Notes

Smoking History States Large Presence of TILs as well as Effectiveness involving PD-1 Restriction throughout PD-L1 Expression-negative Non-small Cellular Cancer of the lung People.
for example, differences in excipients, differences between clusters and residual confounding cannot be ruled out.We conducted next generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EIDs) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR-1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predict sensitivity to FGFR inhibitors in the clinic.An antisense oligonucleotide that targets the Hippo pathway protein YAP1, long thought "undruggable," has shown preclinical promise and is under evaluation in a phase I trial.
Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection.

A total of 252 prospective serial plasma specimens from 103 patients with colorectal cancer undergoing curative-intent surgery were analyzed and correlated with recurrence.

Of 103 patients, 84 [stage I (9.5%), II (23.8%), III (47.6%), IV (19%)] had evaluable plasma drawn after completion of definitive therapy, defined as surgery only (
= 39) or completion of adjuvant therapy (
= 45). In "landmark" plasma drawn 1-month (median, 31.5 days) after definitive therapy and >1 year follow-up, 15 patients had detectable ctDNA, and all 15 recurred [positive predictive va of epigenomic and genomic alterations enhanced sensitivity. These findings support the potential clinical utility of plasma-only ctDNA MRD detection.
This study performed a comprehensive molecular characterization of microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) gastrointestinal (GI) tumors to elucidate predictors of response to PD-1 blockade.

Forty-five patients with MSI-H/dMMR GI tumors, including gastric cancer, colorectal cancer, cholangiocarcinoma, small intestine cancer, pancreatic cancer, and duodenal cancer, receiving PD-1 blockade were analyzed. We conducted the genomic profiling of GI tumors by whole-exome sequencing or targeted next-generation sequencing. The tumor microenvironment was evaluated by transcriptomic analysis and multiplex fluorescence IHC.

Patients with low tumor mutational burdens (TMBs) had lower objective response rates (ORRs; 0% vs. 48.8%) and a significantly shorter progression-free survival (PFS; 2.3 vs. selleck chemicals llc 15.6 months; HR, 6.20;
= 0.002) than those with high TMBs. Among common gene alterations in GI tumors, only
mutations, which were mutually exclusive with a low TMB, were significantly associated with a lower ORRs than wild-type
(21.4 vs. 54.8%; odds, 4.45;
= 0.045). Compared with wild-type
mutations in the phosphatase domain were associated with significantly lower ORRs (12.5 vs. 54.8%;
= 0.049), shorter PFS (2.6 vs. 15.6 months; HR, 5.04;
< 0.001), lower intratumoral CD8
T-cell levels, higher intratumoral CD204
macrophage levels, and PI3K/AKT/mTOR pathway enrichment, whereas
mutations in the C2 domain were not.

Low TMBs and
mutations, especially mutations in the phosphatase domain associated with an immunosuppressive environment, were mutually exclusive and might be negative predictors of PD-1 blockade responses in patients with MSI-H/dMMR GI tumors.
Low TMBs and PTEN mutations, especially mutations in the phosphatase domain associated with an immunosuppressive environment, were mutually exclusive and might be negative predictors of PD-1 blockade responses in patients with MSI-H/dMMR GI tumors.Similar risk reduction but fewer side effects would predict more uptake and compliance with low (5 mg) versus full (20 mg) dose tamoxifen. Benefit with low dose is demonstrated for perimenopausal/postmenopausal women with intraepithelial neoplasia and high lesion Ki-67. Longer follow-up needed to determine benefit with low lesion Ki-67.See related article by DeCensi et al., p. 3576.
Despite the improvement of therapeutic regimens, several patients with multiple myeloma (MM) still experience early relapse (ER). This subset of patients currently represents an unmet medical need.

We pooled data from seven European multicenter phase II/III clinical trials enrolling 2,190 patients with newly diagnosed MM from 2003 to 2017. Baseline patient evaluation included 14 clinically relevant features. Patients with complete data (
= 1,218) were split into training (
= 844) and validation sets (
= 374). In the training set, a univariate analysis and a multivariate logistic regression model on ER within 18 months (ER18) were made. The most accurate model was selected on the validation set. We also developed a dynamic version of the score by including response to treatment.

The Simplified Early Relapse in Multiple Myeloma (S-ERMM) score was modeled on six features weighted by a score 5 points for high lactate dehydrogenase or t(4;14); 3 for del17p, abnormal albumin, or bone marrow plasma cells >60%; and 2 for λ free light chain. The S-ERMM identified three patient groups with different risks of ER18 Intermediate (Int) versus Low (OR = 2.39,
< 0.001) and High versus Low (OR = 5.59,
< 0.001). S-ERMM High/Int patients had significantly shorter overall survival (High vs. Low HR = 3.24,
< 0.001; Int vs. Low HR = 1.86,
< 0.001) and progression-free survival-2 (High vs. Low HR = 2.89,
< 0.001; Int vs. Low HR = 1.76,
< 0.001) than S-ERMM Low. The Dynamic S-ERMM (DS-ERMM) modulated the prognostic power of the S-ERMM.

On the basis of simple, widely available baseline features, the S-ERMM and DS-ERMM properly identified patients with different risks of ER and survival outcomes.
On the basis of simple, widely available baseline features, the S-ERMM and DS-ERMM properly identified patients with different risks of ER and survival outcomes.
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