Several studies have found an association between higher body mass index (BMI) and improved clinical outcomes in cancer patients receiving programmed cell death protein-1 (PD-1)/programmed cell ...death-ligand 1 (PD-L1) checkpoint inhibitors. In a previous study, we found that overweight/obese patients were significantly more likely to experience any grade immune-related adverse events (irAEs) compared to non-overweight patients.
We conducted a 'real-life', multi centre, retrospective observational study aimed at comparing the incidence of irAEs among cancer patients treated with PD-1/PD-L1 inhibitors according to baseline BMI.
One thousand and seventy advanced cancer patients were evaluated. The median age was 68 years (range: 21–92), male/female ratio was 724/346. Primary tumours were: non-small-cell lung carcinoma (NSCLC) (653 patients), melanoma (233 patients), renal cell carcinoma (RCC) (152 patients) and others (29 patients). Median BMI was 25 (13.6–46.6); according to World Health Organisation (WHO) classification, 44 patients (4.1%) were defined as underweight, 480 patients (44.9%) as having a normal weight, 416 patients (38.9%) as overweight and 130 patients (12.1%) as obese. Higher BMI was significantly related to higher occurrence of any grade immune-related adverse events irAEs (p < 0.0001), G3/G4 irAEs (p < 0.0001) and irAEs leading to discontinuation (LTD) (p < 0.0001). Overweight and obesity were confirmed predictors for irAEs of any grade at both univariate and multivariate analysis. The adjusted odds ratios (ORs) (compared to normal-weight) were 10.6; 95% confidence interval (95%CI): 7.5–14.9 for overweight, and 16.6 (95%CI: 10.3–26.7) for obese patients. Obesity was the only factor significantly related to a higher incidence of G3/G4 irAEs (OR = 11.9 95%CI: 6.4–22.3, p < 0.0001) and LTD irAEs (OR = 8.8 95%CI: 4.3–18.2, p < 0.0001). Overweight and obese patients experienced a significantly higher occurrence of cutaneous, endocrine, gastro-intestinal (GI), hepatic and 'others' irAEs, compared to normal-weight patients. Only obese patients experienced a significantly higher occurrence of pulmonary and rheumatic irAEs, compared to normal-weight patients.
Considering the previously evidenced association between higher BMI and better outcome, the current finding about the relationship between BMI and irAEs occurrence can contribute to consideration of these findings as the upside of the downside, which underlies an 'immunogenic phenotype'.
•Several studies have found an association between higher BMI and improved outcomes in patients receiving PD-1/PD-L1 checkpoint inhibitors.•The upside of the downside of this obesity paradox, might be the association between BMI and immune-related adverse events (irAEs).•In this large case series, we found a significant association, between BMI and irAEs.
Immune-related adverse events (irAEs) developed during immunotherapy with anti-PD-1 agents, could be a predictive surrogate marker of clinical benefit in patients with advanced non–small-cell lung ...cancer (NSCLC).
Patients with NSCLC, treated with anti-PD-1 agents, were retrospectively evaluated. Univariate and multivariate analyses were performed to evaluate the relationships between types of irAEs (differentiated according to system/organ involved and to single-site/multiple-site), overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). We further performed a 6-week landmark analysis.
A total of 559 patients were enrolled; 231 patients (41.3%) developed irAEs of any grade and 50 patients (8.9%) G3/G4 events; 191 of them (82.6%) developed “single-site” irAEs and 40 (17.4%) “multiple-site” irAEs. At multivariate analysis, higher ORR was related to irAEs of any grade (P < .0001), “single-site” irAEs (P < .0001), endocrine (P = .0043) and skin irAEs (P = .0005). Longer PFS was related to irAEs of any grade (P < .0001), “single-site” irAEs (P < .0001), “multiple-site” irAEs (P = .0374), endocrine irAEs (P = .0084) and skin irAEs (P = .0001). Longer OS was related to irAEs of any grade (P < .0001), “single-site” irAEs (P < .0001), endocrine irAEs (P = .0044), gastrointestinal irAEs (P = .0437), skin irAEs (P = .0006), and others irAEs (P = .0378). At the 6-week landmark analysis, irAEs of any grade was confirmed an independent predictor of higher ORR, longer PFS, and longer OS.
Our study confirmed that irAEs are concordantly related to higher ORR, longer PFS, and longer OS with anti-PD-1 immunotherapy in patients with NSCLC.
The aim of this study was to investigate with a large sample size, the predictive and prognostic positive roles of occurrence of immune-related adverse events in patients with non–small-cell lung cancer treated with PD-1 inhibitors. The study confirmed that immune-related adverse events are independent predictors of higher overall response rate, longer progression-free survival and longer overall survival.
To provide further information on the clinical and pathological prognostic factors in triple-negative breast cancer (TNBC), for which limited and inconsistent data are available.
Pathological ...characteristics and clinical records of 841 TNBCs diagnosed between 1994 and 2015 in four major oncologic centers from Sardinia, Italy, were reviewed. Multivariate hazard ratios (HRs) for mortality and recurrence according to various clinicopathological factors were estimated using Cox proportional hazards models.
After a mean follow-up of 4.3 years, 275 (33.3%) TNBC patients had a progression of the disease and 170 (20.2%) died. After allowance for study center, age at diagnosis, and various clinicopathological factors, all components of the TNM staging system were identified as significant independent prognostic factors for TNBC mortality. The HRs were 3.13, 9.65, and 29.0, for stage II, III and IV, respectively, vs stage I. Necrosis and Ki-67 > 16% were also associated with increased mortality (HR: 1.61 and 1.99, respectively). Patients with tumor histotypes other than ductal invasive/lobular carcinomas had a more favorable prognosis (HR: 0.40 vs ductal invasive carcinoma). No significant associations with mortality were found for histologic grade, tumor infiltrating lymphocytes, and lymphovascular invasion. Among lymph node positive TNBCs, lymph node ratio appeared to be a stronger predictor of mortality than pathological lymph nodes stage (HR: 0.80 for pN3 vs pN1, and 3.05 for >0.65 vs <0.21 lymph node ratio), respectively. Consistent results were observed for cancer recurrence, except for Ki-67 and necrosis that were not found to be significant predictors for recurrence.
This uniquely large study of TNBC patients provides further evidence that, besides tumor stage at diagnosis, lymph node ratio among lymph node positive tumors is an additional relevant predictor of survival and tumor recurrence, while Ki-67 seems to be predictive of mortality, but not of recurrence.
Abstract
Background
Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely ...investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era.
Methods
We investigated the Meet-URO-15 study dataset of 571 pretreated mRCC patients receiving nivolumab as second or further lines about the prognostic role of the previous nephrectomy (received in either the localized or metastatic setting) in the overall population and according to the Meet-URO score groups.
Results
Patients who underwent nephrectomy showed a significantly reduced risk of death (HR 0.44, 95% CI 0.32–0.60,
p
< 0.001) with a longer median overall survival (OS) (35.9 months vs 12.1 months), 1-year OS of 71.6% vs 50.5% and 2-years OS of 56.5% vs 22.0% compared to those who did not. No significant interaction between nephrectomy and the overall five Meet-URO score risk groups was observed (
p
= 0.17). It was statistically significant when merging group 1 with 2 and 3 and group 4 with 5 (
p
= 0.038) and associated with a longer OS for the first three prognostic groups (
p
< 0.001), but not for groups 4 and 5 (
p
= 0.54).
Conclusions
Our study suggests an overall positive impact of the previous nephrectomy on the outcome of pretreated mRCC patients receiving immunotherapy. The clinical relevance of cytoreductive nephrectomy, optimal timing and patient selection deserves further investigation, especially for patients with Meet-URO scores of 1 to 3, who are the once deriving benefit in our analyses. However, that benefit is not evident for IMDC poor-risk patients (including the Meet-URO score groups 4 and 5) and a subgroup of IMDC intermediate-risk patients defined as group 4 by the Meet-URO score.
Abstract Aim A number of targeted therapies (TTs) are effective in metastatic renal cell carcinoma (mRCC) but clinical outcomes with the sequential use of three TTs have been poorly investigated, ...this study evaluates their outcome. Methods Patients with clear cells mRCC treated with three TTs were retrospectively studied. Therapies were classified as vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) or mammalian target of rapamycin inhibitors (mTORi). Progression free survival (PFS), overall survival (OS) and total PFS (tPFS) – defined as the time from start of first-line to progression on third-line treatment – were estimated using the Kaplan–Meier method and curves were compared with log-rank test. Results A total of 2065 patients with mRCC were consecutively treated with first-line TT in 23 centres in Italy. Overall 281/2065 patients (13%) were treated with three TTs. Median OS and tPFS were 44.7 and 34.1 months, respectively and were longer in patients receiving the sequence vascular endothelial growth factor inhibitors (VEGFi)–VEGFi–mTORi compared with those receiving VEGFi–mTORi–VEGFi with a statistical difference in OS (50.7 versus 37.8 months, p = 0.004; 36.5 versus 29.3 months, p = 0.059, respectively). Conclusions Few patients received three lines of TTs. The sequence VEGFi–VEGFi–mTORi was associated with improved survival with respect to VEGFi–mTORi–VEGFi and primary resistance to first-line was a negative predictive and prognostic factor.
Triple Negative breast cancer (TNBC) includes a heterogeneous group of tumors with different clinico-pathological features, molecular alterations and treatment responsivity. Our aim was to evaluate ...the clinico-pathological heterogeneity and prognostic significance of TNBC histologic variants, comparing "special types" to high-grade invasive breast carcinomas of no special type (IBC-NST).
This study was performed on data obtained from TNBC Database, including pathological features and clinical records of 1009 TNBCs patients diagnosed between 1994 and 2015 in the four most important Oncology Units located in different hospitals in Sardinia, Italy. Kaplan-Meier analysis, log-rank test and multivariate Cox proportional-hazards regression were applied for overall survival (OS) and disease free survival (DFS) according to TNBC histologic types.
TNBC "special types" showed significant differences for several clinico-pathological features when compared to IBC-NST. We observed that in apocrine carcinomas as tumor size increased, the number of metastatic lymph nodes manifestly increased. Adenoid cystic carcinoma showed the smallest tumor size relative to IBC-NST. At five-year follow-up, OS was 92.1, 100.0, and 94.5% for patients with apocrine, adenoid cystic and medullary carcinoma, respectively; patients with lobular and metaplastic carcinoma showed the worst OS, with 79.7 and 84.3%, respectively. At ten-years, patients with adenoid cystic (100.0%) and medullary (94.5%) carcinoma showed a favourable prognosis, whereas patients with lobular carcinoma showed the worst prognosis (73.8%). TNBC medullary type was an independent prognostic factor for DFS compared to IBC-NST.
Our study confirms that an accurate and reliable histopathologic definition of TNBC subtypes has a significant clinical utility and is effective in the therapeutic decision-making process, with the aim to develop innovative and personalized treatments.
Background Immune-checkpoint inhibitors (ICIs) have significantly improved metastatic renal cell carcinoma (mRCC) prognosis, although their efficacy in patients with bone metastases (BMs) remains ...poorly understood. We investigated the prognostic role of natremia in pretreated RCC patients with BMs receiving immunotherapy. Materials and methods This retrospective multicenter study included RCC patients with BMs receiving nivolumab as second-line therapy or beyond. Inclusion criteria involved baseline sodium levels (pre-ICI) and sodium levels after 4 weeks of nivolumab initiation (post-ICI). The population was divided into two groups based on the median value, and response rates, progression-free survival (PFS), and overall survival (OS) were assessed. Results Among 120 eligible patients, those with pre-treatment sodium levels ≥140 mEq/L showed longer OS (18.7 vs. 12.0 months, p=0.04). Pre-treatment sodium levels ≥140 mEq/L were associated with better OS compared to levels <140 mE/L (18.7 vs. 12.0, p=0.04). Post-treatment sodium levels ≥140 mEq/L were associated with improved PFS (9.6 vs . 3.2 months) and OS (25.1 vs. 8.8 months) (p=0.05 and p<0.01, respectively). Patients with consistent sodium levels ≥140 mEq/L at both time points exhibited the best outcomes compared to those with lower values (PFS 11.5 vs. 3.3 months and OS 42.2 vs. 9.0 months, respectively, p<0.01). Disease control rate was significantly higher in the latter group (p<0.01). Multivariate analysis confirmed the prognostic significance of sodium levels. Conclusion Elevated sodium levels (≥140 mEq/L) pre- and post-ICI treatment correlate with better survival outcomes in mRCC patients with BMs. This finding suggests sodium level assessment as a potential prognostic factor in these patients and warrants further investigation, particularly in combination immunotherapy settings.
Background:
Traditional total knee implants designs, usually, are not able to reproduce the physiological kinematics of the knee, leaving almost 20% of the patients, those who underwent a total knee ...arthroplasty (TKA), not fully satisfied. Modern inserts are nowadays designed with a fully congruent medial compartment to reproduce the normal medial pivoting biomechanics of the knee. The aim of this article was to evaluate preliminary clinical improvement using the Medial Congruent (MC) insert as specific level of constraint.
Materials and methods:
A total of 10 consecutive patients have been enrolled in this study and treated using an MC tibial polyethylene insert. The Oxford Knee Score (OKS) and the Knee Society Score (KSS) have been assessed preoperatively and at 3-month, 6-month, and 1-year follow-up (FU) and used as validated measurements to evaluate early clinical improvements. Postoperative radiological examination was reviewed looking for radiolucent lines or loosening of the components.
Results:
Average improvement in OKS was from 19.5 to 41.2, whereas KSS improved with an average score from 64.7 preoperatively to 167.5 at the final FU showing good to excellent results in 95% of the treated knees. Evaluating the range of motion, the average maximum active movement was 124° and none of the patients needing for a revision surgery or manipulation under anesthesia. No complications were observed at the final FU as septic or aseptic loosening or vascular or neurologic injury.
Discussion and conclusions:
Medial Congruent insert showed good to excellent clinical results at 1-year FU. Range of motion and subjective outcomes were satisfying and comparable with results obtained in literature using traditional TKA design.
Background
Treatment choice for metastatic renal cell carcinoma (mRCC) patients is still based on baseline clinical and laboratory factors.
Methods
By a pre-specified analysis of the Meet-URO 15 ...multicentric retrospective study enrolling 571 pretreated mRCC patients receiving nivolumab, baseline and early dynamic variations (Δ) of neutrophil, lymphocyte, and platelet absolute cell counts (ACC) and their inflammatory ratios (IR) were evaluated alongside their association with the best disease response and overall (OS) and progression-free survival (PFS). Multivariable analyses on OS and PFS between baseline and Δ ACC and IR values were investigated with receiving operating curves-based cut-offs.
Results
The analysis included 422 mRCC patients. Neutrophil-to-lymphocyte ratio (NLR) increased over time due to consistent neutrophil increase (p < 0.001). Higher baseline platelets (p = 0.044) and lower lymphocytes (p = 0.018), increasing neutrophil Δ (p for time-group interaction <0.001), higher baseline IR values (NLR: p = 0.012, SII: p = 0.003, PLR: p = 0.003), increasing NLR and systemic immune-inflammatory index (SII) (i.e., NLR x platelets) Δ (p for interaction time-group = 0.0053 and 0.0435, respectively) were associated with disease progression. OS and PFS were significantly shorter in patients with baseline lower lymphocytes (p < 0.001 for both) and higher platelets (p = 0.004 and p < 0.001, respectively) alongside early neutrophils Δ (p = 0.046 and p = 0.033, respectively). Early neutrophils and NLR Δ were independent prognostic factors for both OS (p = 0.014 and p = 0.011, respectively) and PFS (p = 0.023 and p = 0.001, respectively), alongside baseline NLR (p < 0.001 for both) and other known prognostic variables.
Conclusions
Early neutrophils and NLR Δ may represent new dynamic prognostic factors with clinical utility for on-treatment decisions.
The treatment of heavily pretreated patients with metastatic renal cell carcinoma (mRCC) represents an unmet medical need and is still challenging.
The primary objective was to assess the ...effectiveness of the lenvatinib plus everolimus combination and the secondary objective was the toxicity profile of this combination.
We conducted a longitudinal retrospective study examining mRCC patients pre-treated with one or more lines of therapy among different cancer centers in Italy.
The study included patients who received the combination of lenvatinib plus everolimus as either a second-line treatment or beyond. We assessed progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), response rate (RR), and toxicity profile. In addition, we explored the potential relationship between treatment effectiveness and clinical and laboratory parameters.
In all, 33 patients were assessed, the median age was 60 years, 57% had an Eastern Cooperative Oncology Group performance status of 1-2 and. 63% received ⩾ 3 prior lines of therapy. 62% were 'intermediate risk' according to the International Metastatic Renal Cell Carcinoma Database Consortium and 30% were 'poor risk'. The RR was 42% (no complete response), 18% stable disease. Median OS was 11.2 months (95% CI 6.8-19.9), median PFS was 6.7 months (95% CI 0.6-30.8), and median TTF was 6.7 months (95% CI 4.8-16.6). A shorter OS was significantly associated with lymph node metastases (
= 0.043, 95% CI), neutrophils/ lymphocytes ratio (NLR) ⩾ 3 (
= 0.007), hemoglobin/red cell distribution width ratio cutoff value <0.7 was significant (
= 0.03) while a shorter PFS was associated with lung (
= 0.048) and brain metastases (
= 0.023). The most frequent G1 toxicity was diarrhea (24%), G2 was fatigue (30%), and hypertension and skin toxicity (6%) for G3.
Our findings suggest a clinically relevant effectiveness of lenvatinib plus everolimus combination with an acceptable toxicity profile for heavily pretreated patients with mRCC.
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