LKB1 is a key sensor of metabolic stress, including hypoxia and glucose deprivation, two features of the tumor microenvironment exacerbated by antiangiogenic therapy. We investigated the role of LKB1 ...as a potential predictive marker of sensitivity to bevacizumab in advanced non-small cell lung cancer (aNSCLC).
We retrospectively analyzed LKB1 expression by IHC in 98 samples from 125 patients with aNSCLC, including 59 patients treated with chemotherapy and 39 treated with chemotherapy plus bevacizumab. IHC intensity was recoded in two classes (negative/weak vs. moderate/intense) and correlated with outcome according to treatment arm. Patient-derived tumor xenografts (PDXs) were used to investigate mechanisms involved in preclinical models.
In the whole study population (125), median OS and PFS were 11.7 95% confidence interval (CI), 9.1-15.3 and 6.7 (95% CI, 5.7-7.2) months, respectively. Differential impact of the marker on outcome of the 98 patients was highlighted according to the treatment. Patients with negative/weak LKB1 status did not have a statistically significant benefit from bevacizumab added to chemotherapy (HR for patients treated with bevacizumab: 0.89; 95% CI, 0.51-1.56;
= 0.6803), whereas patients expressing moderate/intense LKB1 and receiving bevacizumab had significant lower risk of death compared with those not receiving bevacizumab (HR, 0.26; 95% CI, 0.10-0.64;
= 0.0035). Loss of LKB1 was associated with reduced AMPK activation in PDXs and increased tumor necrosis following bevacizumab administration, highlighting impaired control of the metabolic stress caused by this antiangiogenic drug.
Our data hint at a possible predictive impact of LKB1 expression in patients with aNSCLC treated with chemotherapy plus bevacizumab.
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Abstract Background Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) with initially unresected tumours represent a particular subset of patients with a poor outcome. Various international research ...groups pooled their data in a joint study in order to investigate prognostic variables and treatment modalities. Methods The study population consisted of 304 patients <21 years old treated between 1980 and 2005 using a multimodality therapeutic strategy. Results Synovial sarcoma and malignant peripheral nerve sheath tumour (MPNST) were the most frequent histotypes. Most patients received initial chemotherapy: major responses were recorded in 41% and minor in 16% of cases. Overall survival (OS) was 60.0% and 51.5% at 5 and 10 years, respectively, and it was significantly associated with patient’s age, histological subtype, tumour site and size, quality of delayed surgical resection, radiotherapy administration and response to induction chemotherapy. MPNST associated to neurofibromatosis type 1 was the tumour type with the worst rate of response to chemotherapy and the worst outcome. Conclusions In unresected NRSTS patients, radiotherapy and delayed surgery are of crucial importance. Patients who respond to chemotherapy have better chance of survival. However, given the relatively poor prognosis, research on intensive multimodal treatment approaches and novel strategies is warranted.
The impact of survivorship bias in glioblastoma research Pasqualetti, Francesco; Barberis, Alessandro; Zanotti, Sofia ...
Critical reviews in oncology/hematology,
August 2023, 2023-Aug, 2023-08-00, 20230801, Letnik:
188
Journal Article
Recenzirano
Despite advances in the therapy of Central Nervous System (CNS) malignancies, treatment of glioblastoma (GB) poses significant challenges due to GB resistance and high recurrence rates following ...post-operative radio-chemotherapy. The majority of prognostic and predictive GB biomarkers are currently developed using tumour samples obtained through surgical interventions. However, the selection criteria adopted by different neurosurgeons to determine which cases are suitable for surgery make operated patients not representative of all GB cases. Particularly, geriatric and frail individuals are excluded from surgical consideration in some cancer centers. Such selection generates a survival (or selection) bias that introduces limitations, rendering the patients or data chosen for downstream analyses not representative of the entire community. In this review, we discuss the implication of survivorship bias on current and novel biomarkers for patient selection, stratification, therapy, and outcome analyses.
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•The progress in biomarker identification for the prognosis and treatment of glioblastoma (GB) is currently unsatisfactory.•The collection of tumour samples for the discovery of novel biomarkers presents numerous limitations.•Exclusion of patients from surgery limits correct representation of the entire GB population, introduces a selection bias and reduces the relevance of translational studies.•The implementation of liquid biopsy has the potential to address the issue of selection bias in GB translational studies.
Background
Malignant peripheral nerve sheath tumors (MPNST) are rare tumors of childhood. The role of standard chemotherapy in unresectable MPNST is still unclear. We report the outcome and ...prognostic factors in the EpSSG risk‐adapted prospective study for localized pediatric MPNST.
Methods
Patients were stratified into four treatment groups defined by surgical resection, tumor size, and tumor grade (G): (a) surgery‐only group—resected tumors G1; (b) adjuvant radiotherapy group—R0/R1, G2 tumors; (c) adjuvant chemotherapy group—R0/R1, G3 tumors; and (d) neoadjuvant chemotherapy group—R2 resected tumors and/or nodal involvement. Chemotherapy consisted of four courses of ifosfamide‐doxorubicin and two courses of ifosfamide concomitant with radiotherapy (50.4‐54 Gy).
Results
Overall, the study included 51 patients. The 5‐year event‐free survival (EFS) and overall survival (OS) were 52.9% (95% confidence interval, 38.1‐65.8) and 62.1% (46.7‐74.3), respectively. The 5‐year EFS was 92% (56.6‐98.9) for treatment group 1 (N = 13), 33% (0.9‐77.4) for treatment group 2 (N = 4), 29% (4.1‐61.2) for treatment group 3 (N = 7), and 42% (23.1‐60.1) for treatment group 4 (N = 27). Response rate to chemotherapy (partial response + complete response) in patients with measurable disease was 46%. The presence of neurofibromatosis type 1 (NF1; 51% of patients) was an independent poor prognostic factor for OS and EFS.
Conclusion
The outcome for patients with resectable MPNST was excellent. Standard ifosfamide‐doxorubicin for unresectable MPNST rendered the best reported outcome. Children with NF1 disease seem to have worse prognosis.
Breast cancer diagnosis and treatment compromise well-being in a pervasive way, and negative consequences may remain after recovery. The psychological side of breast cancer has been extensively ...investigated; however, the role of intrusive thoughts and intolerance of uncertainty have been studied less systematically.
The present study aimed to prospectively evaluate worry content, depression, anxiety, and post-traumatic stress symptoms and to define the role of the trait of worry and intolerance of uncertainty (IU) related to breast cancer.
Patients with their first breast cancer diagnosis were enrolled in a single-center, prospective observational trial. The trait of worry and IU were assessed using the Penn State Worry Questionnaire (PSWQ) and the Intolerance of Uncertainty Scale-Revised (IUS-R). The psychological aspects were evaluated using the Worry Domains Questionnaire (WDQ), the Beck Anxiety (BAI), Beck Depression Inventory-II (BDI-II), and the Impact of Event Scale-Revised (IES-R). Questionnaires were administered in a randomized sequence at diagnosis (T0), 3 months post-diagnosis (T1), and 12 months post-diagnosis (T2).
One hundred and fifty eligible patients were enrolled in the study and provided the T0 assessment. Further compliance rates were 57% at T1 and 64% at T2. All patients showed a significant and continuous increase in the IES-R scale (
< 0.0001) from diagnosis to the end of the study, while no significant changes were observed for the WDQ, BAI, and BDI-II scales. The clinical PSWQ levels and/or high levels of the IUS-R score were the only variables that aided the distinction between patients who maintain high levels of depression, anxiety, and post-traumatic disorders and those who did not.
An early assessment of the components of the trait of worry and intolerance of uncertainty could be critical in identifying patients with a higher psychopathological risk. Furthermore, if future studies confirm the present findings, support and monitoring throughout the prognosis may present crucial benefits, and possibly affect the course of treatment.
Immune Checkpoint Inhibitors (ICIs) lead to durable response and a significant increase in long-term survival in patients with advanced malignant melanoma (MM) and Non-Small Cell Lung Cancer (NSCLC). ...The identification of serum cytokines that can predict their activity and efficacy, and their sex interaction, could improve treatment personalization.
In this prospective study, we enrolled immunotherapy-naïve patients affected by advanced MM and NSCLC treated with ICIs. The primary endpoint was to dissect the potential sex correlations between serum cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, GM-CSF, MCP-1, TNF-ɑ, IP-10, VEGF, sPD-L1) and the objective response rate (ORR). Secondly, we analyzed biomarker changes during treatment related to ORR, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Blood samples, collected at baseline and during treatment until disease progression (PD) or up to 2 years, were analyzed using Luminex xMAP or ELLA technologies.
Serum samples from 161 patients (98 males/63 females; 92 MM/69 NSCLC) were analyzed for treatment response. At baseline, IL-6 was significantly lower in females (F) versus males (M); lower levels of IL-4 in F and of IL-6 in both sexes significantly correlated with a better ORR, while higher IL-4 and TNF-ɑ values were predictive of a lower ORR in F versus M. One hundred and sixty-five patients were evaluable for survival analysis: at multiple Cox regression, an increased risk of PD was observed in F with higher baseline values of IL-4, sPD-L1 and IL-10, while higher IL-6 was a negative predictor in males. In males, higher levels of GM-CSF predict a longer survival, whereas higher IL-1β predicts a shorter survival. Regardless of sex, high baseline IL-8 values were associated with an increased risk of both PD and death, and high IL-6 levels only with shorter OS.
Serum IL-1β, IL-4, IL-6, IL-10, GM-CSF, TNF-ɑ, and sPD-L1 had a significant sex-related predictive impact on ORR, PFS and OS in melanoma and NSCLC patients treated with ICIs. These results will potentially pave the way for new ICI combinations, designed according to baseline and early changes of these cytokines and stratified by sex.
Background
As alveolar soft part sarcomas (ASPS) are rare with no prospective series within pediatric sarcoma trials, the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) examined the ...clinical data and outcomes of ASPS enrolled in a multinational study of nonrhabdomyosarcoma soft tissue sarcomas (NRSTS).
Patients and methods
Twenty‐two patients with ASPS were enrolled into the EpSSG NRSTS 2005 study. After surgical resection, subsequent treatment depended on the stratification of patients for completeness of resection and Intergroup Rhabdomyosarcoma Study (IRS) stage, size, and French Federation of Cancer Centres Sarcoma Group (FNCLCC) grade. Chemotherapy using ifosfamide and doxorubicin was performed in IRS group III. Radiotherapy was performed in IRS groups II and III, and FNCLCC grades 2 and 3 tumors.
Results
The median age at diagnosis was 11.5 years (range 2.7–17.5 years). The majority in the series had localized disease (20), with small IRS I tumors (12), and in total 19 had surgical resection upfront. Of the four patients who received conventional chemotherapy, there were no responses. Three of 20 patients with localized tumors and all metastatic patients developed metastases. The median follow up of patients with localized disease is 61.7 months (range 25.7–135.5 months) from diagnosis. The 5‐year event‐free survival is 94.7% (95% confidence interval: 68.1–99.2), and therefore the overall survival (OS) is 100%.
Conclusion
This report demonstrates the ability to run prospective pediatric studies in NRSTS in multiple European countries, despite the small numbers of ASPS patients. We can conclude that for the majority with small resected tumors, there were few events and no deaths.
Background
Adolescents with cancer are enrolled in clinical trials at far lower rates than children. This report compares the number of adolescents (15–19‐year‐olds) and children (0–14‐year‐olds) ...enrolled in the protocols of the European pediatric Soft tissue sarcoma Study Group (EpSSG) with the number of cases expected to occur.
Methods
The observed‐to‐expected (O/E) ratio was detected in the EpSSG countries contributing most of the cases, that is, Italy, France, Spain, the Netherlands, United Kingdom, and Ireland. The observed cases included patients enrolled in any of the EpSSG protocols from October 2008 to October 2015, when all EpSSG protocols were open in these countries. The number of expected cases was calculated from the incidence rates estimated throughout the RARECAREnet database in the countries’ population‐based cancer registries.
Results
In the countries considered, 2,118 cases aged 0–19 years were enrolled in the EpSSG trials from 2008 to 2015: 82.8% were children and 17.2% were adolescents. The O/E ratio was 0.30 among patients 15–19 years old, as opposed to 0.64 for those 0–14 years old. The O/E ratio differed for the different subtypes: in adolescents, it was 0.64 and 0.18 for rhabdomyosarcoma (RMS) and non‐rhabdomyosarcoma soft tissue sarcomas (NRSTS), respectively; in children, it was 0.77 and 0.50, respectively. The O/E ratios differed across the countries considered.
Conclusions
Adolescents were less well represented than children on the EpSSG protocols, with better enrolment for RMS than for NRSTS for all age groups.
Introduction
Cutaneous melanoma is rare in childhood and published studies have mainly been retrospective single‐institution series or small case series. Given the absence of clinical protocols ...dedicated to pediatric melanoma, the treatment approach is generally extrapolated from the ones applied to adults.
Methods
Coordinated by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT), this study collected patients prospectively registered between 2002 and 2012 under national cooperative projects dedicated to rare pediatric tumors in Italy, Poland, Germany, and France. Additional cases were collected from dermatology registries in Germany and Israel.
Results
A total of 219 patients aged 0–18 years (median 14.4) were included in the analysis. Sentinel lymph node biopsy was performed in 112 patients (76% of those with Breslow thickness > 0.75 mm) and was positive in 37.5%. Systemic therapy was used in 33 cases. In stage III cases, survival rates were similar for patients who received (23 cases) or not (21 cases) adjuvant therapy. For the whole series, 3‐year overall and disease‐free survival rates were 91.4% and 84.0%, respectively (median follow‐up 41.8 months). Tumor site, tumor stage, and ulceration influenced survival rates. Patients treated by pediatric oncologists (n = 140) were more likely to have advanced disease than those treated by dermatologists (n = 79).
Discussion
This study would suggest that the clinical history of melanoma in children and adolescents might resemble that of adult counterpart. Cooperative efforts are needed to make new drugs more readily available to pediatric patients to increase the outcome of patient with advanced disease.
Abstract Background Previous studies have reported a poor outcome for synovial sarcoma patients whose tumours relapse. Methods This study analysed 44 relapsing cases in a series of 118 consecutive ...patients <21 yr of age with non-metastatic synovial sarcoma prospectively enrolled in Italian paediatric protocols between 1979 and 2006. In an effort to identify a possible risk-adapted stratification enabling a better planning of second-line treatment, the relapsing patients’ outcome was analysed vis-à-vis their clinical picture at onset, first-line treatments, clinical findings at the time of first relapse and second-line treatment modalities. Results The first event was a local recurrence in only 15 cases, and metastatic in 29 (associated with local relapse too in 7 cases). The time to relapse ranged from 4 to 108 months (median 20 months). Overall survival was 29.7% and 21.0% five and ten years after relapsing, respectively. The variables influencing survival were the timing and type of relapse (combined) and the chances of a secondary remission, which correlated strongly with the feasibility of complete surgery. Conclusions Our study confirmed a largely unsatisfactory prognosis after recurrences in children and adolescents with synovial sarcoma: the chances of survival can be estimated on the basis of several variables for the purposes of planning risk-adapted salvage protocols. An aggressive surgical approach should be recommended. New effective systemic agents are warranted, and experimental therapies can be offered to patients with little chance of salvage.
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