Alliance A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal cancer.

BACKGROUND: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after TNT may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes. METHODS: In this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N +) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N + vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Patients will be randomized to receive neoadjuvant long-course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3-4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8-12 (± 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 312 evaluable patients (156 per arm) will provide statistical power of 90.5% to detect a 17% increase in cCR rate, at a one-sided alpha = 0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse event rates. Biospecimens including archival tumor tissue, plasma and buffy coat, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and had accrued 330 patients as of May 2024. Study support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . DISCUSSION: Building on data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed The Janus Rectal Cancer Trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT05610163; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG).

Watch & wait - Post neoadjuvant imaging for rectal cancer.

Rectal cancer management has evolved over the past decade with the emergence of total neoadjuvant therapy (TNT). For select patients who achieve a clinical complete response following TNT, organ preservation by means of the watch-and-wait (WW) strategy is an increasingly adopted alternative that preserves rectal function and quality of life without compromising oncologic outcomes. Recently, published 5-year results from the OPRA trial demonstrated that organ preservation can be achieved in approximately half of patients managed with the WW strategy, with most local regrowth events occurring within two years. Considering the potential for local regrowth, the implementation of the WW strategy mandates rigorous clinical and radiographic surveillance. Magnetic resonance imaging (MRI) serves as the conventional imaging modality for local staging and surveillance of rectal cancer given its excellent soft-tissue resolution. This review will discuss the current evidence for the WW strategy and the role of restaging rectal MRI in determining patient eligibility for this strategy. Restaging rectal MRI acquisition parameters and treatment response assessment, including important factors to assess, pitfalls, and classification systems, will be discussed in the context of the WW strategy.

Discovery of Oncogenic Mediator Genes in Rectal Cancer Chemotherapy Response using Gene Expression Data from Matched Tumor and Patient-Derived Organoid.

Rectal cancer (RC) presents significant treatment challenges, particularly in the context of chemotherapy resistance. Addressing this, our study pioneers the use of matched RC tumor tissue and patient-derived organoid (PDO) models coupled with the innovative computational tool, Moonlight, to explore the gene expression landscape of RC tumors and their response to chemotherapy. We analyzed 18 tissue samples and 32 matched PDOs, ensuring a high-fidelity representation of the tumor bioloy. Our comprehensive integration strategy involved differential expression analyses (DEAs) and gene regulatory network (GRN) analyses, facilitating the identification of 5,199 genes governing at least one regulon. By using the biological processes (BPs) collected from Moonlight closely related to cancer, we pinpointed 2,118 regulator-regulon groups with potential roles in oncogenic processes. Further, through integration of Moonlight and DEA results identified 334 regulator-regulon groups significantly enriched in both tissue and PDO samples, classifying them as oncogenic mediators (OMs). Among these, four genes (NCKAP1L, LAX1, RAD51AP1, and NAT2) demonstrated an association with drug responsiveness and recurrence-free survival (RFS), offering new insights into the molecular mechanisms of chemotherapy response in RC. Our integrated approach not only underscores the translational fidelity of PDOs, but also harnesses the analytical prowess of Moonlight, setting a new benchmark for targeted therapy research in rectal cancer.

Impact of a Multimodal Analgesia Protocol on Inpatient and Outpatient Opioid Use in Acute Trauma.

BACKGROUND: Multimodal analgesia protocols have been implemented after elective surgery to reduce opioid use, however there is limited data on utility after polytrauma. Therefore, we investigated the impact of a multimodal analgesia protocol on inpatient and post-discharge outpatient opioid use after polytrauma. METHODS: A retrospective review of patients admitted to a Level I trauma center between September 2017-February 2018 (prior to multimodal protocol; "pre-cohort") and October 2018-April 2019 (after multimodal protocol; "post-cohort") was performed. An outpatient controlled substance registry was utilized to capture morphine milligram equivalents (MME) and gabapentin dispensed in the 6 mo after injury. RESULTS: 620 patients were included (295 pre-cohort, 325 post-cohort). Total inpatient MME decreased from 177.5 mg-130 mg (P= 0.01) between the cohorts. Daily inpatient MME decreased from 70.8 mg-44.7 mg (P< 0.01). Intravenous hydromorphone decreased from 2 mg in the pre-cohort to 1 mg in the post-cohort (P= 0.02). Inpatient oxycodone decreased from 45 mg-30 mg (P= 0.01). Concurrently, gabapentin increased from 0 mg-400 mg in the post-cohort (P< 0.01). Patients in the post-cohort were prescribed fewer MMEs than the pre-cohort at discharge (P< 0.05). However, the number of patients prescribed gabapentin increased from 6.1%-16% (P< 0.01). CONCLUSION: Implementation of an updated multimodal analgesia protocol decreased total MME, daily MME, hydromorphone, and oxycodone consumed while increasing gabapentin use. This suggests that while reducing opioid usage in-hospital is critical to reducing outpatient usage, multimodal pain protocols may lead to an increase in gabapentin prescriptions and utilization after discharge.

Acute and Chronic Hematologic Implications of Emergency and Elective Splenectomy.

INTRODUCTION: Thrombocytosis and leukocytosis are common after splenectomy. The potential effect of emergency surgery on these postoperative findings is unknown. We hypothesized that emergency splenectomy leads to a more profound and persistent hematologic change as compared to elective splenectomy. METHODS: A retrospective review was conducted of patients who underwent elective or trauma splenectomy. Records were queried for platelet (PLT) and white blood cell (WBC) count prior to splenectomy, on postoperative days 1-5, and at day 14, 1 month, 3 months, 6 months, and 1 year. Complications, including thromboembolic events, infection, need for repeat operation, and readmission within 30 days of discharge, were recorded. RESULTS: 463 patients were identified as being eligible for the study, with 173 patients in the elective cohort and 145 patients in each of the isolated trauma splenectomy and polytrauma cohorts. Both cohorts had peak thrombocytosis at week 2 postoperatively. However, polytrauma patients had a significantly higher peak platelet count (P < 0.01). The PLT:WBC ratio was lower in both trauma cohorts pre-operatively and postoperative day 1. Trauma splenectomy had a higher PLT:WBC ratio on days 2 and 3 whereas polytrauma had a lower ratio on days 4 and 5. Emergency cases had greater reoperation and infection rates, whereas elective cases were more likely to require readmission. Postoperative thromboembolic events were only higher in the polytrauma cohort. CONCLUSIONS: While trauma splenectomy resulted in more profound postoperative leukocytosis and thrombocytosis, there was no correlation with timing of infection or risk of thromboembolic events. These findings suggest that thrombocytosis and leukocytosis may be associated with thrombotic and infectious events but their presence alone does not indicate direct risks of concomitant infection or thrombosis.

The Role of Chemoprophylactic Agents in Modulating Platelet Aggregability After Traumatic Brain Injury.

BACKGROUND: The pathophysiology behind the subacute but persistent hypercoagulable state after traumatic brain injury (TBI) is poorly understood but contributes to morbidity induced by venous thromboembolism. Because platelets and their microvesicles have been hypothesized to play a role in post-traumatic hypercoagulability, administration of commonly used agents may ameliorate this coagulability. We hypothesized that utilization of aspirin, ketorolac, amitriptyline, unfractionated heparin, or enoxaparin would modulate the platelet aggregation response after TBI. METHODS: Concussive TBI was induced by weight drop. Mice were then randomized to receive aspirin, ketorolac, amitriptyline, heparin, enoxaparin, or saline control at 2 and 8 h after TBI. Mice were sacrificed at 6 or 24 h after injury to determine coagulability by rotational thromboelastometry (ROTEM), platelet function testing with impedance aggregometry, and microvesicle enumeration. Platelet sphingolipid metabolites were analyzed by mass spectrometry. RESULTS: ROTEM demonstrated increased platelet contribution to maximum clot firmness at 6 h after TBI in mice that received aspirin or amitriptyline, but this did not persist at 24 h. By contrast, adenosine diphosphate- and arachidonic acid-induced platelet aggregation at 6 h was significantly lower in mice receiving ketorolac, aspirin, and amitriptyline compared with mice receiving saline at 6 h after injury and only arachidonic acid-initiated platelet aggregation was decreased by aspirin at 24 h. There were no differences in microvesicle production at either time point. Platelet sphingosine-1-phosphate levels were decreased at 6 h in the group receiving amitriptyline and increased at 24 h along with platelet ceramide levels at 24 h in the amitriptyline group. CONCLUSION: After TBI, amitriptyline decreased platelet aggregability and increased contribution to clot in a manner similar to aspirin. The amitriptyline effects on platelet function and sphingolipid metabolites may represent a possible role of the acid sphingomyelinase in the hypercoagulability observed after injury. In addition, inhibition of platelet reactivity may be an underappreciated benefit of low molecular weight heparins, such as enoxaparin.

UCH-L1 is a Poor Serum Biomarker of Murine Traumatic Brain Injury After Polytrauma.

BACKGROUND: Several serum biomarkers have been studied to diagnose incidence and severity of traumatic brain injury (TBI), but a reliable biomarker in TBI has yet to be identified. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) has been proposed as a biomarker in clinical and preclinical studies, largely in the setting of isolated TBI or concussion. The aim of this study was to evaluate the performance of UCH-L1 as a serum biomarker in the setting of polytrauma and TBI. METHODS: Multiple variations of murine TBI and polytrauma models were used to evaluate serum biomarkers. The different models included TBI with and without hemorrhagic shock and resuscitation, isolated extremity vascular ligation, extremity ischemia/reperfusion, and blunt tail injury. Blood was drawn at intervals after injury, and serum levels of neuron-specific enolase, UCH-L1, creatine kinase, and syndecan-1 were evaluated by enzyme-linked immunosorbent assay. RESULTS: UCH-L1 levels were not significantly different between TBI, tail injury, and sham TBI. By contrast, neuron-specific enolase levels were increased in TBI mice compared with tail injury and sham TBI mice. UCH-L1 levels increased regardless of TBI status at 30 min and 4 h after hemorrhagic shock and resuscitation. In mice that underwent femoral artery cannulation followed by hemorrhagic shock/resuscitation, UCH-L1 levels were significantly elevated compared with shock sham mice at 4 h (3158 ± 2168 pg/mL, 4 h shock versus 0 ± 0 pg/mL, 4 h shock sham; P < 0.01) and at 24 h (3253 ± 2954 pg/mL, 24 h shock versus 324 ± 482 pg/mL, 24 h shock sham; P = 0.03). No differences were observed in UCH-L1 levels between the sham shock and the arterial ligation, vein ligation, or extremity ischemia/reperfusion groups at any time point. Similar to UCH-L1, creatine kinase was elevated only after shock compared with sham mice at 4, 24, and 72 h after injury. CONCLUSIONS: Our study demonstrates that UCH-L1 is not a specific marker for TBI but is elevated in models that induce central and peripheral nerve ischemia. Given the increase in UCH-L1 levels observed after hemorrhagic shock, we propose that UCH-L1 may be a useful adjunct in quantifying severity of shock or global ischemia rather than as a specific marker of TBI.

Base-modified thymidines capable of terminating DNA synthesis are novel bioactive compounds with activity in cancer cells.

Current FDA-approved chemotherapeutic antimetabolites elicit severe side effects that warrant their improvement; therefore, we designed compounds with mechanisms of action focusing on inhibiting DNA replication rather than targeting multiple pathways. We previously discovered that 5-(α-substituted-2-nitrobenzyloxy)methyluridine-5'-triphosphates were exquisite DNA synthesis terminators; therefore, we synthesized a library of 35 thymidine analogs and evaluated their activity using an MTT cell viability assay of MCF7 breast cancer cells chosen for their vulnerability to these nucleoside derivatives. Compound 3a, having an α-tert-butyl-2-nitro-4-(phenyl)alkynylbenzyloxy group, showed an IC50 of 9±1µM. The compound is more selective for cancer cells than for fibroblast cells compared with 5-fluorouracil. Treatment of MCF7 cells with 3a elicits the DNA damage response as indicated by phosphorylation of γ-H2A. A primer extension assay of the 5'-triphosphate of 3a revealed that 3aTP is more likely to inhibit DNA polymerase than to lead to termination events upon incorporation into the DNA replication fork.