The vacuolar protein sorting-associated protein 13B (VPS13B) is a large and highly conserved protein. Disruption of VPS13B causes the autosomal recessive Cohen syndrome, a rare disorder characterized ...by microcephaly and intellectual disability among other features, including developmental delay, hypotonia, and friendly-personality. However, the underlying mechanisms by which VPS13B disruption leads to brain dysfunction still remain unexplained. To gain insights into the neuropathogenesis of Cohen syndrome, we systematically characterized brain changes in Vps13b-mutant mice and compared murine findings to 235 previously published and 17 new patients diagnosed with VPS13B-related Cohen syndrome. We showed that Vps13b is differentially expressed across brain regions with the highest expression in the cerebellum, the hippocampus and the cortex with postnatal peak. Half of the Vps13b
die during the first week of life. The remaining mice have a normal lifespan and display the core phenotypes of the human disease, including microcephaly, growth delay, hypotonia, altered memory, and enhanced sociability. Systematic 2D and 3D brain histo-morphological analyses reveal specific structural changes in the brain starting after birth. The dentate gyrus is the brain region with the most prominent reduction in size, while the motor cortex is specifically thinner in layer VI. The fornix, the fasciculus retroflexus, and the cingulate cortex remain unaffected. Interestingly, these neuroanatomical changes implicate an increase of neuronal death during infantile stages with no progression in adulthood suggesting that VPS13B promotes neuronal survival early in life. Importantly, whilst both sexes were affected, some neuroanatomical and behavioral phenotypes were less pronounced or even absent in females. We evaluate sex differences in Cohen patients and conclude that females are less affected both in mice and patients. Our findings provide new insights about the neurobiology of VPS13B and highlight previously unreported brain phenotypes while defining Cohen syndrome as a likely new entity of non-progressive infantile neurodegeneration.
Derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) level have been correlated with immune checkpoint inhibitor (ICI) outcomes in patients with melanoma.
...To determine whether pretreatment dNLR and LDH are associated with resistance to ICIs in patients with advanced non-small cell lung cancer (NSCLC).
Multicenter retrospective study with a test (n = 161) and a validation set (n = 305) treated with programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors in 8 European centers, and a control cohort (n = 162) treated with chemotherapy only. Complete blood cell counts, LDH, and albumin levels were measured before ICI treatment. A lung immune prognostic index (LIPI) based on dNLR greater than 3 and LDH greater than upper limit of normal (ULN) was developed, characterizing 3 groups (good, 0 factors; intermediate, 1 factor; poor, 2 factors).
The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS) and disease control rate (DCR).
In the pooled ICI cohort (N = 466), 301 patients (65%) were male, 422 (90%) were current or former smokers, and 401 (87%) had performance status of 1 or less; median age at diagnosis was 62 (range, 29-86) years; 270 (58%) had adenocarcinoma and 159 (34%) had squamous histologic subtype. Among 129 patients with PD-L1 data, 96 (74%) had PD-L1 of at least 1% by immunohistochemical analysis, and 33 (26%) had negative results. In the test cohort, median PFS and OS were 3 (95% CI, 2-4) and 10 (95% CI, 8-13) months, respectively. A dNLR greater than 3 and LDH greater than ULN were independently associated with OS (hazard ratio HR 2.22; 95% CI, 1.23-4.01 and HR, 2.51; 95% CI, 1.32-4.76, respectively). Median OS for poor, intermediate, and good LIPI was 3 months (95% CI, 1 month to not reached NR), 10 months (95% CI, 8 months to NR), and 34 months (95% CI, 17 months to NR), respectively, and median PFS was 2.0 (95% CI, 1.7-4.0), 3.7 (95% CI, 3.0-4.8), and 6.3 (95% CI, 5.0-8.0) months (both P < .001). Disease control rate was also correlated with dNLR greater than 3 and LDH greater than ULN. Results were reproducible in the ICI validation cohort for OS, PFS, and DCR, but were nonsignificant in the chemotherapy cohort.
Pretreatment LIPI, combining dNLR greater than 3 and LDH greater than ULN, was correlated with worse outcomes for ICI, but not for chemotherapy, suggesting that LIPI can serve as a potentially useful tool when selecting ICI treatment, raising the hypothesis that the LIPI might be useful for identifying patients unlikely to benefit from treatment with an ICI.
Hyperprogressive disease (HPD) is a new pattern of progression recently described in patients with cancer treated with programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) ...inhibitors. The rate and outcome of HPD in advanced non-small cell lung cancer (NSCLC) are unknown.
To investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD.
In this multicenter retrospective study that included patients treated between August 4, 2011, and April 5, 2017, the setting was pretreated patients with advanced NSCLC who received PD-1/PD-L1 inhibitors (8 institutions) or single-agent chemotherapy (4 institutions) in France. Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) on at least 2 computed tomographic scans before treatment and 1 computed tomographic scan during treatment was required.
The tumor growth rate (TGR) before and during treatment and variation per month (ΔTGR) were calculated. Hyperprogressive disease was defined as disease progression at the first evaluation with ΔTGR exceeding 50%.
The primary end point was assessment of the HPD rate in patients treated with IO or chemotherapy.
Among 406 eligible patients treated with PD-1/PD-L1 inhibitors (63.8% male), 46.3% (n = 188) were 65 years or older, 72.4% (n = 294) had nonsquamous histology, and 92.9% (n = 377) received a PD-1 inhibitor as monotherapy in second-line therapy or later. The median follow-up was 12.1 months (95% CI, 10.1-13.8 months), and the median overall survival (OS) was 13.4 months (95% CI, 10.2-17.0 months). Fifty-six patients (13.8%) were classified as having HPD. Pseudoprogression was observed in 4.7% (n = 19) of the population. Hyperprogressive disease was significantly associated with more than 2 metastatic sites before PD-1/PD-L1 inhibitors compared with non-HPD (62.5% 35 of 56 vs 42.6% 149 of 350; P = .006). Patients experiencing HPD within the first 6 weeks of PD-1/PD-L1 inhibitor treatment had significantly lower OS compared with patients with progressive disease (median OS, 3.4 months 95% CI, 2.8-7.5 months vs 6.2 months 95% CI, 5.3-7.9 months; hazard ratio, 2.18 95% CI, 1.29-3.69; P = .003). Among 59 eligible patients treated with chemotherapy, 3 (5.1%) were classified as having HPD.
Our study suggests that HPD is more common with PD-1/PD-L1 inhibitors compared with chemotherapy in pretreated patients with NSCLC and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors. Additional studies are needed to determine the molecular mechanisms involved in HPD.
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Background: dNRL (Neutrophils/Leucocytes-Neutrophils) and LDH were recently correlated to ICI benefit in melanoma. We tested if dNLR and LDH could have the same role in NSCLC ...patients. Methods: Baseline dNLR and LDH were collected in 234 patients treated with PD1/PDL1 inhibitors from Nov. 2013 to Dec. 2016, in a discovery (D) cohort (N = 161) from Gustave Roussy and an independent validation (V) cohort (N = 73) from 2 centers. ICI benefit was analyzed according to overall survival (OS), progression free survival (PFS) and response rate (RR) by RECIST 1.1. Kaplan-Meier and Cox regression were performed. Results: In the D cohort, 100 patients (62%) were males, 136 (85%) smokers and PS ≤1, with median age 61.5; 133 patients (81%) stage IV; 100 (62%) had adenocarcinoma and 46 (29%) squamous cells carcinoma; 35 (22%) were KRASmut, 13 (8%) EGFRmut and 3 (2%) ALKpositive. PDL1 expression was positive in 43 (75%), negative in 14 (25%) and unknown in 78. 132 (82%) patients received PD1 inhibitors; the median of prior lines was 1 (1-11). dNLR > 3 and LDH > upper normal limit (UNL) were independent factors for poor OS (HR 4,67, p = 0.011 and HR 2,65, p = 0.002, respectively) and poor PFS (HR 4,71, p = 0.001 and HR 1,68, p = 0.042 respectively). The median follow-up (FU) was 12 months (m) 95% CI 11-14, the median PFS 3m 2-4 and the median OS 10m 8-13. In the V cohort, with a median FU of 11m 8-14, dNLR > 3 and LDH > UNL were significantly associated with poor OS (both p = 0.001), with a trend toward association with PFS (p = 0.06, p = 0.08, respectively). A Lung Immune Predictive Index (LIPI) was tested considering dNLR > 3 and LDH > UNL, with three groups. In D cohort, the median OS for good (no factor), intermediate (one factor) and poor (two factors) was 34m 17-NR, 10m 8-NR, 3m 1-NR, respectively (p = 0.0001), and PFS was similarly correlated (p = 0.001). Same results were demonstrated in the V cohort. Conclusions: Baseline dNLR > 3 and LDH > UNL can predict the benefit of ICI in advanced NSCLC patients. The LIPI at baseline is an easy tool to identify the candidates to immunotherapy. Confirmation cohorts are ongoing to validate the predictive role of the LIPI.
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