Adjuvant chemotherapy versus observation following neoadjuvant therapy and surgery for resectable stage I-II pancreatic cancer.

Background: Neoadjuvant therapy (NT), either with systemic treatment alone or in combination with radiation, is often utilized in the management of pancreatic adenocarcinoma to increase the likelihood of margin-negative resection. Following NT and resection, additional adjuvant chemotherapy (AC) can be considered for select patients and has been shown to improve overall survival (OS). This National Cancer Data Base (NCDB) analysis was performed to evaluate the outcomes of AC versus observation for resected pancreatic adenocarcinoma treated with NT. Methods: The NCDB was queried for primary stage I-II cT1-3N0-1M0 resected pancreatic adenocarcinoma treated with NT (2004-2015). Baseline patient, tumor, and treatment characteristics were extracted. The primary endpoint was OS. With a 6-month conditional landmark, Kaplan-Meier analysis, multivariable Cox proportional hazards method, 1:1 propensity score matching were used to analyze the data. Results: A total of 1737 eligible patients were identified, of which 1247 underwent postoperative observation compared to 490 with AC. The overall median follow-up was 34.7 months. The addition of AC showed improved survival on the multivariate analysis (HR 0.78, p<0.001). Of 490 propensity-matched pairs, all variables were well balanced, including age (p=0.61), Charlson-Deyo comorbidity score (p=0.80), ypT stage (p=0.93), ypN stage (p=0.83), surgical margin (p=0.83), duration of postoperative inpatient admission (p=0.96), and 30-day unplanned readmission after resection (p=0.34). AC remained statistically significant for improved OS, with median OS of 26.3 months vs 22.3 months and 2-year OS of 63.9% vs 52.9% for the observation cohort (p<0.001). Treatment interaction analysis showed OS benefit of AC for patients with smaller tumors (HR 0.67, p<0.001 for <3.1 cm vs HR 0.93, p=0.48 for ≥3.1 cm). Conclusion: Using propensity score matched analysis, our findings suggest a survival benefit for adjuvant chemotherapy compared to observation following NT and surgery for resectable pancreatic adenocarcinoma, especially in patients with smaller tumors. Prospective studies are needed to identify subset of patients that would benefit from adjuvant chemotherapy.

Association of survival with stereotactic body radiation therapy following induction chemotherapy for unresected locally advanced pancreatic cancer.

Background: Induction chemotherapy (iC) followed by concurrent chemoradiation has been shown to improve overall survival (OS) for locally advanced pancreatic cancer (LAPC). However, the survival benefit of stereotactic body radiation therapy (SBRT) versus conventionally fractionated radiation therapy (CFRT) following iC remains unclear. Methods: The National Cancer Database (NCDB) was queried for primary stage III, cT4N0-1M0 LAPC (2004-2015). Kaplan-Meier analysis, Cox proportional hazards method, and propensity score matching were used. Results: Among 872 patients, 738 patients underwent CFRT and 134 patients received SBRT. Median follow-up was 24.3 months and 22.9 months for the CFRT and SBRT cohorts, respectively. The use of SBRT showed improved survival in both the multivariate analysis (HR 0.78, p=0.025) and 120 propensity-matched pairs (median OS 18.1 vs 15.9 months, p=0.004) compared to the CFRT. Conclusion: This NCDB analysis suggests survival benefit with the use of SBRT versus CFRT following iC for the LAPC.

Systematic Review of Single-Fraction Stereotactic Body Radiation Therapy for Early Stage Non-Small-Cell Lung Cancer and Lung Oligometastases: How to Stop Worrying and Love One and Done.

Adoption of single-fraction lung stereotactic body radiation therapy (SBRT) for patients with medically inoperable early stage non-small-cell lung cancer (NSCLC) or oligometastatic lung disease, even during the coronavirus disease 2019 (COVID-19) pandemic, was limited despite encouraging phase II trial results. Barriers to using single-fraction SBRT may include lack of familiarity with the regimen and lack of clarity about the expected toxicity. To address these concerns, we performed a systematic review of prospective literature on single-fraction SBRT for definitive treatment of early stage and oligometastatic lung cancer. A PubMed search of prospective studies in English on single-fraction lung SBRT was conducted. A systematic review was performed of the studies that reported clinical outcomes of single-fraction SBRT in the treatment of early stage non-small-cell lung cancer and lung oligometastases. The current prospective literature including nine trials supports the use of single-fraction SBRT in the definitive treatment of early stage peripheral NSCLC and lung oligometastases. Most studies cite local control rates of >90%, mild toxicity profiles, and favorable survival outcomes. Most toxicities reported were grade 1-2, with grade ≥3 toxicity in 0-17% of patients. Prospective trial results suggest potential consideration of utilizing single-fraction SBRT beyond the COVID-19 pandemic.

Evaluation of risk stratification using gene expression assays in patients with breast cancer receiving neoadjuvant chemotherapy.

PURPOSE: To evaluate the association of various gene expression assays with pathologic complete response (pCR) in the setting of neoadjuvant chemotherapy among patients with breast cancer METHODS: The National Cancer Database (NCDB) was queried for women diagnosed between 2010 and 2017 with stage I-III breast cancer who underwent neoadjuvant chemotherapy and either 21-gene recurrence score (RS) or 70-gene signature (GS). Logistic multivariable analysis (MVA) was performed to identify variables associated with pCR. RESULTS: A total of 3009 patients met our inclusion criteria. The median follow up was 48.0 months (interquartile range 32.2-66.7 months). On logistic MVA for all patients, those with a high risk from GS (adjusted odds ratio [aOR] 3.23, 95% confidence interval [CI] 1.49-8.13, p = 0.006) or with RS ≥ 31 (aOR 1.99, 95% CI 1.41-2.82, p < 0.001) were more likely to have pCR. When compared to RS ≥ 31, a high risk from GS was not associated with pCR (aOR 1.01, 95% CI 0.75-1.37, p = 0.94). However, among those with favorable hormone receptor status, similar findings were noted, except that those with a high risk group from GS were less likely to have pCR compared to those with RS ≥ 31 (aOR 0.65, 95% CI 0.43-0.96, p = 0.03). When analyses were repeated using a high risk group from RS defined as RS ≥ 26 among those with favorable hormone receptor status, RS ≥ 26 was not associated with pCR when compared to the high risk from GS (aOR 0.74, 0.50-1.07, p = 0.12). CONCLUSIONS: To our knowledge, this is the largest study using a nationwide oncology database suggesting that high recurrence risk groups in both assays were associated with pCR. Among those with favorable hormone receptor status, RS ≥ 31 may be a more selective prognostic marker for pCR.

Structure-function analyses of two plant meso-diaminopimelate decarboxylase isoforms reveal that active-site gating provides stereochemical control.

meso-Diaminopimelate decarboxylase catalyzes the decarboxylation of meso-diaminopimelate, the final reaction in the diaminopimelate l-lysine biosynthetic pathway. It is the only known pyridoxal-5-phosphate-dependent decarboxylase that catalyzes the removal of a carboxyl group from a d-stereocenter. Currently, only prokaryotic orthologs have been kinetically and structurally characterized. Here, using complementation and kinetic analyses of enzymes recombinantly expressed in Escherichia coli, we have functionally tested two putative eukaryotic meso-diaminopimelate decarboxylase isoforms from the plant species Arabidopsis thaliana We confirm they are both functional meso-diaminopimelate decarboxylases, although with lower activities than those previously reported for bacterial orthologs. We also report in-depth X-ray crystallographic structural analyses of each isoform at 1.9 and 2.4 Å resolution. We have captured the enzyme structure of one isoform in an asymmetric configuration, with one ligand-bound monomer and the other in an apo-form. Analytical ultracentrifugation and small-angle X-ray scattering solution studies reveal that A. thaliana meso-diaminopimelate decarboxylase adopts a homodimeric assembly. On the basis of our structural analyses, we suggest a mechanism whereby molecular interactions within the active site transduce conformational changes to the active-site loop. These conformational differences are likely to influence catalytic activity in a way that could allow for d-stereocenter selectivity of the substrate meso-diaminopimelate to facilitate the synthesis of l-lysine. In summary, the A. thaliana gene loci At3g14390 and At5g11880 encode functional. meso-diaminopimelate decarboxylase enzymes whose structures provide clues to the stereochemical control of the decarboxylation reaction catalyzed by these eukaryotic proteins.

Whole-Genome Sequences of Salmonella enterica subsp. enterica Serovar Typhimurium Strains TT6675 and TT9097 Employed in the Isolation and Characterization of a Giant Phage Mutant Collection.

We report here the genome sequences of Salmonella enterica subsp. enterica serovar Typhimurium strains TT6675 and TT9097, which we utilize for genetic analyses of giant bacterial viruses. Our analyses identified several genetic variations between the two strains, most significantly confirming strain TT6675 as a serine suppressor and TT9097 as a nonsuppressor.