabilities of patients with metastatic testicular GCT with TER (TER) or without TER (NTER) in their primaries corrected for known prognostic factors. Progression-free survival (5y-PFS) and overall survival at 5 years (5y-OS) were estimated by the Kaplan-Meier method. ResultsAmong 6792 patients with metastatic testicular NSGCT, 3224 (47%) had TER in their primary, and 3568 (53%) did not. In the IGCCCG good prognosis group, the 5y-PFS was 87.8% in TER versus 92.0% in NTER patients (p = 0.0001), the respective 5y-OS were 94.5% versus 96.5% (p = 0.0032). The corresponding figures in the intermediate prognosis group were 5y-PFS 76.9% versus 81.6% (p = 0.0432) in TER and NTER and 5y-OS 90.4% versus 90.9% (p = 0.8514), respectively. In the poor prognosis group, there was no difference, neither in 5y-PFS [54.3% in TER patients versus 55.4% (p = 0.7472) in NTER], nor in 5y-OS [69.4% versus 67.7% (p = 0.3841)]. NSGCT patients with TER had more residual masses (65.3% versus 51.7%, p < 0.0001), and therefore received post-chemotherapy surgery more frequently than NTER patients (46.8% versus 32.0%, p < 0.0001). ConclusionTeratoma in the primary tumour of patients with metastatic NSGCT negatively impacts on survival in the good and intermediate, but not in the poor IGCCCG prognostic groups.

Association of lung immune prognostic index with survival outcomes in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

Lung immune prognostic index is based on derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase level. Lung immune prognostic index has reported association with survival outcomes in patients with various malignancies undergoing treatment with immune checkpoint inhibitors. However, the prognostic impact of pre-treatment lung immune prognostic index in patients with metastatic renal cell carcinoma receiving nivolumab plus ipilimumab treatment remains unclear. This study examines the association between lung immune prognostic index and outcomes in this setting. We retrospectively evaluated 156 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab at eight institutions. We assessed the associations between pre-treatment lung immune prognostic index and survival outcomes including progression-free survival, second progression-free survival (PFS2), cancer-specific survival and overall survival. Patients were classified into good (n=84, 54%), intermediate (n=52, 33%) and poor (n=20, 13%) lung immune prognostic index groups. Progression-free survival did not significantly differ between lung immune prognostic index groups, but there was significant difference in PFS2, cancer-specific survival and overall survival. In multivariable Cox proportional hazard analyses, high pre-treatment lung immune prognostic index was a significant predictor of poor PFS2 (vs. good group, intermediate group: P=0.01 and poor group: P=0.04) and poor overall survival (vs. good group, intermediate group: P=0.01 and poor group: P<0.01). Moreover, the patients with poor lung immune prognostic index had significantly poorer cancer-specific survival than those with good LIPI (P<0.01). High pre-treatment LIPI is suggested by our results to be a significant independent predictor of poor prognosis in patients receiving nivolumab plus ipilimumab for metastatic renal cell carcinoma.

Performance of CT in the locoregional staging of colon cancer: detailed radiology-pathology correlation with special emphasis on tumor deposits, extramural venous invasion and T staging.

To investigate the performance of computed tomography (CT) in the local staging of colon cancer in different segments, with emphasis on parameters that have been found to be significant for rectal cancer, namely, extramural venous invasion (EMVI) and tumor deposits (TDs). CT and pathology data from 137 patients were independently reviewed by radiology and pathology teams. The performance of CT in categorizing a given patient into good, versus poor prognostic groups was assessed for each segment, as well as the presence of lymph nodes (LNs), TDs and EMVIs. Discordant cases were re-evaluated to determine potential sources of error. Elastic stain was applied for EMVI discordance. The T staging accuracy was 80.2%. For T stage stratification, CT performed slightly better in the left colon, and the lowest accuracy was in the transverse colon. Under-staging was more common (in 12.4%), and most of the mis-staged cases were in sigmoid colon. According to the first comprehensive correlative analysis, the sensitivity, specificity, and accuracy of CT for detecting TDs were found to be 57.9%, 92.4%, 87.6%, respectively. These figures were 44.7%, 72.7%, and 63.5% for LN, and 58.5%, 82.1% and 73% for EMVI. The detection rate was better for multifocal EMVI. The detection rate was also comparable (although substantially underestimated) for LNs, with the half of the LNs missed by CT being < 5mm. Four patients that were classified as TD by CT, disclosed to be LNs by pathology. Correlative analysis led to refinement of the pathology criteria, with subsequent modifications of the initial reports in 13 (9.5%) patients. Overall, CT performed well in the evaluation of colon cancer, as did TD and EMVI. It is advisable to include these parameters in CT-based staging. Radiologists should be aware of the pitfalls that occur more commonly in different segments.

Carboplatin, paclitaxel, and pembrolizumab followed by pembrolizumab maintenance for primary treatment of incompletely resected epithelial ovarian cancer.

Incompletely resected epithelial ovarian cancer represents a poor prognostic subset of patients. Novel treatment strategies are needed to improve outcomes for this population. We evaluated a treatment strategy combining platinum-based chemotherapy with pembrolizumab followed by pembrolizumab maintenance therapy in the first-line treatment after incomplete resection of epithelial ovarian cancer patients. This was a single-arm, non-randomized pilot study of carboplatin, taxane, and immune checkpoint inhibitor, pembrolizumab, followed by 12 months of maintenance pembrolizumab in patients with incompletely resected epithelial ovarian cancer (EOC). A total of 29 patients were enrolled and evaluated for efficacy and safety. The best response to therapy was complete response in 16 (55%) patients, partial response in 9 (31%) patients, and 3 (10%) patients with progression of disease. The median progression-free survival (PFS) was 13.2 months. Grade 3 and 4 toxicities occurred in 20% of patients. In all, 7 patients discontinued therapy due to adverse events. Quality-of-life scores remained high during therapy. Response to therapy did not correlate with PD-L1 tumor expression. Combination platinum-taxane therapy with pembrolizumab did not increase median progression-free survival in this cohort of patients. EOC is an immunogenic disease, but immune checkpoint inhibitor therapy has yet to impact outcomes. The current study utilized pembrolizumab in combination with standard chemotherapy followed by a maintenance treatment strategy in incompletely resected EOC. Progression-free survival was not extended in this poor prognostic group with combined chemotherapy and immunotherapy. https://clinicaltrials.gov/, identifier NCT 027766582.

HRD related signature 3 predicts clinical outcome in advanced tubo-ovarian high-grade serous carcinoma

ObjectivesWe evaluated usability of single base substitution signature 3 (Sig3) as a biomarker for homologous recombination deficiency (HRD) in tubo-ovarian high-grade serous carcinoma (HGSC). Materials and methodsThis prospective observational trial includes 165 patients with advanced HGSC. Fresh tissue samples (n = 456) from multiple intra-abdominal areas at diagnosis and after neoadjuvant chemotherapy (NACT) were collected for whole-genome sequencing. Sig3 was assessed by fitting samples independently with COSMIC v3.2 reference signatures. An HR scar assay was applied for comparison. Progression-free survival (PFS) and overall survival (OS) were studied using Kaplan–Meier and Cox regression analysis. ResultsSig3 has a bimodal distribution, eliminating the need for an arbitrary cutoff typical in HR scar tests. Sig3 could be assessed from samples with low (10%) cancer cell proportion and was consistent between multiple samples and stable during NACT. At diagnosis, 74 (45%) patients were HRD (Sig3+), while 91 (55%) were HR proficient (HRP, Sig3-). Sig3+ patients had longer PFS and OS than Sig3- patients (22 vs. 13 months and 51 vs. 34 months respectively, both p < 0.001). Sig3 successfully distinguished the poor prognostic HRP group among BRCAwt patients (PFS 19 months for Sig3+ and 13 months for Sig3- patients, p < 0.001). However, Sig3 at diagnosis did not predict chemoresponse anymore in the first relapse. The patient-level concordance between Sig3 and HR scar assay was 87%, and patients with HRD according to both tests had the longest median PFS. ConclusionsSig3 is a prognostic marker in advanced HGSC and useful tool in patient stratification for HRD.

Synergy of Ruxolitinib and Carfilzomib in Targeting the PAX5::JAK2 fusion I n Vitro: Potential Therapeutic Advantage for a Subset of Ph-like Acute Lymphoblastic Leukemia

INTRODUCTION PAX5::JAK2 is a gene fusion that drives a subset of Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) and confers aggressive disease, poor prognosis and poor response to treatment. PAX5::JAK2 is present in approximately 12% of Ph-like ALL cases. Targeted therapy is urgently required to improve outcomes. We evaluated the efficacy of JAK inhibitor ruxolitinib (RUX) and proteosome inhibitors carfilzomib (CFZ) and bortezomib (BTZ) as monotherapy and in combination against PAX5::JAK2 transfected Ba/F3 cells in vitro. Downregulation of proteosome genes via reduction in STAT3 phosphorylation is a shared mechanism of RUX and proteosome inhibitors. Given that the PAX5::JAK2 fusion results in increased STAT3 phosphorylation driving proliferation, it was proposed that the combination of proteosome inhibitors and RUX would demonstrate synergy in inhibiting proliferation of PAX5::JAK2 driven leukemic cells. METHODS Mouse derived Ba/F3 cells, an IL-3 dependent B-ALL model, were transfected with the PAX5::JAK2 fusion and demonstrated IL-3 independence. We applied, as single treatments, differing concentrations of RUX and the proteosome inhibitors CFZ and BTZ to PAX5::JAK2 transfected Ba/F3 cells and two control cell lines - IL-3 dependent empty vector Ba/F3 cells and an IL-3 independent KG1a myeloid cell line. Differing concentrations of CFZ and 200nM of RUX were then applied in combination. 200nM of RUX was selected because it is a dose at which the drug has minimal effect as a single agent. Inhibitors were applied to cells for 72 hours then percentage of live and dead cells at each concentration was ascertained by flow cytometry using Annexin V and LIVE/DEAD fixable aqua dead cell stain. Downstream STAT5 and STAT3 activation in basal state, and as a response to treatment, was assessed using phosphoflow. We demonstrated mechanisms of growth inhibition via reduction in STAT5 and STAT3 phosphorylation by the inhibitors. RESULTS RUX, CFZ and BTZ were all effective against PAX5::JAK2 transfected Ba/F3 cells with a median lethal dose (LD50) of 514nM (CI 498-530nM) for RUX, 38nM (CI 36-39nM) for CFZ and 19nM (CI 18-20nM) for BTZ. RUX had a variable effect on IL-3 dependent empty vector control cells which also demonstrate JAK/STAT activation, but no effect on the IL-3 independent KG1a cells. CFZ had a lesser effect on empty vector control cells with a LD50 of 59nM (CI 58-60nM) and no effect on KG1a control cells. BTZ had a significant effect on both control cell lines, predicting off-target toxicity and consequently was not applied in combination with RUX. RUX and CFZ in combination demonstrated an LD50 of 21nM (CI 18-25nM) (see figure 1) which is significantly lower than the LD50s for either agent used as monotherapy. Combination index for RUX and CFZ at 45nM was 0.80 and at 50nM was 0.49, suggesting moderate synergy. Phosphoflow demonstrated reduced pSTAT5 with the application of RUX and CFZ to PAX5::JAK2 transfected Ba/F3 cells with mean fluorescence intensity (MFI) reducing from 351 to 285 in inhibitor treated cells, while for STAT3 MFI reduced from 396 to 249. (see figure 2) There was no effect on MFI for control cell lines. This demonstrates that the mechanism for growth inhibition is inhibition of JAK/STAT signaling due to the reduction in pSTAT3 and pSTAT5. CONCLUSIONS We showed in vitro that RUX, CFZ and BTZ are all potent against the high risk PAX5::JAK2 fusion. RUX and CFZ in combination demonstrated moderate synergy against PAX5::JAK2 and inhibited proliferation through their effect on JAK/STAT pathways. The RUX/CFZ combination, drugs widely available in clinical practice, is particularly promising given the apparent synergistic effect on limiting leukemic cell growth. Such treatments warrant clinical trials for management of the poor prognostic group of Ph-like ALL with PAX5::JAK2, given that they may enhance efficacy and lessen toxicity. Clinical trials have already demonstrated efficacy and safety of RUX and CFZ as single agents in combination with chemotherapy for the treatment of B-ALL which indicates the feasibility of combining the two agents clinically in Ph-like ALL.

Outcomes of relapsed clinical stage I versus de novo metastatic testicular cancer patients: an analysis of the IGCCCG Update database

BackgroundActive surveillance after orchiectomy is the preferred management in clinical stage I (CSI) germ-cell tumours (GCT) associated with a 15 to 30% relapse rate.Patients and methodsIn the IGCCCG Update database, we compared the outcomes of gonadal disseminated GCT relapsing from initial CSI to outcomes of patients with de novo metastatic GCT.ResultsA total of 1014 seminoma (Sem) [298 (29.4%) relapsed from CSI, 716 (70.6%) de novo] and 3103 non-seminoma (NSem) [626 (20.2%) relapsed from CSI, 2477 (79.8%) de novo] were identified. Among Sem, no statistically significant differences in PFS and OS were found between patients relapsing from CSI and de novo metastatic disease [5-year progression-free survival (5y-PFS) 87.6% versus 88.5%; 5-year overall survival (5y-OS) 93.2% versus 96.1%). Among NSem, PFS and OS were higher overall in relapsing CSI patients (5y-PFS 84.6% versus 80.0%; 5y-OS 93.3% versus 88.7%), but there were no differences within the same IGCCCG prognostic groups (HR = 0.89; 95% CI: 0.70–1.12). Relapses in the intermediate or poor prognostic groups occurred in 11/298 (4%) Sem and 112/626 (18%) NSem.ConclusionRelapsing CSI GCT patients expect similar survival compared to de novo metastatic patients of the same ICCCCG prognostic group. Intermediate and poor prognosis relapses from initial CSI expose patients to unnecessary toxicity from more intensive treatments.

Association of the Estrogen Receptors Beta Expression with the Ki-67 Proliferative Index in Breast Cancer

Background. Estrogen receptors beta (ERβ) are an important biological regulator and target of antiestrogens, however, unlike estrogen receptors alpha (ERɑ), their significance in the prognosis and treatment of breast cancer remains unclear. Purpose. Evaluation of the ERβ prognostic value in the comparative assessment of frequency and level of the marker expression in groups with good and poor prognosis by Ki-67 proliferative index score in breast cancer. Methods. ERβ expression level (% of cells expressing the marker) in 68 breast tissue samples was quantified by immunofluorescence and flow cytometry. Primary antibodies to ERβ (clone 14C8, ab288) and secondary antibodies conjugated with DyLight650 (ab98729) were used. In the same samples, the Ki-67 expression level was assessed by the immunohistochemical method. Results. The ERβ and Ki-67 were detected in 100% breast tissue samples with high heterogeneity of the markers’ expression in different patients. Statistical analysis of good and poor prognosis in accordance with the Ki-67 proliferative index score (Ki-67≤20% and Ki-67&gt;20%) showed the prognostic value of the ERβ expression level of 50%. There was no association between the Ki-67 and ERβ expression levels in the same tumor sample (Spearman's rank correlation coefficient R=–0,16; P&gt;0,05). At the same time, high expression of ERβ≥50% was 2,3 times more frequently detected in the good vs poor prognostic group by Ki-67 — 41% vs 18%, P=0,02. Conclusion. The ERβ expression level ≥50% in the tumor can be considered as a factor of good prognosis of breast cancer.

Control of Ph+ and additional chromosomal abnormalities in chronic myeloid leukemia by tyrosine kinase inhibitors.

Chronic myeloid leukemia (CML) is a type of blood cancer that is known to affect hematopoietic stem cells. The presence of the Philadelphia chromosome (Ph+) is the major characteristic of CML. A protein expressed by the Philadelphia chromosome shows elevated tyrosine kinase activity and is considered a tumorigenic factor. The first line of therapy that had been established for CML was "imatinib," a potent tyrosine kinase inhibitor. Various other second- and third-generation TKIs are taken into account in cases of imatinib failure/resistance. With the subsequent rise in the development of tyrosine kinase inhibitors, optimization in the treatment of CML and amplified total survival were observed throughout TKI dosage. As the disease progresses, additional chromosomal abnormalities (ACAs) have been reported, but their prognostic effect and impact on the response to treatment are still unknown. However, some substantial understandings have been achieved into the disease transformation mechanisms, including the role of somatic mutations, ACAs, and several different genomic mutations that occur during diagnosis or have evolved during treatment. The acquisition of ACAs impedes CML treatment. Due to additional chromosomal lesions, there are greater chances of future disease progression at the time of CML diagnosis beyond the Ph+ translocation. The synchronous appearance of two or more ACAs leads to lower survival and is classified as a poor prognostic group. The key objective of this review is to provide detailed insights into TKIs and their role in controlling Ph+ and ACAs, along with their response, treatment, overall persistence, and survival rate.

Tumor subtypes and signature model construction based on chromatin regulators for better prediction of prognosis in uveal melanoma.

Background: Uveal Melanoma (UM) is the most prevalent primary intraocular malignancy in adults. This study assessed the importance of chromatin regulators (CRs) in UM and developed a model to predict UM prognosis. Methods: Gene expression data and clinical information for UM were obtained from public databases. Samples were typed according to the gene expression of CRs associated with UM prognosis. The prognostic key genes were further screened by the protein interaction network, and the risk model was to predict UM prognosis using the least absolute shrinkage and selection operator (LASSO) regression analysis and performed a test of the risk mode. In addition, we performed gene set variation analysis, tumor microenvironment, and tumor immune analysis between subtypes and risk groups to explore the mechanisms influencing the development of UM. Results: We constructed a signature model consisting of three CRs (RUVBL1, SIRT3, and SMARCD3), which was shown to be accurate, and valid for predicting prognostic outcomes in UM. Higher immune cell infiltration in poor prognostic subtypes and risk groups. The Tumor immune analysis and Tumor Immune Dysfunction and Exclusion (TIDE) score provided a basis for clinical immunotherapy in UM. Conclusion: The risk model has prognostic value for UM survival and provides new insights into the treatment of UM.