Perioperative Modified FOLFIRINOX for Resectable Pancreatic Cancer: A Nonrandomized Controlled Trial.

Importance: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection. Objective: To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival. Design, Setting, and Participants: This open-label, single-arm, phase 2 nonrandomized controlled trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023. Interventions: Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression. Main Outcomes and Measures: The primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator. Results: Of 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07). Conclusions and Relevance: This nonrandomized controlled trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies. Trial Registration: ClinicalTrials.gov Identifier: NCT02047474.

Reversible Charge Transfer Doping in Atomically Thin In2O3 by Viologens.

Atomically thin oxide semiconductors are emerging as potential materials for their potentiality in monolithic 3D integration and sensor applications. In this study, a charge transfer method employing viologen, an organic compound with exceptional reduction potential among n-type organics, is presented to modulate the carrier concentration in atomically thin In2O3 without the need of annealing. This study highlights the critical role of channel thickness on doping efficiency, revealing that viologen charge transfer doping is increasingly pronounced in thinner channels owing to their increased surface-to-volume ratio. Upon viologen doping, an electron sheet density of 6.8 × 1012 cm-2 is achieved in 2 nm In2O3 back gate device while preserving carrier mobility. Moreover, by the modification of the functional groups, viologens can be conveniently removed with acetone and an ultrasonic cleaner, making the viologen treatment a reversible process. Based on this doping scheme, we demonstrate an n-type metal oxide semiconductor inverter with viologen-doped In2O3, exhibiting a voltage gain of 26 at VD = 5 V. This complementary pairing of viologen and In2O3 offers ease of control over the carrier concentration, making it suitable for the next-generation electronic applications.

Wide-range and area-selective threshold voltage tunability in ultrathin indium oxide transistors.

The scaling of transistors with thinner channel thicknesses has led to a surge in research on two-dimensional (2D) and quasi-2D semiconductors. However, modulating the threshold voltage (VT) in ultrathin transistors is challenging, as traditional doping methods are not readily applicable. In this work, we introduce a optical-thermal method, combining ultraviolet (UV) illumination and oxygen annealing, to achieve broad-range VT tunability in ultrathin In2O3. This method can achieve both positive and negative VT tuning and is reversible. The modulation of sheet carrier density, which corresponds to VT shift, is comparable to that obtained using other doping and capacitive charging techniques in other ultrathin transistors, including 2D semiconductors. With the controllability of VT, we successfully demonstrate the realization of depletion-load inverter and multi-state logic devices, as well as wafer-scale VT modulation via an automated laser system, showcasing its potential for low-power circuit design and non-von Neumann computing applications.

Morphologic Severity of Atypia Is Predictive of Lung Cancer Diagnosis.

In cytologic analysis of lung nodules, specimens classified as atypia cannot be definitively diagnosed as benign or malignant. Atypia patients are typically subject to additional procedures to obtain repeat samples, thus delaying diagnosis. We evaluate morphologic categories predictive of lung cancer in atypia patients. This retrospective study stratified patients evaluated for primary lung nodules based on cytologic diagnoses. Atypia patients were further stratified based on the most severe verbiage used to describe the atypical cytology. Logistic regressions and receiver operator characteristic curves were performed. Of 129 patients with cytologic atypia, 62.8% later had cytologically or histologically confirmed lung cancer and 37.2% had benign respiratory processes. Atypia severity significantly predicted final diagnosis even while controlling for pack years and modified Herder score (p = 0.012). Pack years, atypia severity, and modified Herder score predicted final diagnosis independently and while adjusting for covariates (all p < 0.001). This model generated a significantly improved area under the curve compared to pack years, atypia severity, and modified Herder score (all p < 0.001) alone. Patients with severe atypia may benefit from repeat sampling for cytologic confirmation within one month due to high likelihood of malignancy, while those with milder atypia may be followed clinically.

Dissecting the Oncogenic Roles of Keratin 17 in the Hallmarks of Cancer.

There is an unmet need to identify and validate tumor-specific therapeutic targets to enable more effective treatments for cancer. Heterogeneity in patient clinical characteristics as well as biological and genetic features of tumors present major challenges for the optimization of therapeutic interventions, including the development of novel and more effective precision medicine. The expression of keratin 17 (K17) is a hallmark of the most aggressive forms of cancer across a wide range of anatomical sites and histological types. K17 correlates with shorter patient survival, predicts resistance to specific chemotherapeutic agents, and harbors functional domains that suggest it could be therapeutically targeted. Here, we explore the role of K17 in the hallmarks of cancer and summarize evidence to date for K17-mediated mechanisms involved in each hallmark, elucidating functional roles that warrant further investigation to guide the development of novel therapeutic strategies.