NuZZ: Numerical Zig-Zag for general models Pagani, Filippo; Chevallier, Augustin; Power, Sam ...
Statistics and computing,
02/2024, Letnik:
34, Številka:
1
Journal Article
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Markov chain Monte Carlo (MCMC) is a key algorithm in computational statistics, and as datasets grow larger and models grow more complex, many popular MCMC algorithms become too computationally ...expensive to be practical. Recent progress has been made on this problem through development of MCMC algorithms based on Piecewise Deterministic Markov Processes (PDMPs), irreversible processes which can be engineered to converge at a rate which is independent of the size of the dataset. While there has understandably been a surge of theoretical studies following these results, PDMPs have so far only been implemented for models where certain gradients can be bounded in closed form, which is not possible in many relevant statistical problems. Furthermore, there has been substantionally less focus on practical implementation, or the efficiency of PDMP dynamics in exploring challenging densities. Focusing on the Zig-Zag process, we present the Numerical Zig-Zag (NuZZ) algorithm, which is applicable to general statistical models without the need for bounds on the gradient of the log posterior. This allows us to perform numerical experiments on: (i) how the Zig-Zag dynamics behaves on some test problems with common challenging features; and (ii) how the error between the target and sampled distributions evolves as a function of computational effort for different MCMC algorithms including NuZZ. Moreover, due to the specifics of the NuZZ algorithms, we are able to give an explicit bound on the Wasserstein distance between the exact posterior and its numerically perturbed counterpart in terms of the user-specified numerical tolerances of NuZZ.
In patients with metastatic colorectal cancer (mCRC), baseline circulating tumour DNA (ctDNA) variant allele fraction (VAF) might serve as a surrogate of disease burden and should be evaluated in ...comparison with CEA and RECIST-defined sum of target lesions.
In this pre-planned analysis of the VALENTINO trial, we included patients with RAS wild-type mCRC receiving upfront FOLFOX/panitumumab with available baseline liquid biopsy. CtDNA was analysed by means of a 14-gene NGS panel. For each patient, the gene with the highest VAF in ctDNA was selected.
The final cohort included 135 patients. The median VAF was 12.6% (IQR: 2.0-45.2%). Higher VAF was observed in patients with liver metastases and with synchronous metastases presentation. Patients with high VAF had poorer median OS compared to those with low VAF (21.8 vs 36.5 months; HR: 1.82, 95%CI: 1.20-2.76; p = 0.005). VAF outperformed baseline CEA and target lesion diameter in the prognostic stratification and remained significantly correlated with OS (p = 0.003) in a multivariate model. VAF was not significantly correlated with dimensional response and PFS.
CtDNA measured by VAF is prognostic in patients with RAS wild-type mCRC. Response and PFS after an anti-EGFR-based first-line strategy are independent from initial tumour burden.
The treatment scenario of metastatic colorectal cancer (mCRC) has been rapidly enriched with new chemotherapy combinations and biological agents that lead to a remarkable improvement in patients' ...outcome. Kinase gene fusions account for less than 1% of mCRC overall but are enriched in patients with high microsatellite instability,
wild-type colorectal cancer. mCRC patients harboring such alterations show a poor prognosis with standard treatments that could be reversed by adopting novel therapeutic strategies. Moving forward to a positive selection of mCRC patients suitable for targeted therapy in the era of personalized medicine, actionable gene fusions, although rare, represent a peculiar opportunity to disrupt a tumor alteration to achieve therapeutic goal. Here we summarize the current knowledge on potentially actionable gene fusions in colorectal cancer available from retrospective experiences and promising preliminary results of new basket trials.
Tumors bearing homologous recombination deficiency are extremely sensitive to DNA double strand breaks induced by several chemotherapeutic agents. ATM gene, encoding a protein involved in DNA damage ...response, is frequently mutated in colorectal cancer (CRC), but its potential role as predictive and prognostic biomarker has not been fully investigated. We carried out a multicenter effort aimed at defining the prognostic impact of ATM mutational status in metastatic CRC (mCRC) patients. Mutational profiles were obtained by means of next-generation sequencing. Overall, 35 out of 227 samples (15%) carried an ATM mutation. At a median follow-up of 56.6 months, patients with ATM mutated tumors showed a significantly longer median overall survival (OS) versus ATM wild-type ones (64.9 vs 34.8 months; HR, 0.50; 95% CI, 0.29-0.85; P = 0.01). In the multivariable model, ATM mutations confirmed the association with longer OS (HR, 0.57; 95% CI, 0.33-0.98; P = 0.04). The prognostic impact of ATM mutations was independent from TP53 mutational status and primary tumor location. High heterogeneity score for ATM mutations, possibly reflecting the loss of wild-type allele, was associated with excellent prognosis. In conclusion, we showed that ATM mutations are independently associated with longer OS in patients with mCRC.
Beyond programmed death ligand 1 (PD-L1), no other biomarkers for immunotherapy are used in daily practice. We previously created EPSILoN (Eastern Cooperative Oncology Group performance status (ECOG ...PS), smoking, liver metastases, lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR)) score, a clinical/biochemical prognostic score, in 154 patients treated with second/further-line immunotherapy. This study's aim was to validate EPSILoN score in a different population group.
193 patients were included at National Cancer Institute of Milan (second-line immunotherapy, 61%; further-line immunotherapy, 39%). Clinical/laboratory parameters such as neutrophil-to-lymphocyte ratio and lactate dehydrogenase levels were collected. Kaplan-Meier and Cox hazard methods were used for survival analysis.
Overall median progression-free survival and median overall survival were 2.3 and 7.6 months, respectively. Multivariate analyses for Progression-Free Survival (PFS) identified heavy smokers (hazard ratio (HR) 0.71,
= 0.036) and baseline LDH < 400 mg/dL (HR 0.66,
= 0.026) as independent positive factors and liver metastases (HR 1.48,
= 0.04) and NLR ≥ 4 (HR 1.49,
= 0.029) as negative prognostic factors. These five factors were included in the EPSILoN score which was able to stratify patients in three different prognostic groups, high, intermediate and low, with PFS of 6.0, 3.8 and 1.9 months, respectively (HR 1.94,
< 0.001); high, intermediate and low prognostic groups had overall survival (OS) of 24.5, 8.9 and 3.4 months, respectively (HR 2.40,
< 0.001).
EPSILoN, combining five baseline clinical/blood parameters (ECOG PS, smoking, liver metastases, LDH, NLR), may help to identify advanced non-small-cell lung cancer (aNSCLC) patients who most likely benefit from immune checkpoint inhibitors (ICIs).
The first year of the COVID-19 pandemic put considerable strain on healthcare systems worldwide. In order to predict the effect of the local epidemic on hospital capacity in England, we used a ...variety of data streams to inform the construction and parameterisation of a hospital progression model, EpiBeds, which was coupled to a model of the generalised epidemic. In this model, individuals progress through different pathways (e.g. may recover, die, or progress to intensive care and recover or die) and data from a partially complete patient-pathway line-list was used to provide initial estimates of the mean duration that individuals spend in the different hospital compartments. We then fitted EpiBeds using complete data on hospital occupancy and hospital deaths, enabling estimation of the proportion of individuals that follow the different clinical pathways, the reproduction number of the generalised epidemic, and to make short-term predictions of hospital bed demand. The construction of EpiBeds makes it straightforward to adapt to different patient pathways and settings beyond England. As part of the UK response to the pandemic, EpiBeds provided weekly forecasts to the NHS for hospital bed occupancy and admissions in England, Wales, Scotland, and Northern Ireland at national and regional scales.
Introduction
The combination of anti-EGFRs and doublet chemotherapy is considered the optimal upfront option for patients with
RAS
/
BRAF
wild-type left-sided metastatic colorectal cancer (mCRC). The ...prophylactic or reactive treatment with tetracyclines for EGFR inhibitor-induced skin toxicity is currently clinical practice, though non-conclusive results are available.
Methods
We performed a post hoc analysis of the Valentino study that randomized
RAS
wild-type mCRC patients to two panitumumab-based maintenance regimens after the first-line induction, aimed at assessing the safety and efficacy of the administration of a pre-emptive doxycycline prophylaxis for anti-EGFR-related skin toxicity. We assessed the rate of treatment-related and panitumumab-related adverse events (AEs), treatment intensity, progression-free survival (PFS), and overall survival (OS).
Results
A total of 226 patients, out of the 229 enrolled in the Valentino study, were eligible for the analysis. Overall, 143 (63%) and 83 (37%) patients received or not the antibiotic prophylaxis for skin toxicity. Any grade and G3/4 panitumumab-related AEs were reported in 89% versus 92% (
p
= 0.650) and 27% versus 27% (
p
= 1.000) patients who received or not the pre-emptive prophylaxis, respectively. Any grade and G3/4 skin rash occurred in 81% versus 90% (
p
= 0.085) and 27% versus 25% (
p
= 0.876) patients receiving or not the prophylaxis, respectively. No significant differences in terms of treatment duration, treatment delays or dose reductions, PFS, and OS were observed in the two sub-populations.
Conclusion
The adequate management of anti-EGFR-related skin toxicity is fundamental to optimize the outcome of mCRC patients, balancing the survival benefit with patients’ quality of life, especially in the first-line setting.
Neuroendocrine tumors (NETs) are classified based on morphology and are graded based on their proliferation rate as either well-differentiated low-grade (G1) to intermediate (G2-G3) or poorly ...differentiated high-grade neuroendocrine carcinomas (NEC G3). Recently, in gastroenteropancreatic (GEP) NETs, a new subgroup of well-differentiated high-grade tumors (NET G3) has been divided from NEC by WHO due to its different clinical-pathologic features. Although several mutational analyses have been performed, a molecular classification of NET is an unmet need in particular for G3, which tends to be more aggressive and have less benefit to the available therapies. Specifically, new possible prognostic and, above all, predictive factors are highly awaited, giving the basis for new treatments. Alteration of
,
, and
is mainly reported, but also druggable alterations, including
and high microsatellite instability (MSI-H), have been documented in subsets of patients. In addition, PD-L1 demonstrated to be highly expressed in G3 NETs, probably becoming a new biomarker for G3 neuroendocrine neoplasm (NEN) discrimination and a predictive one for immunotherapy response. In this review, we describe the current knowledge available on a high-grade NET molecular landscape with a specific focus on those harboring potentially therapeutic targets in the advanced setting.
The prevalence of Skeletal Related Adverse Events (SREs) in EGFR mutated non-small cell lung cancer (NSCLC) patients with bone metastases, treated with modern tyrosine kinase inhibitors (TKIs), has ...been scarcely investigated.
We retrospectively evaluated the data of EGFR mutated NSCLC patients with bone metastases treated with TKIs in 12 Italian centers from 2014 to 2019, with the primary aim to explore type and frequency of SREs.
Seventy-seven out of 274 patients enrolled (28%) developed at least one major SRE: 55/274 (20%) bone fractures, 30/274 (11%) spinal cord compression, 5/274 (2%) hypercalcemia. Median time to the onset of SRE was 3.63 months. Nine patients (3%) underwent bone surgery and 150 (55%) radiation therapy on bone. SREs were more frequently observed within the 12 months from TKI start than afterwards (71
29%, p 0.000). Patient Performance Status and liver metastases where independently associated with the risk of developing SREs. Median TKI exposure and overall survival were 11 and 28 months, respectively. Bone resorption inhibitors were associated with a lower risk of death (HR 0.722, 95% CI: 0.504-1.033, p = 0.075) although not statistically significant at multivariate analysis.
Bone metastatic NSCLC patients with EGFR mutated disease, treated with EGFR TKIs, have a relatively long survival expectancy and are at high risk to develop SREs. The early SRE occurrence after the TKI start provides the rationale to administer bone resorption inhibitors.
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