Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer.

Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2-7.6). Median progression-free survival was 6.9 months (95% CI, 5.7-7.4) and median overall survival was 15.9 months (95% CI, 11.8-18.8). Treatment-related adverse events (TRAEs) occurred in all patients; grade 3-4 in 27.7% and no grade 5. No TRAEs led to adagrasib discontinuation. Exploratory analyses suggest circulating tumor DNA may identify features of response and acquired resistance. SIGNIFICANCE: Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer.

Threatment Strategies for Recurrent Hepatocellular Carcinoma Patients: Ablation and its Combination Patterns.

With the development of guidance technology and ablation equipment, ablative procedures have emerged as important loco-regional alternatives to surgical resection for recurrent hepatocellular carcinoma (rHCC) patients. Currently, ablation modalities used in clinical practice mainly include radiofrequency ablation (RFA), microwave ablation (MWA), laser ablation (LA), cryoablation (CRA), high-intensity focused ultrasound (HIFU), and irreversible electroporation (IRE). Accumulated comparative data of ablation versus surgical resection reveal noninferior responses and outcomes but superior adverse effects. Moreover, studies demonstrate that ablation may serve as an excellent procedure for rHCC given its exact minimal invasiveness and immune modulation. We focus on the current status of ablation in clinical practice for rHCC and discuss new research in the field, including ablation combined with these other modalities, such as targeted therapy and immunotherapy.

Low Bone Mineral Density and the Risk of Benign Paroxysmal Positional Vertigo.

OBJECTIVE: This study aimed to comprehensively analyze the relationship between low bone mineral density (BMD) and the risk of benign paroxysmal positional vertigo (BPPV) based on the large prospective population-based UK Biobank (UKB) cohort. STUDY DESIGN: Prospective population-based cohort study. SETTING: The UKB. METHODS: This prospective cohort study included UKB participants recruited between 2006 and 2010 who had information on BMD and did not have BPPV before being diagnosed with low BMD. Univariable and multivariable logistic regression models were constructed to assess the association between low BMD (overall low BMD, osteopenia, and osteoporosis) and BPPV. We further conducted sex and age subgroup analysis, respectively. Finally, the effects of antiosteoporosis and female sex hormone medications on BPPV in participants with osteoporosis were evaluated. RESULTS: In total, 484,303 participants were included in the final analysis, and 985 developed BPPV after a maximum follow-up period of 15 years. Osteoporosis was associated with a higher risk of BPPV (odds ratio [OR] = 1.37, P = .0094), whereas osteopenia was not. Subgroup analyses suggested that the association between osteoporosis and BPPV was significant only in elderly females (≥60 years, OR = 1.51, P = .0007). However, no association was observed between antiosteoporosis or female sex hormone medications and BPPV in the participants with osteoporosis. CONCLUSION: Osteoporosis was associated with a higher risk of developing general BPPV, especially in females aged ≥ 60 years old, whereas osteopenia was not associated with BPPV.

A novel HLA-B*58:141 allele identified by next-generation sequencing in a potential hematopoietic cell recipient.

We report a novel HLA-B*58 allele, now named B*58:141, identified by next-generation sequencing.

Staying up late increases cardiovascular disease risk in women with polycystic ovary syndrome.

STUDY QUESTION: What is the association between late bedtime, night sleep duration, and lifetime cardiovascular disease (CVD) risk in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Both late bedtime (≥1:00) and short sleep duration (<7 h/night) were independently associated with a high-lifetime CVD risk among women with PCOS. WHAT IS KNOWN ALREADY: Previous studies indicated that sleep disturbances, including altered sleep duration and staying up late (SUL), occurred more frequently among women with PCOS compared to women without PCOS. Studies have shown that both PCOS and sleep disturbances are associated with deterioration in cardiometabolic health in the longer term. However, there are limited data regarding the possible association between sleep disturbances and CVD risk among reproductive-aged women with PCOS. STUDY DESIGN, SIZE, DURATION: From the original 393 women identified at our center, a total of 213 women with PCOS aged 18-40 years were enrolled in a cross-sectional study between March 2020 and July 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Bedtime and night sleep duration were obtained from a standardized self-administered questionnaire. The prediction for atherosclerotic CVD risk in the China risk model was applied to estimate the lifetime CVD risk in the PCOS population. Restricted cubic spline regression was applied to explore the non-linear association between sleep duration and lifetime CVD risk in a series of models. Multivariable logistic regression analyses were performed to determine the association between bedtime, night sleep duration, and lifetime CVD risk. MAIN RESULTS AND THE ROLE OF CHANCE: In our study, we found that the proportion of SUL was 94.25% and the mean (±SD) of night sleep duration was 7.5 ± 1.1 h in women with PCOS. Restricted cubic spline regression analysis showed a U-shaped relation between sleep duration and lifetime CVD risk. After adjusting for occasional drinking, fasting insulin, triglyceride, low-density lipoprotein cholesterol, and testosterone in multivariable logistic analyses, compared with going to bed at 23-24 o'clock, those who went to bed after 1 o'clock were independently associated with high-lifetime CVD risk [odds ratio (OR) = 3.87, 95% CI: 1.56-9.62]; compared with optimal sleep duration (7-8 h/night), short sleep (<7 h/night) was also independently associated with high-lifetime CVD risk (OR = 2.46, 95% CI: 1.01-5.97). LIMITATIONS, REASONS FOR CAUTION: Inferring causality is limited owing to the cross-sectional design. All sleep variables data were obtained from a standardized self-administered questionnaire rather than measurements using objective approaches. Even after adjusting for potential confounders, we still cannot completely rule out the possibility of residual confounding from unmeasured factors such as socioeconomic status. Future studies with larger sample sizes are needed to further explore the relation between long sleep duration and lifetime CVD risk. Although these findings are not generalizable to non-SUL PCOS populations, they could be used for guiding multidimensional treatment. Lastly, there is no non-PCOS group in the current cross-sectional study, which limits the interpretation of the findings from the PCOS group. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to report that both late bedtime (≥1:00) and short sleep duration (<7 h/night) were independently associated with a high-lifetime CVD risk among reproductive-aged women with PCOS, in a sample of Chinese adults. Predicting cardiovascular risk and examining the association between sleep disturbances and predicted CVD risk among women with PCOS help to highlight the need for early interventions on sleep to improve their cardiovascular outcomes. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Natural Science Foundation of Fujian Province (No. 2020J011242), the Fujian provincial health technology project (No. 2022CXB016), the Joint Research Projects of Health and Education Commission of Fujian Province (No. 2019-WJ-39), and the Medical and Health project of Xiamen Science & Technology Bureau (No. 3502Z20214ZD1001). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Circ_0104700 contributes to acute myeloid leukemia progression by enhancing MCM2 expression through targeting miR-665.

OBJECTIVE: Acute myeloid leukemia (AML) is a common blood cancer associated with poor prognosis and high mortality. In this study, we investigated the role and underlying mechanism of action of circ_0104700 in the pathogenesis of AML. METHODS: Circ_0104700 was screened from the GEO database and detected in AML samples and cell lines. The effect of circ_0104700 on AML was analyzed using a methylcellulose colony assay, CCK-8 assay, and cell cycle and apoptosis analyses. The mechanism was explored using bioinformatic analysis, quantitative reverse transcription-PCR, dual-luciferase reporter assays, northern blotting and western blot analysis in AML cells. RESULTS: Circ_0104700 expression was higher in AML patients and AML cell lines. Functionally, circ_0104700 depletion attenuated cell viability and induced apoptosis in MV-4-11 and Kasumi-1 cells. Circ_0104700 depletion enhanced the G0/G1-phase proportion but reduced the proportion of S-phase cells in MV-4-11 and Kasumi-1 cells. circ_0104700 served as a competing endogenous RNA of miR-665 and enhanced MCM2 expression by sponging miR-665 in MV-4-11 and Kasumi-1 cells. Silencing circ_0104700 repressed the proliferation and cell cycle and induced apoptosis of MV-4-11 and Kasumi-1 cells by inhibiting miR-665. MCM2 depletion alleviated the proliferation and cell cycle and enhanced the apoptosis of MV-4-11 and Kasumi-1 cells by inactivating JAK/STAT signaling. JAK/STAT signaling was involved in circ_0104700-mediated malignant phenotypes of MV-4-11 and Kasumi-1 cells. CONCLUSION: circ_0104700 contributed to AML progression by enhancing MCM2 expression by targeting miR-665. Our findings provide novel potential therapeutic targets for AML, including circ_0104700, miR-665, and MCM2.

Phase II trial of neoadjuvant sitravatinib plus nivolumab in patients undergoing nephrectomy for locally advanced clear cell renal cell carcinoma.

Sitravatinib is an immunomodulatory tyrosine kinase inhibitor that can augment responses when combined with programmed death-1 inhibitors such as nivolumab. We report a single-arm, interventional, phase 2 study of neoadjuvant sitravatinib in combination with nivolumab in patients with locally advanced clear cell renal cell carcinoma (ccRCC) prior to curative nephrectomy (NCT03680521). The primary endpoint was objective response rate (ORR) prior to surgery with a null hypothesis ORR = 5% and the alternative hypothesis set at ORR = 30%. Secondary endpoints were safety; pharmacokinetics (PK) of sitravatinib; immune effects, including changes in programmed cell death-ligand 1 expression; time-to-surgery; and disease-free survival (DFS). Twenty patients were evaluable for safety and 17 for efficacy. The ORR was 11.8%, and 24-month DFS probability was 88·0% (95% CI 61.0 to 97.0). There were no grade 4/5 treatment-related adverse events. Sitravatinib PK did not change following the addition of nivolumab. Correlative blood and tissue analyses showed changes in the tumour microenvironment resulting in an immunologically active tumour by the time of surgery (median time-to-surgery: 50 days). The primary endpoint of this study was not met as short-term neoadjuvant sitravatinib and nivolumab did not substantially increase ORR.

Adagrasib in Advanced Solid Tumors Harboring a KRASG12C Mutation.

PURPOSE: Adagrasib, a KRASG12C inhibitor, has demonstrated clinical activity in patients with KRASG12C-mutated non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). KRASG12C mutations occur rarely in other solid tumor types. We report evaluation of the clinical activity and safety of adagrasib in patients with other solid tumors harboring a KRASG12C mutation. METHODS: In this phase II cohort of the KRYSTAL-1 study (ClinicalTrials.gov identifier: NCT03785249; phase Ib cohort), we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C-mutated advanced solid tumors (excluding NSCLC and CRC). The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival (PFS), overall survival, and safety. RESULTS: As of October 1, 2022, 64 patients with KRASG12C-mutated solid tumors were enrolled and 63 patients treated (median follow-up, 16.8 months). The median number of prior lines of systemic therapy was 2. Among 57 patients with measurable disease at baseline, objective responses were observed in 20 (35.1%) patients (all partial responses), including 7/21 (33.3%) responses in pancreatic and 5/12 (41.7%) in biliary tract cancers. The median duration of response was 5.3 months (95% CI, 2.8 to 7.3) and median PFS was 7.4 months (95% CI, 5.3 to 8.6). Treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of patients and grade 3-4 in 27.0%; there were no grade 5 TRAEs. TRAEs did not lead to treatment discontinuation in any patients. CONCLUSION: Adagrasib demonstrates encouraging clinical activity and is well tolerated in this rare cohort of pretreated patients with KRASG12C-mutated solid tumors.

Compared to preoperative plasma levels post-operative urokinase-type plasminogen activator-1 levels are persistently elevated for 6 weeks after minimally invasive colorectal resection.

Background: Urokinase-type plasminogen activator-1 (uPA) is a serine protease that converts plasminogen to plasmin after binding to uPA receptor (uPAR). Plasmin catalyzes the regeneration of basement membrane, extracellular matrix, and other tissues. uPA alone and with plasmin leads to activation of angiogenic growth factors that impact tumor cell proliferation, adhesion, and migration. uPA over expression has been noted in colorectal cancer (CRC) and high tissue levels have been correlated with prognosis. uPA/uPAR promotes immune cell activation in healing surgical wounds and may alter perioperative uPA plasma levels. Postoperative (postop) plasma levels, if elevated, may impact the early growth of residual metastases. The impact of minimally invasive colorectal resection (MICR) surgery for CRC on plasma uPA levels is unknown. This study's aim was to measure plasma uPA levels during the first postop month. Methods: CRC patients undergoing MICR who enrolled in an Institutional Review Board (IRB) approved data/plasma bank for whom adequate plasma was available were included in the study. Patients who had chemotherapy or radiotherapy within 4 weeks, those who received blood transfusions perioperatively and immunosuppressed patients were excluded. Clinical and pathological data were prospectively collected as were blood samples preoperatively, postop day (POD) 1, 3 and at least 1 late time point between POD 7-41. Plasma was isolated and stored at -80 ℃. Late samples were bundled into 7-day blocks and considered as single time points. Total uPA levels (ng/mL) were analyzed in duplicate via enzyme-linked immunosorbent assay (ELISA) and results reported as mean ± standard deviation (SD). The Wilcoxon paired t-test was used for analysis. Results: Ninety-three patients undergoing MICR for CRC [colonic 68%; rectal 32%; average age 65.6 years, laparoscopic 63%, hand-assisted minimally invasive surgery (MIS) 37%] who met criteria were studied. Cancer stage breakdown was; stage I, 30%, stage II, 29%, stage III, 34%, stage IV, 7%. The median preoperative (preop) uPA plasma level (ng/mL) was 529.8 [95% confidence interval (CI): 462.8, 601.1] (n=93). Significant elevations in median levels vs. preop were present during POD 3 (542.8, 95% CI: 518.8, 597.3, n=86, P=0.003), POD 7-13 (688.1, 95% CI: 591.7, 753.0, n=72, P<0.001), POD 14-20 (764.9, 95% CI: 704.1, 911.6, n=27, P<0.001), POD 21-27 (685.6, 95% CI: 443.8, 835.8, n=15, P<0.001), and on POD 28-41 (800.3, 95% CI: 626.9, 940.6, n=21, P<0.001). The colon cancer subgroup's preop and POD 14-20 median results were significantly higher than the corresponding rectal cancer results; otherwise, at the other 5 postop time points there were no significant differences between the rectal and colon cancer subgroups. In addition, no association was found between cancer stage and preop uPA levels and no significant differences were found in postop uPA levels between the hand-assisted laparoscopic group and the lap assisted subgroup at any of the postop time points. Conclusions: Persistently elevated plasma uPA levels at 5/6 postop time point (P<0.05), in combination with other previously demonstrated long duration proangiogenic plasma protein changes, may render the plasma proangiogenic within the period of the first month post-surgery and may promote angiogenesis within the residual tumor foci. The clinical significance pertaining to these changes, if any, is uncertain and remains to be proven.

MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Nonsquamous NSCLC Progressing On or After Checkpoint Inhibitor Therapy or Chemotherapy.

INTRODUCTION: Sitravatinib, a receptor tyrosine kinase inhibitor targeting TYRO3, AXL, MERTK receptors, and vascular epithelial growth factor receptor 2, can shift the tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with checkpoint inhibitors (CPIs) may augment antitumor activity. METHODS: The phase 2 MRTX-500 study evaluated sitravatinib (120 mg daily) with nivolumab (every 2 or 4 wk) in patients with advanced nonsquamous NSCLC who progressed on or after previous CPI (CPI-experienced) or chemotherapy (CPI-naive). CPI-experienced patients had a previous clinical benefit (PCB) (complete response, partial response, or stable disease for at least 12 weeks then disease progression) or no PCB (NPCB) from CPI. The primary end point was objective response rate (ORR); secondary objectives included safety and secondary efficacy end points. RESULTS: Overall, 124 CPI-experienced (NPCB, n = 35; PCB, n = 89) and 32 CPI-naive patients were treated. Investigator-assessed ORR was 11.4% in patients with NPCB, 16.9% with PCB, and 25.0% in CPI-naive. The median progression-free survival was 3.7, 5.6, and 7.1 months with NPCB, PCB, and CPI-naive, respectively; the median overall survival was 7.9 and 13.6 months with NPCB and PCB, respectively (not reached in CPI-naive patients; median follow-up 20.4 mo). Overall, (N = 156), any grade treatment-related adverse events (TRAEs) occurred in 93.6%; grade 3/4 in 58.3%. One grade 5 TRAE occurred in a CPI-naive patient. TRAEs led to treatment discontinuation in 14.1% and dose reduction or interruption in 42.9%. Biomarker analyses supported an immunostimulatory mechanism of action. CONCLUSIONS: Sitravatinib with nivolumab had a manageable safety profile. Although ORR was not met, this combination exhibited antitumor activity and encouraged survival in CPI-experienced patients with nonsquamous NSCLC.

Osteopontin Levels Are Persistently Elevated for 4 weeks Following Minimally Invasive Colorectal Cancer Resection.

INTRODUCTION: Osteopontin (OPN) is an integrin binding phosphorylated glycoprotein secreted by macrophages and leukocytes that is found in extracellular fluids and sites of inflammation; various forms of CD44 serve as receptors. Osteopontin, expressed by numerous cancers, enhances tumor progression and angiogenesis via the PI3K/AKT and ERK mediated pathways in concert with Vascular Endothelial Growth Factor (VEGF); OPN also plays a role in wound healing. The impact of minimally invasive colorectal resection (MICR) for colorectal cancer (CRC) on plasma OPN levels is unknown. This study's goal was to assess blood levels during the first month after MICR. METHOD: Patients undergoing MICR for CRC who were enrolled in an IRB approved tissue/prospective data bank for whom preoperative, postop Day (POD) 1, POD 3, and at least 1 late postop plasma sample (POD 7-34) were available were studied. Osteopontin levels were determined in duplicate via enzyme linked immunosorbent assay (ELISA) (results reported as mean ± SD). The Wilcoxon signed rank test was used for analysis (significance P < .05). RESULTS: A total of 101 CRC patients (63% colon and 37% rectal) met study criteria. The mean preop OPN level was 89.2 ± 36.8 (ng/ml) for the entire group. Significantly elevated (P < .001) mean plasma levels were detected, vs preop, on POD1 (198.0 ± 67.4; n = 101), POD 3 (186.0 ± 72.6, n = 101), POD 7-13 (154.1 ± 70.2, n = 70), POD14-20 (146.7 ± 53.4, n=32), and POD 21-27 (123.0 ± 56.9, n = 25). No difference was noted at the POD 27-34 timepoint (P > .05). CONCLUSION: Plasma OPN levels are significantly elevated over baseline for a month after MICR for CRC. The early rise in OPN levels may be related to the postop acute inflammatory response. The persistent elevation noted in weeks 2-4, however, may be a manifestation of wound healing in which OPN plays a role. Similar persistent plasma elevations of VEGF, angiopoietin 2 (ANG 2), and 11 other proangiogenic proteins have been noted and, collectively, may promote angiogenesis in residual tumors.

The Controversy of Pepsinogen A/Pepsin A in Detecting Extra-Gastroesophageal Reflux.

BACKGROUND: Pepsinogen A (PGA)/pepsin A is often used as a diagnostic marker of extra-gastroesophageal reflux. We aimed to explore whether its positivity in upper aerodigestive tract (UADT) was specific enough to diagnose reflux. METHODS: PGA/pepsin A protein levels were examined in 10 types of tissues and 10 types of body fluid by immunological staining, western blot or Elisa, using three different commercially available brands simultaneously. Liquid chromatography-tandem mass spectrometry parallel reaction monitoring (LC-MS/MS PRM) served as a gold reference for the detection of PGA/pepsin A proteins. PGA gene expression was analyzed by reverse transcriptase sequencing methods for tissue samples. Specifically, 24 hour pH monitoring technique was conducted for patients who donated saliva samples. RESULTS: Eight out of ten types of human tissue samples (stomach, esophagus, lung, kidney, colon, parotid gland, nasal turbinate and nasal polyps) were confirmed positive for PGA/pepsin A gene and protein by genetic and PRM technique, respectively. Two out of ten types of body fluid samples (gastric fluid, urine) were confirmed positive for PGA/pepsin A protein by PRM technique. The consistence rates of PGA/pepsin A positivity among three commercial antibody brands and Elisa kit were poor, and Elisa results of salivary did not match with 24-hour pH monitoring. CONCLUSIONS: Multiple tissues and body fluid could be detected baseline expression levels of PGA/pepsin A gene and protein. However, those commercially available PGA/pepsin A antibodies achieved poor sensitivity and specificity, therefore, relying on the detection of PGA/pepsin A in UADT by single antibodies to diagnose extra-gastroesophageal reflux without a specific positive cut-off value is unreliable.

Ovarian tissue bank for fertility preservation and anti-menopause hormone replacement.

Traditional fertility preservation methods such as embryo or oocyte cryopreservation cannot meet the needs of a cancer patient or for personal reasons. The cryopreservation of ovarian tissue can be an alternative and has become a hot spot to preserve fertility or hormone replacement. The freezing of ovarian tissue can be carried out at any time without ovarian hyperstimulation to retrieve follicles. It is an ideal strategy to preserve reproductive function in children, adolescent cancer patients, and patients who are in urgent need of cancer treatment. With the increasing demands of women with premature ovarian failure or in menopause, ovarian tissue transplantation is also an alternative for hormone replacement that can provide physiological doses of hormone levels, which can avoid a series of risks such as thrombosis, breast cancer, or other hormone-dependent tumors, caused by oral hormone replacement. Hence, ovarian tissue banking can be regarded as a mainstream strategy for fertility preservation and anti-menopause hormone replacement in further clinical investigation.

First-in-human phase 1/1b study to evaluate sitravatinib in patients with advanced solid tumors.

Sitravatinib (MGCD516), a spectrum-selective receptor tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MERTK) and split kinase family receptors, has demonstrated preclinical anti-tumor activity and modulation of tumor microenvironment. This first-in-human phase 1/1b study included sitravatinib dose exploration and anti-tumor activity evaluation in selected patients with advanced solid tumors. Primary objectives included assessment of safety, pharmacokinetics and clinical activity of sitravatinib. Secondary objectives included identifying doses for further investigation and exploring molecular markers for patient selection. In phase 1, 32 patients received 10-200 mg, while phase 1b dose expansion comprised 161 patients (150 mg n = 99, 120 mg n = 62). Maximum tolerated dose was determined as 150 mg daily. Dose-limiting toxicity was reported in 4/28 evaluable phase 1 patients (three at 200 mg, one at 80 mg). In phase 1b, 120 mg was defined as the recommended dose due to tolerability. Treatment-related adverse events (TRAEs) were experienced by 174/193 patients (90.2%); grade ≥ 3 TRAEs in 103 patients (53.4%). Most common TRAEs were diarrhea, fatigue, hypertension and nausea; TRAEs led to treatment discontinuation in 26 patients (13.5%) and death in one patient. Sitravatinib was steadily absorbed and declined from plasma with a terminal elimination half-life of 42.1-51.5 h following oral administration. Overall objective response rate was 11.8% in phase 1b, 13.2% in patients with non-small cell lung cancer (NSCLC) and 4.2% in patients with NSCLC with prior checkpoint inhibitor experience. Sitravatinib demonstrated manageable safety and modest clinical activity in solid tumors. NCT02219711 (first posted August 14, 2014).

Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation.

BACKGROUND: Adagrasib, a KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib showed clinical activity and had an acceptable adverse-event profile in the phase 1-1b part of the KRYSTAL-1 phase 1-2 study. METHODS: In a registrational phase 2 cohort, we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C -mutated non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy and anti-programmed death 1 or programmed death ligand 1 therapy. The primary end point was objective response assessed by blinded independent central review. Secondary end points included the duration of response, progression-free survival, overall survival, and safety. RESULTS: As of October 15, 2021, a total of 116 patients with KRASG12C -mutated NSCLC had been treated (median follow-up, 12.9 months); 98.3% had previously received both chemotherapy and immunotherapy. Of 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months (95% confidence interval [CI], 6.2 to 13.8), and the median progression-free survival was 6.5 months (95% CI, 4.7 to 8.4). As of January 15, 2022 (median follow-up, 15.6 months), the median overall survival was 12.6 months (95% CI, 9.2 to 19.2). Among 33 patients with previously treated, stable central nervous system metastases, the intracranial confirmed objective response rate was 33.3% (95% CI, 18.0 to 51.8). Treatment-related adverse events occurred in 97.4% of the patients - grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 events) - and resulted in drug discontinuation in 6.9% of patients. CONCLUSIONS: In patients with previously treated KRASG12C -mutated NSCLC, adagrasib showed clinical efficacy without new safety signals. (Funded by Mirati Therapeutics; ClinicalTrials.gov number, NCT03785249.).

Artificial Ovary for Young Female Breast Cancer Patients.

In recent decades, there has been increasing attention toward the quality of life of breast cancer (BC) survivors. Meeting the growing expectations of fertility preservation and the generation of biological offspring remains a great challenge for these patients. Conventional strategies for fertility preservation such as oocyte and embryo cryopreservation are not suitable for prepubertal cancer patients or in patients who need immediate cancer therapy. Ovarian tissue cryopreservation (OTC) before anticancer therapy and autotransplantation is an alternative option for these specific indications but has a risk of retransplantation malignant cells. An emerging strategy to resolve these issues is by constructing an artificial ovary combined with stem cells, which can support follicle proliferation and ensure sex hormone secretion. This promising technique can meet both demands of improving the quality of life and meanwhile fulfilling their expectation of biological offspring without the risk of cancer recurrence.

A colonoscopic overtube system that creates a 'therapeutic zone' and permits retraction facilitates endoscopic submucosal dissection, was associated with fewer deep bowel wall injuries and instrument exchanges, and required less lifting solution vs classic endoscopic submucosal dissection in an ex vivo bovine model.

INTRODUCTION: Endoscopic submucosal dissection (ESD) is the 'gold standard' for large flat polyps; nevertheless, the rate of adoption in the USA is low. In ESD, the polyp is 'surgically' detached with a needle knife after a submucosal lift; gravity and the dissection cap are used for retraction. ESD would be easier if active retraction were possible. In an ex vivo bovine colon model, this study assessed an overtube system (Boston Scientific ORISE Tissue Retraction System, TRS) that permits retraction and creates 'an operative field' for removal of rectal/sigmoid lesions. METHOD: Classic ESD (C-ESD) was compared to TRS-facilitated ESD (TRS-ESD). Cleaned/preserved bovine large bowel was used, and two 2-cm 'lesions'/colon were branded onto the mucosal surface 25 and 35 cm from the anus. Submucosal saline lifts were made using a thin catheter and a standard needle knife. We tracked case length, number of instrument exchanges (to refresh lift), the volume of lift solution, the fullness of resection, and deep muscle injuries. RESULTS: Fifty ESDs were carried out in 25 colons (25 C-ESD, 25 TRS-ESD). Complete resections were noted in all cases. The TRS method required fewer instrument exchanges (median 5) vs C-ESD (median 9, p < 0.0001) and less lift solution (median 39 ml) than the C-ESD cases (median 55 ml, p = 0.0003). TRS-ESD was associated with fewer deep muscle injuries (median 2) than C-ESD (median 3, p = 0.0191). Finally, the TRS group's median case length (34.5 min) was shorter than that of C-ESD (41 min, p = 0.0543). CONCLUSION: The TRS system provides retraction and facilitates ESD regarding the number of lift injections, the volume of lift solution needed, and avoidance of muscle injuries. Of note, there is an apparent TRS learning curve, and the device mandates a distal-to-proximal approach and initial 360 degree mucosal incision. Further study is warranted.

Exosomal lncRNA and mRNA profiles in polycystic ovary syndrome: bioinformatic analysis reveals disease-related networks.

RESEARCH QUESTION: What is the role of exosomal lncRNAs and mRNAs profiles and their interaction networks in regulating the development of polycystic ovary syndrome (PCOS)? DESIGN: LncRNA microarray was used to analyse the expression profiles of lncRNA and mRNA in follicular fluid exosomes from three patients with polycystic ovary syndrome (PCOS) and three control women. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to explore biological functions of exosomal mRNAs in PCOS. Six PCOS-related genes were selected, and coding-non-coding gene co-expression (CNC) networks and competing endogenous RNA (ceRNA) networks analysis were combined to reveal lncRNA-miRNA-mRNA interaction networks. RESULTS: A total of 5373 differentially expressed exosomal lncRNAs and 3381 differentially expressed exosomal mRNAs were identified (fold change ≥2 and P < 0.05). Gene ontology analysis indicated that 14 terms of biological process were related to reproductive development. KEGG pathway analysis revealed PCOS-related pathways, such as MAPK signalling pathway and some inflammation-related signalling pathways. Interaction networks of lncRNAs, miRNAs and six PCOS-related genes (IRS1, CYP11A1, BMP6, FSHR, WNT4 and CYP19A1) were constructed. The CNC networks and ceRNA networks analysis uncovered some novel PCOS-related exosomal lncRNA-miRNA-mRNA regulatory networks. CONCLUSIONS: Differential expression profiles of exosomal lncRNAs and mRNAs were identified, and some PCOS-related biological processes and regulatory networks were indicated. LncRNAs and mRNAs in follicular fluid exosomes may play important roles in the follicular development of PCOS.

First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1).

PURPOSE: Adagrasib (MRTX849) is an oral, highly selective, small-molecule, covalent inhibitor of KRASG12C. We report results from a phase I/IB study of adagrasib in non-small-cell lung cancer, colorectal cancer, and other solid tumors harboring the KRASG12C mutation. MATERIALS AND METHODS: Patients with advanced KRASG12C-mutant solid tumors were treated with adagrasib 150 mg orally once daily, 300 mg once daily, 600 mg once daily, 1,200 mg once daily, or 600 mg orally twice a day using an accelerated titration design, which transitioned to a modified toxicity probability interval design when a predefined degree of toxicity was observed or target adagrasib exposure was achieved. Safety, pharmacokinetics, and clinical activity were evaluated. RESULTS: Twenty-five patients were enrolled and received at least one dose of adagrasib. The recommended phase II dose (RP2D) was 600 mg twice a day on the basis of safety, tolerability, and observed pharmacokinetics properties. No maximum tolerated dose was formally defined. After a median follow-up of 19.6 months, eight of 15 patients (53.3%; 95% CI, 26.6 to 78.7) with RECIST-evaluable KRASG12C-mutant non-small-cell lung cancer treated at 600 mg twice a day achieved a confirmed partial response. The median duration of response was 16.4 months (95% CI, 3.1 to not estimable). The median progression-free survival was 11.1 months (95% CI, 2.6 to not estimable). One of two patients with KRASG12C-mutant colorectal cancer treated at 600 mg twice a day achieved a partial response (duration of response, 4.2 months). At the RP2D, the most common treatment-related adverse events (any grade) were nausea (80.0%), diarrhea (70.0%), vomiting (50.0%), and fatigue (45.0%). The most common grade 3-4 treatment-related adverse event was fatigue (15.0%). CONCLUSION: Adagrasib 600 mg twice a day was well tolerated and exhibited antitumor activity in patients with advanced solid tumors harboring the KRASG12C mutation.

Sustained postoperative plasma elevations of plasminogen activator inhibitor-1 following minimally invasive colorectal cancer resection.

Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor that inhibits urokinase-type plasminogen activator and tissue-type plasminogen activator. PAI-1 participates in angiogenesis, wound healing and tumor invasion, and additionally regulates endothelial cell proliferation, angiogenesis and tumor growth. The purpose of the present study was to measure plasma PAI-1 levels perioperatively in patients with colorectal cancer (CRC) undergoing minimally invasive colorectal resection (MICR). Patients with CRC who underwent elective MICR were eligible for the study. All patients were enrolled in an approved data/plasma bank. Patients with preoperative, postoperative day (POD) 1, POD 3, and at least one POD 7-34 plasma sample collection were studied. Plasma PAI-1 levels were determined in duplicate using ELISA, and the medians and 95% confidence intervals (CIs) were determined. The correlations between postoperative plasma PAI-1 levels and length of surgery were evaluated. PAI-1 levels were compared between patients who underwent laparoscopic-assisted vs. hand-assisted surgery. The preoperative PAI-1 levels of stage I, II, III and IV pathological stage subgroups were also compared. A total of 91 patients undergoing MICR for CRC were studied. The mean incision length was 8.0±3.9 cm, and the length of stay was 6.8±4.3 days. Compared with the median preoperative levels (17.30; 95% CI: 15.63-19.78 ng/ml), significantly elevated median levels were observed on POD 1 (28.86; 95% CI: 25.46-31.22 ng/ml; P<0.001), POD 3 (18.87; 95% CI: 17.05-21.78 ng/ml; P=0.0037), POD 7-13 (26.97; 95% CI: 22.81-28.74 ng/ml; P<0.001), POD 14-20 (25.92; 95% CI: 17.85-35.89 ng/ml; P=0.001) and POD 21-27 (22.63; 95% CI: 20.03-30.09 ng/ml; P<0.001). The PAI-1 levels in the hand-assisted group were higher compared with those in the laparoscopic-assisted group for 4 weeks after surgery; however, a significant difference was found only on POD 1. Therefore, plasma PIA-1 levels were found to be significantly elevated for 4 weeks after MICR, and the surgery-related acute inflammatory response may account for the early postoperative PIA-1 increase. Furthermore, PAI-1-associated VEGF-induced angiogenesis in the healing wounds may account for the late postoperative elevations, and increased PAI-1 levels may promote angiogenesis in residual tumor deposits.