Germline Testing for Veterans with Advanced Prostate Cancer: Concerns about Service-Connected Benefits.

To better understand Veterans' decisions about germline testing, we conducted a single-site, qualitative study of 32 Veterans with advanced prostate cancer. Seven days after oncologist-patient discussions about germline testing, we conducted semi-structured interviews with patients exploring their decision-making process using an interview guide. Four of 14 Veterans with service-connected disability benefits for prostate cancer declined germline testing for fear of losing benefits, as their livelihood depended on these benefits. All 18 Veterans without service-connected benefits agreed to testing. Veterans declining germline testing for this concern can lead to suboptimal cancer care because targeted treatments that could improve their outcomes may go unrecognized. Our findings contributed to new language in the Veterans Benefits Administration Compensation and Pension Manual clarifying that genetic testing showing hereditary predisposition is insufficient to deny service-connected benefits for conditions presumed to be caused by military exposures. Clinicians should communicate this protection when counseling Veterans about genetic testing.

Early recanalization after tenecteplase versus alteplase: Experience in a large stroke network.

INTRODUCTION: Previously published data are conflicting regarding the ability of tenecteplase versus alteplase to produce early recanalization of an intracranial large vessel occlusion. We compared the performance of each thrombolytic in a stroke network. METHODS: We queried our prospectively collected code stroke registry for basilar, internal carotid, or proximal middle cerebral artery occlusion patients treated with intravenous thrombolysis from 11/17/2021-9/16/2023. The primary outcome was early recanalization, defined using angiographic or clinical criteria. Secondary and safety outcomes included 90-day functional independence and symptomatic intracranial hemorrhage. A multivariable regression analysis was performed to determine independent associations with the primary outcome. RESULTS: 233 patients, with mean age 66.9 (16.6) years and median National Institutes of Health Stroke Scale score 15 (10-21), were included. One-hundred twenty-four of 233 (53.2 %) patients were treated with alteplase while 109/233 (46.8 %) were treated with tenecteplase. Endovascular thrombectomy was performed in 82 % of subjects. Early recanalization rates were similar between the groups (alteplase 22.6 %, tenecteplase 14.7 %; p = 0.14), as were rates of 90-day independent neurological function, symptomatic intracranial hemorrhage, and mortality. Patients with an internal carotid artery occlusion or with higher presenting stroke severity were less likely to achieve early recanalization. CONCLUSIONS: Tenecteplase and alteplase have similar rates of early recanalization, 90-day functional independence, and safety outcomes in large vessel occlusion patients. Occlusion site and stroke severity predict response to thrombolysis. Future studies may investigate other factors associated with a positive response to thrombolytics as expanded treatment indications are explored.

Impact of Posttreatment SPECT/CT on Patient Management During 177Lu-PSMA-617 Radiopharmaceutical Therapy.

177Lu can be imaged after administration using SPECT/CT. Most work to date has focused on using posttreatment imaging to measure normal organ and tumor dose. We aimed to assess the impact of posttreatment SPECT/CT on the management of patients undergoing 177Lu-prostate-specific membrane antigen (PSMA) radiopharmaceutical therapy (RPT). Methods: In this retrospective study, 122 patients underwent PSMA RPT with subsequent SPECT/CT 24 h after treatment. We determined a qualitative response at each cycle and reviewed patient charts to assess the impact that posttreatment SPECT/CT had on patient management. Changes in patient management were classified as changes on the basis of progression and response, and specific cycles when they occurred were noted. Miscellaneous changes in patient management were also evaluated. Results: Among the 122 consecutive patients examined, 42%-56% exhibited stable disease, whereas 19%-39% of patients exhibited response on visual assessment across treatment cycles. In total, 49% (n = 60) of patients experienced changes in management, of which 57% (n = 34) were due to progression, 40% (n = 24) were due to response, and 3% (n = 2) were due to miscellaneous changes. Changes due to disease progression were observed mostly after cycles 2 and 4. Changes due to response to RPT occurred mostly after cycles 3 and 4. Conclusion: At our center, 49% of patients experienced changes in management based on posttreatment SPECT/CT, and most of these changes occurred at cycles 2 and 4. Integrating posttreatment SPECT/CT into routine PSMA RPT protocols can aid in patient management.

Neurological outcomes for patients meeting radiographic criteria for DEFUSE 3 and SELECT2.

BACKGROUND: The DEFUSE 3 and SELECT2 thrombectomy trials included some patients with similar radiographic profiles, although the rates of good functional outcomes differed widely between the studies. OBJECTIVE: To report neurological outcomes for patients who meet CT and CT perfusion (CTP) inclusion criteria common to both DEFUSE 3 and SELECT2. METHODS: Retrospective study of thrombectomy patients, presenting between November 2016 and December 2023 to a large health system, with Alberta Stroke Program Early CT score ≥6, core infarction 50-69 mL, mismatch ratio ≥1.8, and mismatch volume ≥15 mL. The primary outcome was 90-day modified Rankin Scale score 0-2. A logistic regression analysis was performed to identify independent predictors of the primary outcome. RESULTS: 85 patients, with mean age 64.6 (16.6) years and median National Institutes of Health Stroke Scale score 18 (15-23), were included. Thirty-eight of 85 patients (44.7%) were functionally independent at 90 days. Predictors of functional independence included age (OR=0.943, 95% CI 0.908 to 0.980; P=0.003), initial glucose (OR=0.989, 95% CI 0.978 to 1.000; P=0.044), and time last known well to skin puncture (OR=0.997, 95% CI 0.994 to 1.000; P=0.028). The area under the curve for the multivariable model predicting the primary outcome was 0.82 (95% CI 0.73 to 0.92). CONCLUSION: Nearly half of patients meeting radiographic criteria common to DEFUSE 3 and SELECT2 are functionally independent at 90 days, similar to rates reported for the treated DEFUSE 3 cohort. This might be due to their moderate core volumes and large ischemic penumbra.

A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2-Altered Advanced Solid Tumor Malignancies (NCI 10170).

We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response. SIGNIFICANCE: WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-altered solid tumors despite compelling preclinical data indicating a synthetic lethal effect, which did not translate into robust tumor regression. Loss of the H3K36me3 trimethylation mark caused by SETD2-deficiency was confirmed in the majority of evaluable tumors. A subset of patients derived clinical benefit as manifested by minor tumor regressions and prolonged SD.

Role of Antioxidant Vitamins in Oral Submucous Fibrosis: A Narrative Review.

Oral submucous fibrosis (OSMF) has a high rate of malignant transformation and is an insidious chronic inflammatory disease. Though this disorder seems to be multifactorial in origin, betel quid chewing appears to be the main etiologic factor. Various treatment strategies have been attempted but none proven to cure the disorder because of its multimodal pathogenesis. Reactive oxygen species (ROS) appear to have a role in cancer formation. As OSMF is an oral premalignant disorder and found to be associated with carcinogens like areca nut and tobacco, it is believed to have some relationship with ROS. Tissue damage due to ROS along with other mechanisms may result in the complex pathophysiology of OSMF. The antioxidant system in the body helps to prevent damage caused by highly reactive ROS and helps in the repair of tissues. To study the levels of oxidative stress and antioxidant vitamins in OSMF condition, the present review was done. We carried out a thorough literature search to identify original reports and studies determining the status of oxidative stress and antioxidant vitamins in OSMF condition using several databases including Google Scholar, PubMed, and Scopus. Our review observed that the oxidative stress increased in the condition of OSMF as shown by an increase in malonaldehyde (MDA) and a decrease in antioxidant vitamins like vitamin A, vitamin C, and vitamin E. Also, after the intake of antioxidant vitamins, there was symptomatic improvement in OSMF patients. With the help of identifying oxidative stress and antioxidant status, we can assess the clinical stage of OSMF and can develop a comprehensive treatment plan.

WNT5B drives osteosarcoma stemness, chemoresistance and metastasis.

BACKGROUND: Treatment for osteosarcoma, a paediatric bone cancer with no therapeutic advances in over three decades, is limited by a lack of targeted therapies. Osteosarcoma frequently metastasises to the lungs, and only 20% of patients survive 5 years after the diagnosis of metastatic disease. We found that WNT5B is the most abundant WNT expressed in osteosarcoma tumours and its expression correlates with metastasis, histologic subtype and reduced survival. METHODS: Using tumor-spheroids to model cancer stem-like cells, we performed qPCR, immunoblotting, and immunofluorescence to monitor changes in gene and protein expression. Additionally, we measured sphere size, migration and forming efficiency to monitor phenotypic changes. Therefore, we characterised WNT5B's relevance to cancer stem-like cells, metastasis, and chemoresistance and evaluated its potential as a therapeutic target. RESULTS: In osteosarcoma cell lines and patient-derived spheres, WNT5B is enriched in stem cells and induces the expression of the stemness gene SOX2. WNT5B promotes sphere size, sphere-forming efficiency, and cell proliferation, migration, and chemoresistance to methotrexate (but not cisplatin or doxorubicin) in spheres formed from conventional cell lines and patient-derived xenografts. In vivo, WNT5B increased osteosarcoma lung and liver metastasis and inhibited the glycosaminoglycan hyaluronic acid via upregulation of hyaluronidase 1 (HYAL1), leading to changes in the tumour microenvironment. Further, we identified that WNT5B mRNA and protein correlate with the receptor ROR1 in primary tumours. Targeting WNT5B through inhibition of WNT/ROR1 signalling with an antibody to ROR1 reduced stemness properties, including chemoresistance, sphere size and SOX2 expression. CONCLUSIONS: Together, these data define WNT5B's role in driving osteosarcoma cancer stem cell expansion and methotrexate resistance and provide evidence that the WNT5B pathway is a promising candidate for treating osteosarcoma patients. KEY POINTS: WNT5B expression is high in osteosarcoma stem cells leading to increased stem cell proliferation and migration through SOX2. WNT5B expression in stem cells increases rates of osteosarcoma metastasis to the lungs and liver in vivo. The hyaluronic acid degradation enzyme HYAL1 is regulated by WNT5B in osteosarcoma contributing to metastasis. Inhibition of WNT5B with a ROR1 antibody decreases osteosarcoma stemness.

Comparative evaluation of alkaline ionized water and normal water on oral microbial flora: An in-vitro study.

Background: Various artificial chemical agents have been evaluated over many years with respect to their antimicrobial effect in oral cavity. The gold standard for removal of plaque is usage of chlorhexidine, but it can cause alteration in taste sensation and staining of teeth. Electrolytes and oxidizing water may be useful against microbes, but its clinical application has still not been evaluated. Hence this present study was conducted to evaluate the effectiveness of the alkaline ionized water on oral microbial flora. Materials and Methods: Ten non-carious, un-restored and intact freshly extracted human teeth were collected and sectioned using a round bur. Each tooth was sectioned longitudinally in two parts and stored in closed sterile containers which was filled with alkaline ionized water (Group 1) and normal water (Group 2), respectively for 15 days. The microbial growth was analyzed prior to dipping in the solutions, 3 days, 7 days and 15 days. The pH of alkaline ionized water and normal water was evaluated using pH meter before placing teeth in different solutions. Results were analyzed using t-test and the level of significance was set at ≤ 0.05. Results: No difference in bacterial colony was observed before test and after 3 days among Group 1 and Group 2, respectively. After 7 days and 15 days, statistically significant decrease in bacterial colony count was seen among Group 1 as compared to Group 2 (P ≤ 0.05). Conclusion: It was then concluded that alkaline ionized water can be effective in reduction of oral microbial flora.

68Ga-FAP-2286 PET of Solid Tumors: Biodistribution, Dosimetry, and Comparison with 18F-FDG.

Fibroblast activation protein (FAP), expressed in the tumor microenvironment of a variety of cancers, has become a target of novel PET tracers. The purpose of this report is to evaluate the imaging characteristics of 68Ga-FAP-2286, present the first-to our knowledge-dosimetry analysis to date, and compare the agent with 18F-FDG and FAPI compounds. Methods: Patients were administered 219 ± 43 MBq of 68Ga-FAP-2286 and scanned after 60 min. Uptake was measured in up to 5 lesions per patient and within the kidneys, spleen, liver, and mediastinum (blood pool). Absorbed doses were evaluated using MIM Encore and OLINDA/EXM version 1.1 using the International Commission on Radiological Protection publication 103 tissue weighting factor. Results: Forty-six patients were imaged with 68Ga-FAP-2286 PET. The highest average uptake was seen in sarcoma, cholangiocarcinoma, and colon cancer. The lowest uptake was found in lung cancer and testicular cancer. The average SUVmax was significantly higher on 68Ga-FAP-2286 PET than on 18F-FDG PET in cholangiocarcinoma (18.2 ± 6.4 vs. 9.1 ± 5.0, P = 0.007), breast cancer (11.1 ± 6.8 vs. 4.1 ± 2.2, P < 0.001), colon cancer (13.8 ± 2.2 vs. 7.6 ± 1.7, P = 0.001), hepatocellular carcinoma (9.3 ± 3.5 vs. 4.7 ± 1.3, P = 0.01), head and neck cancer (11.3 ± 3.5 vs. 7.6 ± 5.5, P = 0.04), and pancreatic adenocarcinoma (7.4 ± 1.8 vs. 3.7 ± 1.0, P = 0.01). The total-body effective dose was estimated at 1.16E-02 mSv/MBq, with the greatest absorbed organ dose in the urinary bladder wall (9.98E-02 mGy/MBq). Conclusion: 68Ga-FAP-2286 biodistribution, dosimetry, and tumor uptake were similar to those of previously reported FAPI compounds. Additionally,68Ga-FAP-2286 PET had consistently higher uptake than 18F-FDG PET. These results are especially promising in the setting of small-volume disease and differentiating tumor from inflammatory uptake.

Management of Herpes Zoster Infection Using a Combination of Allopathic and Herbal Medication: A Case Report.

Herpes zoster (HZ) also known as shingles is the reactivation of varicella-zoster virus (VZV) that causes chickenpox. It usually occurs in adults after remaining dormant in the dorsal root ganglia or ganglia of the cranial nerves for several years. It typically manifests as vesicle crops in a dermatomal or "zosteriform" pattern, which shows vesicle, ulcer, and scab distribution that is unilateral, clustered, and linear in a dermatome that is supplied by a single nerve. Patients usually experience prodromal symptoms of deep, severe aching or burning pain. Medicinal treatment frequently includes antiviral drugs to decrease the severity of the lesion and steroidal drugs to reduce symptoms of inflammation. It is also a known fact that steroid has several adverse effects on patients due to which therapeutic drugs with lesser side effects may be given to patients such as herbal medications. This case presentation reports a patient with HZ viral infection who was successfully treated with a meticulous combination of conventional allopathic drugs with ayurvedic medication with a significant positive response to the medication.

Rescue from complications after pancreaticoduodenectomies at a low-volume Caribbean center: Value of tailored peri-pancreatectomy protocols.

BACKGROUND: Pancreaticoduodenectomy (PD) is a technically complex operation, with a relatively high risk for complications. The ability to rescue patients from post-PD complications is as a recognized quality measure. Tailored protocols were instituted at our low volume facility in the year 2013. AIM: To document the rate of rescue from post-PD complications with tailored protocols in place as a measure of quality. METHODS: A retrospective audit was performed to collect data from patients who experienced major post-PD complications at a low volume pancreatic surgery unit in Trinidad and Tobago between January 1, 2013 and June 30, 2023. Standardized definitions from the International Study Group of Pancreatic Surgery were used to define post-PD complications, and the modified Clavien-Dindo classification was used to classify post-PD complications. RESULTS: Over the study period, 113 patients at a mean age of 57.5 years (standard deviation [SD] ± 9.23; range: 30-90; median: 56) underwent PDs at this facility. Major complications were recorded in 33 (29.2%) patients at a mean age of 53.8 years (SD: ± 7.9). Twenty-nine (87.9%) patients who experienced major morbidity were salvaged after aggressive treatment of their complication. Four (3.5%) died from bleeding pseudoaneurysm (1), septic shock secondary to a bile leak (1), anastomotic leak (1), and myocardial infarction (1). There was a significantly greater salvage rate in patients with American Society of Anesthesiologists scores ≤ 2 (93.3% vs 25%; P = 0.0024). CONCLUSION: This paper adds to the growing body of evidence that volume alone should not be used as a marker of quality for patients requiring PD. Despite low volumes at our facility, we demonstrated that 87.9% of patients were rescued from major complications. We attributed this to several factors including development of rescue protocols, the competence of the pancreatic surgery teams and continuous, and adaptive learning by the entire institution, culminating in the development of tailored peri-pancreatectomy protocols.

Characterization of a novel root-associated diazotrophic rare PGPR taxa, Aquabacter pokkalii sp. nov., isolated from pokkali rice: new insights into the plant-associated lifestyle and brackish adaptation.

Salinity impacts crop growth and productivity and lowers the activities of rhizosphere microbiota. The identification and utilization of habitat-specific salinity-adapted plant growth-promoting rhizobacteria (PGPR) are considered alternative strategies to improve the growth and yields of crops in salinity-affected coastal agricultural fields. In this study, we characterize strain L1I39T, the first Aquabacter species with PGPR traits isolated from a salt-tolerant pokkali rice cultivated in brackish environments. L1I39T is positive for 1-aminocyclopropane-1-carboxylate deaminase activity and nitrogen fixation and can promote pokkali rice growth by supplying fixed nitrogen under a nitrogen-deficient seawater condition. Importantly, enhanced plant growth and efficient root colonization were evident in L1I39T-inoculated plants grown under 20% seawater but not in zero-seawater conditions, identifying brackish conditions as a key local environmental factor critical for L1I39T-pokkali rice symbiosis. Detailed physiological studies revealed that L1I39T is well-adapted to brackish environments. In-depth genome analysis of L1I39T identified multiple gene systems contributing to its plant-associated lifestyle and brackish adaptations. The 16S rRNA-based metagenomic study identified L1I39T as an important rare PGPR taxon. Based on the polyphasic taxonomy analysis, we established strain L1I39T as a novel Aquabacter species and proposed Aquabacter pokkalii sp nov. Overall, this study provides a better understanding of a marine-adapted PGPR strain L1I39T that may perform a substantial role in host growth and health in nitrogen-poor brackish environments.

Tunable Release of Ions from Graphene Oxide Laminates for Sustained Antibacterial Activity in a Biomimetic Environment.

Silver has long been recognized for its potent antimicrobial properties, but achieving a slow and longer-term delivery of silver ions presents significant challenges. Previous efforts to control silver ion dosages have struggled to sustain release for extended periods in biomimetic environments, especially in the presence of complex proteins. This challenge is underscored by the absence of technology for sustaining antimicrobial activity, especially in the context of orthopedic implants where long-term efficacy, extending beyond 7 days, is essential. In this study, the tunable, slow, and longer-term release of silver ions from the two-dimensional (2D) nanocapillaries of graphene oxide (GO) laminates incorporated with silver ions (Ag-GO) for antimicrobial applications are successfully demonstrated. To closely mimic a physiologically relevant serum-based environment, a novel in vitro study model using 100% fetal bovine serum (FBS) is introduced as the test medium for microbiology, biocompatibility, and bioactivity studies. To emulate fluid circulation in a physiological environment, the in vitro studies are challenged with serum exchange protocols on different days. The findings show that the Ag-GO coating can sustainably release silver ions at a minimum dosage of 10 µg cm-2 day-1, providing an effective and sustained antimicrobial barrier for over ten days.

Barbed Suspension Bridge Pharyngoplasty: Introducing a Novel Technique for Barbed Pharyngoplasty.

Surgical management of Obstructive Sleep Apnea (OSA) and Snoring has undergone many major and minor changes over a period of last decade. The most common surgical approach for OSA is uvulopalatopharyngoplasty (Stuck et al. in Sleep Med 50:152-165, 2018). The main goals of treatment of OSA are to decrease the risk of deleterious health effects and improve quality of sleep (Evans et al. in Otolaryngol Clin North Am 53: 319-328, 2020). Since bimanual surgical techniques in the depth of oral cavity have been tricky, search for a less demanding & easy to learn technique is always on. The surgical technique should also provide long term results with manageable complications. Barbed suture has been in sporadic use for the last decade amongst sleep apnea surgeons for its advantage of knotless application and distributed suture tension. However, the barbed suture which has been used is absorbable and is used only to close the surgical wound on the soft palate. In this paper we are describing our technique of using the 3-0 Polybutester non absorbable barbed suture to perform a novel technique of palatal surgery, in which we suspend the lower part of the soft palate permanently as a suspension bridge between the right and left Pterygomandibular raphae, so that the lower part of the soft palate cannot move posteriorly to touch the posterior pharyngeal wall preventing airway obstruction whereas it can still move superiorly freely while swallowing or during phonation. This technique can prove to be a technically less demanding one which provides excellent long-term results in snoring and OSA with manageable complications.

Elevated temperature-driven coordinative reconstruction of an unsaturated single-Ni-atom structure with low valency on a polymer-derived matrix for the electrolytic oxygen evolution reaction.

A high-temperature pyrolysis-controlled coordination reconstruction resulted in a single-Ni-atom structure with a Ni-Nx-C structural unit (x = N atom coordinated to Ni). Pyrolysis of Ni-phen@ZIF-8-RF at 700 °C resulted in NiNP-NC-700 with predominantly Ni nanoparticles. Upon elevating the pyrolysis temperature from 700 to 900 °C, a coordination reconstruction offers Ni-Nx atomic sites in NiSA-NC-900. A combined investigation with X-ray absorption spectroscopy, X-ray photoelectron spectroscopy, and soft X-ray L3-edge spectroscopy suggests the stabilization of low-valent Niδ+ (0 < δ < 2) in the Ni-N-C structural units. The oxygen evolution reaction (OER) is a key process during water splitting in fuel cells. However, OER is a thermodynamically uphill reaction with multi-step proton-coupled electron transfer and sluggish kinetics, due to which there is a need for a catalyst that can lower the OER overpotentials. The adsorption energy of a multi-step reaction on a single metal atom with coordination unsaturation tunes the adsorption of each oxygenated intermediate. The promising OER activity of the NiSA-NC-900/NF anode on nickel foam was followed by the overall water splitting (OWS) using using NiSA-NC-900/NF as anode and Pt coil as the cathodic counterpart, wherein a cell potential of 1.75 V at 10 mA cm-2 was achieved. The cell potential recorded with Pt(-)/(+)NiSA-NC-900/NF was much lower than that obtained for other cells, i.e., Pt(-)/NF and NF(-)/(+)NF, which enhances the potentials of low-valent NiSAs for insightful understanding of the OER. At a constant applied potential of 1.61 V (vs. RHE) for 12 h, an small increase in current for initial 0.6 h followed by a constant current depicts the fair stability of catalyst for 12 h. Our results offer an insightful angle into the OER with a coordinatively reconstructed single-Ni-atom structure at lower valency (<+2).

Keystone pathobionts associated with colorectal cancer promote oncogenic reprograming.

Fusobacterium nucleatum (Fn) and enterotoxigenic Bacteroides fragilis (ETBF) are two pathobionts consistently enriched in the gut microbiomes of patients with colorectal cancer (CRC) compared to healthy counterparts and frequently observed for their direct association within tumors. Although several molecular mechanisms have been identified that directly link these organisms to features of CRC in specific cell types, their specific effects on the epithelium and local immune compartment are not well-understood. To fill this gap, we leveraged single-cell RNA sequencing (scRNA-seq) on wildtype mice and mouse model of CRC. We find that Fn and ETBF exacerbate cancer-like transcriptional phenotypes in transit-amplifying and mature enterocytes in a mouse model of CRC. We also observed increased T cells in the pathobiont-exposed mice, but these pathobiont-specific differences observed in wildtype mice were abrogated in the mouse model of CRC. Although there are similarities in the responses provoked by each organism, we find pathobiont-specific effects in Myc-signaling and fatty acid metabolism. These findings support a role for Fn and ETBF in potentiating tumorigenesis via the induction of a cancer stem cell-like transit-amplifying and enterocyte population and the disruption of CTL cytotoxic function.

A Phase 1/2 multicenter trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

BACKGROUND: Dickkopf-related protein 1 (DKK1) is a Wingless-related integrate site (Wnt) signaling modulator that is upregulated in prostate cancers (PCa) with low androgen receptor expression. DKN-01, an IgG4 that neutralizes DKK1, delays PCa growth in pre-clinical DKK1-expressing models. These data provided the rationale for a clinical trial testing DKN-01 in patients with metastatic castration-resistant PCa (mCRPC). METHODS: This was an investigator-initiated parallel-arm phase 1/2 clinical trial testing DKN-01 alone (monotherapy) or in combination with docetaxel 75 mg/m2 (combination) for men with mCRPC who progressed on ≥1 AR signaling inhibitors. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was the determination of the recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 expansion cohorts was objective response rate by iRECIST criteria in patients treated with the combination. RESULTS: 18 pts were enrolled into the study-10 patients in the monotherapy cohorts and 8 patients in the combination cohorts. No DLTs were observed and DKN-01 600 mg was determined as the RP2D. A best overall response of stable disease occurred in two out of seven (29%) evaluable patients in the monotherapy cohort. In the combination cohort, five out of seven (71%) evaluable patients had a partial response (PR). A median rPFS of 5.7 months was observed in the combination cohort. In the combination cohort, the median tumoral DKK1 expression H-score was 0.75 and the rPFS observed was similar between patients with DKK1 H-score ≥1 versus H-score = 0. CONCLUSION: DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.