The immune modulatory effect of tivozanib, a tyrosine kinase inhibitor, and the underlying immune mechanisms impacting survival of HCC patients have not been investigated. Pre-clinical studies have ...shown that tivozanib reduces Tregs and MDSCs accumulation through inhibition of c-Kit/SCF axis. We rationalized that c-Kit/SCF axis antagonism by tivozanib may reverse tumor-induced immune suppression in HCC patients. The frequency of circulating Tregs, MDSCs, CTLA-4
+
Tregs, PD-1
+
T cells, c-Kit
+
pERK-2
+
Tregs, and c-Kit
+
pERK-2
+
MDSCs were quantified in HCC patients at baseline and two time points during tivozanib treatment. We report for the first time that reduction in Tregs after tivozanib treatment and increased levels of baseline CD4
+
PD-1
+
T cells correlated with significant improvement in overall survival (OS) of the patients and these signatures may be potential biomarkers of prognostic significance. This immune modulation resulted from tivozanib-mediated blockade of c-Kit/SCF signaling, impacting ERK2 phosphorylation on Tregs and MDSCs. Low pre-treatment CD4
+
T cells: Treg ratio and reduction in the frequencies of Foxp3
+
c-Kit
+
pERK
+
Tregs after tivozanib treatment correlated significantly with progression free survival. In a comparative analysis of tivozanib vs sorafenib treatment in HCC patients, we demonstrate that decrease in the baseline numbers or frequencies of Foxp3
+
Tregs, MDSCs and exhausted T cells was significantly greater following tivozanib treatment. Additionally, greater increase in CD4
+
T cell: Treg ratio after tivozanib treatment was associated with significant improvement in OS compared to sorafenib treatment, highlighting the greater efficacy of tivozanib. These insights may help identify patients who likely would benefit from c-Kit/SCF antagonism and inform efforts to improve the efficacy of tivozanib in combination with immunotherapy.
Introduction. Paratesticular sarcomas are defined as tumors that arise within the scrotum and include the subsites of epididymis, spermatic cord, and tunica vaginalis and represent the most common ...type of GU sarcoma. The mainstay of treatment is often surgical resection, combined with histology specific chemotherapy and radiotherapy. Due to the rare nature of the disease, there are limited data to guide management. We present our single-institution retrospective experience regarding the management and treatment of paratesticular sarcomas. Materials and Methods. We queried our oncology registry database for patients treated for testicular, spermatic cord, and scrotal soft tissue sarcomas between 1971 and 2017. Patients in this series had pathological confirmation of a sarcoma diagnosis by a sarcoma-specialized pathologist. Only patients with localized disease were included in this analysis with the exception of patients with a diagnosis of rhabdomyosarcoma where patients with both localized and metastatic disease were included on this study. Results. A total of 34 patients were included in this retrospective analysis. The median was 24 (range, 5–78), and the median tumor size was 6.25 cm. Twenty-six patients had localized disease (76.6%) at the time of diagnosis. A predominance of patients had tumors involving the spermatic cord (45.5%), and the most common histology was rhabdomyosarcoma (35.3%), leiomyosarcoma (26.5%), and well-differentiated liposarcoma (23.5%). The median follow-up was 71.0 months (range, 2.5–534.4 months). A total of 7 patients experienced an isolated local failure (20.6%), four patients developed distant metastatic disease (11.8%), and one patient (2.9%) with synovial sarcoma of the spermatic cord experienced a regional recurrence. The median progression-free survival (PFS) was 99.6 months, 95% CI (45.8–534.3 months), with a three-year PFS rate of 71%, 95% CI (53%–83%), and a 5-year PFS rate of 64% (range, 46%–78%). We did not find any statistically significant associations based on surgery type (p=0.15), the use of chemotherapy, (p=0.36), or final margin status (p=0.21). Two patients who were treated with preoperative radiotherapy had significant wound healing complication with chronic sinus tracts, though these patients did not experience a local recurrence. Conclusions. We provide a characterization of the natural history and treatment patterns of paratesticular sarcomas. While effective at reducing a local recurrence, preoperative radiotherapy was associated with significant toxicity. As a result, we prefer the use of postoperative radiotherapy in patients as clinically indicated. We did not find any specific treatment patterns associated with an improvement in clinical outcomes.
Past studies on suicide have investigated the association of firearm ownership and suicide risk in the United States. The aim of the present study was to build on previous work by examining the ...impact of firearm storage practices and the strictness of firearm regulation on suicide rates at the state level. Data were compiled from primarily three sources. Suicide and firearm ownership information was obtained from the Centers for Disease Control and Prevention. Strictness of handgun regulation was derived from figures available at the Law Center to Prevent Violence, and controls were taken from the US Bureau of the Census. Mixed models were fitted to the data. Household firearm ownership was strongly associated with both suicide by all mechanisms, and firearm suicide. Storage practices had especially elevated consequences on suicide rates. Percent with loaded guns and gun readiness increased suicide rates, and strictness of gun regulation reduced suicide rates. Ready access to firearms can make a difference between life and death. Loaded and unlocked firearms within reach become risk factors for fatal outcomes from suicidal behavior. Future research might want to examine ways of obtaining more recent data on individual firearm ownership. This study proposes several policy recommendations for suicide prevention.
Background: Diffuse large B cell lymphoma (DLBCL) constitutes most cases of both primary and secondary central nervous system lymphoma (CNSL). They represent a highly aggressive subset of non-Hodgkin ...lymphoma and prognosis varies depending on the cell of origin. Immunohistochemistry using antibodies for CD10, BCL-6, and MUM-1, also known as the Hans algorithm, is the most common method for determining the cell of origin and predicting outcomes in DLBCL. The study by Hans et al. found that the germinal center B-cell-like (GCB) group had a much better prognosis compared to the non-GCB group, with 5-year overall survival (OS) of 76% and 34% respectively. Despite chemotherapy, recurrence is common in these patients, and up to 40-50% do not achieve durable remission. It is important to identify who may benefit from more aggressive or experimental therapy at diagnosis. Stereotactic radiosurgery (SRS) is the administration of a localized, high dose of ionizing radiation and limited studies exist exploring SRS as a treatment modality in relapsed/refractory (r/r) CNSL or prognostic implications of the Hans algorithm in these patients. Aim/Objective: To perform a retrospective analysis of outcomes of patients with CNSL, phenotypes determined by the Hans algorithm, treated with SRS at a single comprehensive cancer center. Methods: We studied the demographic, clinical, pathological, and treatment characteristics of r/r CNSL patients (N=27), age ≥ 18 years, who received SRS at Roswell Park Comprehensive Cancer Center between 01/2000 and 01/2023. The Hans algorithm was used to group the patients into non-GCB (N=17) and GCB (N=10) cohorts. Overall survival (OS) and progression-free survival (PFS) were calculated and reported using Kaplan-Meier analyses and log-rank tests. Cox regression models were used to describe cross-cohort comparisons of survival. Results: The median Karnofsky performance status at diagnosis was 70 for both groups. The overall response rate (ORR) to SRS in GCB-type was 80% (7 complete response and 1 partial response; CR, PR). The ORR in non-GCB type was 58% (6 CR and 4 PR). Post-SRS, stem cell transplant (SCT) was avoided in 100% of the patients in the GCB group, while 17% of the patients in the non-GCB group received SCT. The 6-month overall survival (OS) rate was 100% and 46% for the GCB-type and non-GCB type respectively (p=0.096, Figure 1A). The 6-month progression-free survival (PFS) rate was 80% for the GCB-type and 33% for the non-GCB type (p=0.024, Figure 1B). In the GCB group, the median OS was 18.0 months while the median PFS was 13.8 months. In the non-GCB group, the median OS was 4.9 months while the median PFS was 3.6 months. The median time from chemotherapy completion to SRS administration was 8.0 months in the GCB-type and 2.0 months in the non-GCB type. Conclusion: Our data support that the GCB-type predicts a more favorable outcome in CNSL, with improved OS and PFS rates compared to the non-GCB type. In addition, the non-GCB type patients required earlier SRS administration and had a lower ORR to SRS. Classifying CNSL into GCB and non-GCB phenotypes using the Hans algorithm might help characterize patients into groups with different prognoses.
Real world outcomes of trilaciclib in ES-SCLC Elijah, Joseph; Holdsworth, Allison; Wang, Katy ...
Journal of clinical oncology,
06/2023, Letnik:
41, Številka:
16_suppl
Journal Article
Recenzirano
e20637
Background: Carboplatin, etoposide, and atezolizumab (PEA) is the most widely used combination for first-line treatment of extensive-stage small cell lung cancer (ES-SCLC).
...Chemotherapy-induced myelosuppression is a common sequalae that is traditionally managed with lineage-specific supportive care modalities.
Studies that evaluated trilaciclib versus placebo in combination with chemotherapy demonstrated statistically significant improvements in the duration of severe neutropenia (SN), defined as ANC < 500 cells/µL, in cycle 1 and incidence of SN as a result of its transient myeloprotective effects. There remains considerable controversy in the adoption of trilaciclib as a supportive medication in clinical practice. The objective of this quality assessment study was to assess utility of trilaciclib in real-world ES-SCLC patients. Methods: This was a single center study with quasi-experimental design comparing patients with confirmed ES-SCLC who received trilaciclib + PEA (PEAT) from April 2021 to July 2022 versus those who received PEA without trilaciclib (PEA) from February 2020 to February 2021. Patients with limited-stage SCLC, prior treatment with immunotherapies, carboplatin dose AUC < 3.5 with cycle 1, and active clinical trial enrollment were excluded. The primary endpoint evaluated was incidence of SN after cycle 1 and during treatment period. Additional measures related to myelopreservation and patient outcomes were assessed as secondary endpoints. Demographic data was analyzed using descriptive statistics. Dichotomous and continuous variables were compared by Mann-Whitney U or one-sided Fisher’s exact test. Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier (KM) estimate. Results: 34 patients received PEAT and 44 patients received PEA. Demographic and baseline clinical characteristics were similar between both cohorts except for older median age of patients (69 years old vs 64 years old) and higher proportion of male patients (65% vs 39%) in the trilaciclib cohort. Even though there was a numerically lower rate of SN (3%) and hospitalization due to febrile neutropenia (FN) or infection (6%) in the PEAT versus the PEA (18%;11%) cohort, statistical significance was not met (p = 0.07;p = 0.065). Likewise, incidence of FN, platelet transfusion requirements, all-cause chemotherapy reductions, and treatment delays were not statistically different. However, the PEAT cohort as compared to PEA experienced a statistically significant reduction in red blood cell transfusion requirements (3% vs 23%; p = 0.02) and grade 3-4 anemia (6% vs 25%; p = 0.03). PFS and OS between the two cohorts were not statistically different. Conclusions: Based on this single center retrospective study, use of trilaciclib appears to confer improvement in the safety profile of PEA without negatively impacting survival outcomes. Therefore, results of this study support the integration of trilaciclib with PEA for ES-SCLC.
599
Background: Well-differentiated NETs are highly vascular and hence, inhibition of angiogenesis is of interest. VEGF, a key molecule in promoting angiogenesis, has also been shown to promote an ...immunosuppressive tumor microenvironment. Nintedanib, an oral inhibitor of FGFR1–3, VEGFR1–3 and PDGFRA, has previously been evaluated in a phase II clinical trial in well-differentiated, non-pancreatic NETs, where 83% of the evaluable patients were progression-free at 16 weeks and median PFS was 11 months. In preclinical studies, nintedanib has been shown to increase PD-L1 expression in tumor cells, which then results in improved outcomes with immune checkpoint inhibition. There are multiple indicators of T-cell exhaustion, including PD-L1 and LAG-3. LAG-3+ T-cells have been found to correlate with poor response to treatment in neuroendocrine neoplasms. Given these findings, this study evaluates serum VEGF and LAG-3 expression to determine potential biomarkers of response in patients treated with nintedanib. Methods: 27 sets of paired samples collected at baseline and 8-weeks post treatment with nintedanib, from clinical trial NCT02399215 were used for this study. With IRB approval, we tested for serum VEGFa and serum LAG-3 using Luminex test kits: HCKP1-11K-01 (LAG-3) and HCYTA-60K-01 (VEGFa). We compared the baseline, 8-week, and percentage change in serum VEGF and serum LAG-3 levels with Rd Cd8+ pAkt+ T-cells (activated cytotoxic T-cells) as a marker of immune activation, Rd CD25+ pAkt+ T-cells (regulatory T-cells) as a marker of immune suppression, and PFS. Results: The median VEGF levels at baseline and 8-weeks were 10.50 pg/mL and 11.90 pg/mL respectively. The median LAG-3 level at baseline and 8-weeks were 59000 pg/mL and 62900 pg/mL respectively. Higher VEGFa levels in the post-treatment samples were associated with poorer progression free survival (HR= 1.009, 95% HR CI: 0.999, 1.019, with P= 0.0760). Higher levels of VEGF at baseline were also associated with lower numbers of Rd CD8+ pAkt + cells (Pearson coefficient = -0.42, p-value 0.04) at baseline. Increased baseline CD25+ pAkt+ levels were positively correlated with percent change in serum LAG-3 levels between baseline and post-treatment samples. (Pearson Co-efficient: 0.45; p=value: 0.02). Conclusions: Elevated serum VEGFa levels at 8-weeks post treatment correlated with lower PFS. Serum VEGFa level is a potential indicator of effector T-cell suppression, as evidenced by low number of activated cytotoxic T-cells in patients with higher VEGFa levels at baseline. Higher baseline regulatory T-cells were associated with a greater increase in serum LAG-3 levels, suggesting that serum LAG-3 may be an indicator of an immunosuppressive tumor microenvironment.
One in six gay and bisexual men will be diagnosed with prostate cancer in their lifetime. Lesbian, gay, bisexual, and transgender (LGBT) populations are under-represented in cancer research, and ...guidelines on prostate-specific antigen (PSA) screening are limited. We performed a cross-sectional study to assess patterns of PSA screening and decision-making in this cohort. The Behavioral Risk Factor Surveillance System database was queried for LGBT adults for 2014–2016 and 2018, when PSA questions were asked in the annual survey. Multivariable logistic regression was performed to evaluate the association of LGBT status with PSA screening and informed and shared decision-making. A total of 164 370 participants were eligible for PSA screening, representing a weighted estimate of 1.2 million LGBT individuals. Compared to cisgender (CG) straight individuals, CG gay/bisexual cohorts were more likely to participate in PSA screening (CG gay: odds ratio OR 1.07; p < 0.001; CG bisexual: OR 1.06; p < 0.001). CG gay participants were more likely to make informed decisions (OR 1.10; p < 0.001) and engage in shared decision-making (OR 2.55; p < 0.001). Select gay populations were more likely to undergo PSA screening recommended by their clinicians and participate in informed and shared decision-making.
This large study of sexual and gender minorities in the USA suggests that gay and bisexual individuals were more likely to undergo prostate cancer screening and that select gay individuals were more likely to make informed and shared decisions. However, transgender individuals were less likely to have prostate cancer screening and make informed decisions.
Select gay populations are more likely to undergo prostate cancer screening and make informed and shared decisions. However, transgender populations are less likely to have prostate cancer screening and make informed decisions.
Abstract only
728
Background: Anorectal squamous cell carcinomas (SCCs) are rare in the United States with < 10,000 cases annually. Uncommonly, patients present with stage IV disease or recurrence ...after definitive therapy. Limited options exist for these patients. We queried Roswell Park Cancer Institute (RPCI) patient records to determine systemic treatments utilized and outcomes for these patients. Methods: Patients with anal or rectal SCC between 1/1/99 and 7/1/2014 were identified via the cancer registry. 65 patients were flagged for review. From manual review, 31 patients received treatment at RPCI and were deemed evaluable. Demographic data, histology, staging, treatment history, time receiving any specific therapy and response assessment were abstracted from the records. Results: Of the 31 patients, 45% were male, 55% female. Primary tumors were anorectal (84%) or rectal (16%) in origin. 5(16%) presented with rectal SCC. Sites of metastatic disease were most commonly identified as lymph nodes (48%), liver (35) or lung (16%). At the time of analysis 5 (16%) were alive, with 3 (10%) disease free. Median overall survival (OS) was 44.1 months (95% CI, 28.9 - 62.6). The most commonly utilized chemotherapy regimens were 5-fu/cisplatin (n = 22 patients) and taxol (n = 10). Mean time on therapy was 4 months for 5-fu/platinum doublets (n = 24), 4 months for taxanes/platinum combinations (n = 6), 3.4 months for anti-EGFR containing regimens (n = 7) and 2.43 months for taxane monotherapy (n = 10). The most common reasons for discontinuation of therapy were progressive disease (47%) or patient choice (15%). Conclusions: New therapies are desperately needed for advanced anorectal SCCs. At present, 5-FU/cisplatin is the best endorsed and most frequently utilized regimen. Consistent with other reports, platinum doublets and anti-EGFR targeted therapies appear to confer significant benefits, within the realm of 5-fu/cisplatin, with single agent taxanes appearing to have lesser activity. Small absolute patient numbers and lack of reliable response measurements preclude firm conclusions. Future clinical trials to evaluate systemic therapies in advanced anorectal SCCs, including anti-EGFR regimens, are warranted.
Background: Acute myeloid leukemia (AML) is an aggressive hematological malignancy arising from immature myeloid progenitors with notoriously poor outcomes, particularly in the elderly. Venetoclax ...(Ven) plays an essential role in acute myeloid leukemia (AML) directed therapy as it is approved for frontline therapy in combination with azacitidine (Aza), decitabine (Dec), or low-dose cytarabine (LDAC) for patients aged 75 years and older, or those with significant comorbidities. However, venetoclax-based therapy is not curative, and the ideal salvage regimen is unclear in these patients. We performed a retrospective review that analyzed a single center's venetoclax-based regimens to identify rational subsequent lines of therapy after failing venetoclax. Methods: We conducted a retrospective review of adult patients at Roswell Park Comprehensive Cancer Center who had a confirmed AML diagnosis and received a venetoclax-based regimen as upfront therapy between January 2015-February 2023. Demographics, prior hematological disorders, ELN risk stratification, Eastern Cooperative Oncology Group (ECOG) performance status, treatment received in upfront vs relapsed/refractory settings, date of remission/relapse, disease-specific variables molecular data, cytogenetics, and outcomes duration of response, time to progression, MRD status, and overall survival were collected. Of note, in patients who received upfront venetoclax regimen, the subsequent salvage therapy was grouped by targeted (Gliterinib, Enasidenib, Ivosidenib), low-intensity (single agent hypomethylating therapy, gemtuzumab, ozogamicin), or intensive groups (CLAG-M) and analysis was performed for progression-free survival (PFS). The patient demographics and clinical characteristics were summarized by group (i.e. response, regimens) using the Mann-Whitney U and Fisher's exact test. Survival functions were described by the Kaplan-Meier method and compared with the Log-rank test. Analyses were performed in SAS v9.4 (Cary, NC) at a significance level of 0.05. Results: The retrospective study analyzed 97 patients. In the upfront analysis, the median age was 73.4 years (range: 51.4-89.8) and 64 (66.0%) of the patients were male. 65 patients (67.0%) received Aza/Ven, 26 (26.8%) Dec/Ven, and 6 (6.2%) LDAC/Ven. Per ELN 2022 criteria, 13.3% of patients were stratified as favorable,12.2% as intermediate, and 74.4% as adverse risk. Of the adverse risk patients, 67/97 (69.1%) patients received Aza/Ven. Median survival time for all upfront induction regimens was 15.8 months (95% CI: 8.1-22.6), greatest median survival with Aza/Ven of 19.1 months (95% CI:10.4-23.6). Median PFS by all induction regimens was 8.9 months (95% CI: 5.0-13.9) with the greatest median PFS being Aza/Ven at 10.9 months (95% CI: 6.6-20.2); p=0.045). Overall, 29 out of 97 (29.9%) patients received salvage therapy. These included 19 (65.5%) males with 93.1% of patients being Caucasian. The majority of patients (81.5%) had adverse ELN risk stratification (Table 1). Total 1-year survival rate is 0.050 (0.31-0.67), with intensive 0.050 (0.16-0.67), low intensity 0.67 (0.35-0.86), targeted 0.39 (0.18-0.60). Total 3-year survival rate is 0.19 (0.06-0.38) with intensive 0.17 (0.02-0.46), low intensity 0.30 (0.08-0.56), and targeted 0.20 (0.05-0.41). Patients receiving subsequent salvage therapy after upfront venetoclax regimen showed the greatest PFS after receiving low-intensity therapy compared to targeted or intensive regimens with a median survival of 13.9 months (95% CI: 0.0-35.9); p<0.001) (Figure 1). Median survival after intensive therapy was 1.3 months (95% CI:0.5-3.9) and targeted therapy 5.8 months (95% CI: 2.8-10.0). Total OS 14.9 (95% CI: 6.1-22.7) with a low-intensity median survival of 22.7 months (95% CI:1.4-Not Reached (NR)). Conclusion: In this single-center retrospective review, it was found that a low-intensity salvage regimen after the upfront venetoclax regimen showed the greatest PFS compared to targeted or intensive regimens, however, there is no statistically significant difference in OS. Our study results were limited by a small sample size. Further studies are needed to clearly define the ideal salvage regimen for AML patients failing upfront venetoclax-based therapy.
Given the paucity of level 1 evidence, the optimal regimen to control oral mucositis pain remains unclear. Although national guidelines allow consideration of prophylactic gabapentin, prior trials ...showed improved pain control with venlafaxine among patients with diabetic neuropathy. We sought to investigate the role of prophylactic high-dose gabapentin with venlafaxine to reduce oral mucositis pain among patients with head and neck cancer.
We performed a single-institution, phase 2 randomized trial on nonmetastatic squamous cell carcinoma of the head and neck treated with chemoradiation. Patients were randomized to either prophylactic gabapentin (3600 mg daily) with or without venlafaxine (150 mg daily). Primary endpoint was differences in pain levels at the end of chemoradiation. Secondary endpoint was toxicity profiles, quality of life changes, opioid use, and feeding tube placement. Differences between the 2 arms at multiple time points were evaluated using a generalized linear mixed regression model with Sidak correction.
Between May 2018 and March 2021, a total of 62 patients were enrolled and evaluable for analysis (n = 32 for the gabapentin alone arm, n = 30 for the gabapentin + venlafaxine arm). Over 90% of patients tolerated gabapentin well. Head and neck pain level showed a mean value of 45 (standard deviation, 23) and 43 (standard deviation, 21) for the gabapentin alone and the gabapentin + venlafaxine arms, respectively (P = .65). No statistically significant differences were observed in adverse events, opioid use, feeding tube placement, or quality of life.
The addition of venlafaxine to prophylactic gabapentin did not result in improvements in pain control and quality of life among patients with head and neck cancer.
PDF
