The effect of spread through air spaces on postoperative recurrence-free survival in patients with multiple primary lung cancers.

PURPOSE: The purpose of the study was to investigate the effect of spread through air spaces (STAS) on the postoperative prognosis of patients with multiple primary lung cancers staged from IA to IB based on tumor size. METHODS: Clinicopathological and follow-up data of 122 patients with multiple primary lung cancers diagnosed at stages IA-IB and surgically treated at the Department of Thoracic Surgery, Shenzhen people's Hospital from January 2019 to December 2021 were retrospectively analyzed. The study involved 42 males and 80 females. STAS status was used to divide them into two groups (87 cases in STAS (-) and 35 cases in STAS (+)). A logistic regression analysis, univariate and multivariate Cox regression analysis, and Kaplan-Meier curves (K-M) were used to determine how STAS affected recurrence-free survival (RFS) in patients. RESULTS: STAS (+) had a significantly higher recurrence rate than STAS (-). STAS was predicted by smoking history (P = 0.044), main tumor diameter (P = 0.02), and solid nodules on chest CT (P = 0.02). STAS incidence was not significantly different between lobectomy and sublobar resection groups (P = 0.17). Solid nodules on CT, tumor diameter, vascular invasion, pleural invasion, and STAS were significant predictors of recurrence in the univariate Cox regression analysis. Tumor diameter, pleural invasion and STAS were significant prognostic factors for recurrence in the multivariate Cox regression analysis. Furthermore, STAS (+) group was at greater risk of recurrence than STAS (-) group (34% vs. 0%, P < 0.05)。. CONCLUSION: Stage IA-IB multiple primary lung cancer patients with STAS (+) had a higher recurrence rate and a shorter overall survival rate.

The image quality, amyloid-ß detectability, and acquisition time of clinical florbetapir positron emission tomography in Alzheimer's disease and healthy adults.

Background: Florbetapir positron emission tomography (AV45 PET) is a widely employed modality for detecting cerebral amyloid-ß (Aß) deposition. However, in clinical settings, patients with cognitive impairment are frequently unable to sustain adequate stillness during the scanning procedure. Therefore, we aimed to investigate the effects of a short acquisition time on the image quality and Aß detectability of AV45 PET. Methods: In this cross-sectional study, 29 patients with Alzheimer's disease (AD) and 13 healthy participants underwent 15-minute AV45 PET/magnetic resonance imaging scanning. The PET data were subsequently reconstructed into 15-, 10-, 8-, 6-, 4-, 2-, and 1-minute duration groups (G15, G10, G8, G6, G4, G2, and G1). Subjective PET image quality was scored based on a 5-point Likert scale (poor-excellent: 1-5), and objective image quality was evaluated by the signal-to-noise ratio (SNR) of the 1 cm3 region of interest (ROI) inside the cerebellum. Aß detectability was assessed by the calculation of regional standardized uptake value ratio (SUVR) values in all groups. The Kruskal-Wallis rank sum test and paired t-test were performed to compare the subjective scores, SNR, and SUVR values. The visual inspection was also performed by 2 nuclear physicians to give a binary diagnosis to each case. Results: The subjective scores were decreased in the groups with shortened scanning time relative to the G15 group (4.67±0.48, all P<0.05). Notably, a good image quality score was also given to the G10 group (4.40±0.63), and sufficient image quality could be achieved with the G8 (3.86±0.68) and G6 (3.14±0.52) groups. The SNR values were decreased by 10.33%, 17.74%, and 23.26% in the G10, G8, and G6 group, respectively (all P<0.05). Compared with the G15 group (1.48±0.16), the composite SUVR values were increased in the G10 (1.50±0.16), G8 (1.50±0.17), and G6 groups (1.51±0.18, all P<0.05). By visual inspection, the diagnoses of each case in the G10, G8, and G6 group were identical with those in the G15 group. Conclusions: The acquisition time of AV45 PET is required to reach at least 6 minutes to achieve acceptable image quality and maintained Aß detectability.

Lack of incremental value of three-dimensional measurement in assessing invasiveness for lung cancer.

OBJECTIVES: The aim of this study was to evaluate the performance of consolidation-to-tumour ratio (CTR) and the radiomic models in two- and three-dimensional modalities for assessing radiological invasiveness in early-stage lung adenocarcinoma. METHODS: A retrospective analysis was conducted on patients with early-stage lung adenocarcinoma from Guangdong Provincial People's Hospital and Shenzhen People's Hospital. Manual delineation of pulmonary nodules along the boundary was performed on cross-sectional images to extract radiomic features. Clinicopathological characteristics and radiomic signatures were identified in both cohorts. CTR and radiomic score for every patient were calculated. The performance of CTR and radiomic models were tested and validated in the respective cohorts. RESULTS: A total of 818 patients from Guangdong Provincial People's Hospital were included in the primary cohort, while 474 patients from Shenzhen People's Hospital constituted an independent validation cohort. Both CTR and radiomic score were identified as independent factors for predicting pathological invasiveness. CTR in two- and three-dimensional modalities exhibited comparable results with areas under the receiver operating characteristic curves and were demonstrated in the validation cohort (area under the curve: 0.807 vs 0.826, P = 0.059) Furthermore, both CTR in two- and three-dimensional modalities was able to stratify patients with significant relapse-free survival (P < 0.000 vs P < 0.000) and overall survival (P = 0.003 vs P = 0.001). The radiomic models in two- and three-dimensional modalities demonstrated favourable discrimination and calibration in independent cohorts (P = 0.189). CONCLUSIONS: Three-dimensional measurement provides no additional clinical benefit compared to two-dimensional.

Brain-derived subgroups of bipolar II depression associate with inflammation and choroid plexus morphology.

AIM: Elevated inflammation and larger choroid plexus (ChP) volume has been previously identified in mood disorders. Connections between inflammation, ChP, and clinical symptoms in bipolar II depression (BDII-D) are unclear. Data-driven clustering based on neuroanatomical phenotypes may help to elucidate neurobiological associations in BDII-D. METHODS: Inflammatory cytokines, clinical symptoms, and neuroanatomical features were assessed in 150 BDII-D patients. Sixty-eight cortical surface area (SA) and 19 subcortical volumes were extracted using FreeSurfer. The ChP volume was segmented manually using 3D Slicer. Regularized canonical correlation analysis was used to identify significantly correlated components between cortical SA and subcortical volumes (excluding the ChP), followed by k-means clustering to define brain-derived subgroups of BDII-D. Low-grade inflammation was derived by averaging the standardized z scores of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α (TNF-α), which were computed to create a composite z-value score. Partial Pearson correlations followed by multiple comparison correction were conducted to explore associations between inflammation, clinical symptoms, and ChP volume. RESULTS: Subgroup I demonstrated smaller subcortical volume and cortical SA, higher inflammation, and larger ChP volume compared with subgroup II. Greater ChP volume was associated with a higher low-grade inflammation (mean r = 0.289, q = 0.003), CRP (mean r = 0.249, q = 0.007), IL-6 (left r = 0.200, q = 0.03), and TNF-α (right r = 0.226, q = 0.01), while greater IL-1ß was significantly associated with severe depressive symptoms in BDII-D (r = 0.218, q = 0.045). CONCLUSIONS: Neuroanatomically-derived subgroups of BDII-D differed in their inflammation levels and ChP volume. These findings suggest an important role of elevated peripheral inflammation and larger ChP in BDII-D.

[Application Value of ctDNA-based MRD Dedection 
in Early Stage Non-small Cell Lung Cancer after Radical Surgery].

Lung cancer is the most common malignant tumor in the world, among which non-small cell lung cancer (NSCLC) accounts for about 85% of the total number of lung cancers. The 5-year overall survial (OS) of radical surgery NSCLC patients ranged from 92% in stage Ia1 to 26% in stage IIIb, and the continuously decreasing survival time made it a strong clinical need for precise adjuvant therapy to eradicate molecular residual disease (MRD). At present, circulating tumor DNA (ctDNA) as a molecular indicator of MRD has gradually moved from the laboratory to the clinic. The latest consensus proposes that ctDNA with abundance ≥0.02% can be stably detected in the peripheral blood of perioperative NSCLC patients, which is based on the possibility of ctDNA as an MRD indicator. MRD detection technology supports the possibility of monitoring after radical treatment of NSCLC, and ctDNA can predict the recurrence of the disease earlier than the imaging monitoring after treatment of NSCLC, providing valuable time for timely adjustment of adjuvant therapy. In the studies on early postoperative adjuvant therapy of NSCLC, different guidelines differ on whether appropriate adjuvant therapy should be carried out, while MRD can be used as a more accurate predictor to guide postoperative adjuvant therapy, so that patients can benefit from the disease treatment.
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Improved Efficacy in a Fabry Disease Model Using a Systemic mRNA Liver Depot System as Compared to Enzyme Replacement Therapy.

Fabry disease is a lysosomal storage disorder caused by the deficiency of α-galactosidase A. Enzyme deficiency results in a progressive decline in renal and cardiac function, leading to cardiomyopathy and end-stage renal disease. Current treatments available, including enzyme replacement therapies, have provided significant benefit to patients; however, unmet medical needs remain. mRNA therapy, with drug-like properties, has the unique ability to produce therapeutic proteins endogenously. Here we describe the sustained delivery of therapeutic human α-galactosidase protein in vivo via nanoparticle-formulated mRNA in mouse and non-human primate, with a demonstration of efficacy through clinically relevant biomarker reduction in a mouse Fabry disease model. Multi-component nanoparticles formulated with lipids and lipid-like materials were developed for the delivery of mRNA encoding human α-galactosidase protein. Upon delivery of human GLA mRNA to mice, serum GLA protein levels reached as high as ∼1,330-fold over normal physiological values.

Disulfide-linked antibody-maytansinoid conjugates: optimization of in vivo activity by varying the steric hindrance at carbon atoms adjacent to the disulfide linkage.

In this report, we describe the synthesis of a panel of disulfide-linked huC242 (anti-CanAg) antibody maytansinoid conjugates (AMCs), which have varying levels of steric hindrance around the disulfide bond, in order to investigate the relationship between stability to reduction of the disulfide linker and antitumor activity of the conjugate in vivo. The conjugates were first tested for stability to reduction by dithiothreitol in vitro and for plasma stability in CD1 mice. It was found that the conjugates having the more sterically hindered disulfide linkages were more stable to reductive cleavage of the maytansinoid in both settings. When the panel of conjugates was tested for in vivo efficacy in two human colon cancer xenograft models in SCID mice, it was found that the conjugate with intermediate disulfide bond stability having two methyl groups on the maytansinoid side of the disulfide bond and no methyl groups on the linker side of the disulfide bond (huC242-SPDB-DM4) displayed the best efficacy. The ranking of in vivo efficacies of the conjugates was not predicted by their in vitro potencies, since all conjugates were highly active in vitro, including a huC242-SMCC-DM1 conjugate with a noncleavable linkage which showed only marginal activity in vivo. These data suggest that factors in addition to intrinsic conjugate potency and conjugate half-life in plasma influence the magnitude of antitumor activity observed for an AMC in vivo. We provide evidence that bystander killing of neighboring nontargeted tumor cells by diffusible cytotoxic metabolites produced from target cell processing of disulfide-linked antibody-maytansinoid conjugates may be one additional factor contributing to the activity of these conjugates in vivo.

Cantuzumab mertansine in a three-times a week schedule: a phase I and pharmacokinetic study.

PURPOSE: Cantuzumab mertansine (SB-408075; huC242-DM1) is a conjugate of the maytansinoid drug DM1 to the antibody huC242, which targets CanAg antigen. In previous studies, cantuzumab mertansine was considered safe and tolerable, but transaminitis precluded tolerance of higher doses. Based on those studies, it was suggested that treatment at intervals of the half-life of the intact immunoconjugate may allow a higher dose density. This provided the rationale for the three-times weekly treatment explored in this protocol. METHODS: Patients with advanced solid tumors and documented CanAg expression were treated with escalating doses of cantuzumab mertansine IV administered three-times a week in a 3 out of 4 weeks schedule. Plasma samples were assayed to determine pharmacokinetic parameters. RESULTS: Twenty patients (pts) with colon (11/20), rectal carcinomas (2/20), or other malignancies (7/20) were treated with doses ranging from 30 to 60 mg/m2 per day of cantuzumab mertansine IV three-times a week. The maximum tolerated dose (MTD) was 45 mg/m2, and the dose-limiting toxicity was grade 3 transaminitis. Hepatic, hematologic, and neurosensory effects occurred, but were rarely severe with repetitive treatment at doses of 45 mg/m2. CONCLUSIONS: Treatment with cantuzumab mertansine at 45 mg/m2 per day three-times weekly x 3-every-4-week schedule proved that a dose-intense treatment with an immunoconjugate can be safely administered. The pharmacokinetic profile of the intact immunoconjugate indicates that the linker is cleaved with a half-life of about 2 days, resulting in faster clearance of the maytansinoid relative to the antibody. Therefore, with the development of second-generation immunoconjugates, there is a need for improvement of the immunoconjugate linker to take full advantage of the slow clearance of full-length antibody molecules.

Semisynthetic maytansine analogues for the targeted treatment of cancer.

Maytansine, a highly cytotoxic natural product, failed as an anticancer agent in human clinical trials because of unacceptable systemic toxicity. The potent cell killing ability of maytansine can be used in a targeted delivery approach for the selective destruction of cancer cells. A series of new maytansinoids, bearing a disulfide or thiol substituent were synthesized. The chain length of the ester side chain and the degree of steric hindrance on the carbon atom bearing the thiol substituent were varied. Several of these maytansinoids were found to be even more potent in vitro than maytansine. The targeted delivery of these maytansinoids, using monoclonal antibodies, resulted in a high, specific killing of the targeted cells in vitro and remarkable antitumor activity in vivo.

Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen.

Conjugates of the anti-CanAg humanized monoclonal antibody huC242 with the microtubule-formation inhibitor DM1 (a maytansinoid), or with the DNA alkylator DC1 (a CC1065 analogue), have been evaluated for their ability to eradicate mixed cell populations formed from CanAg-positive and CanAg-negative cells in culture and in xenograft tumors in mice. We found that in culture, conjugates of either drug killed not only the target antigen-positive cells but also the neighboring antigen-negative cells. Furthermore, we showed that, in vivo, these conjugates were effective in eradicating tumors containing both antigen-positive and antigen-negative cells. The presence of antigen-positive cells was required for this killing of bystander cells. This target cell-activated killing of bystander cells was dependent on the nature of the linker between the antibody and the drug. Conjugates linked via a reducible disulfide bond were capable of exerting the bystander effect whereas equally potent conjugates linked via a nonreducible thioether bond were not. Our data offer a rationale for developing optimally constructed antibody-drug conjugates for treating tumors that express the target antigen either in a homogeneous or heterogeneous manner.

In vivo behaviour of antibody-drug conjugates for the targeted treatment of cancer.

It is a commonly held belief that most treatments for disseminated cancers are only moderately effective because the agents lack cell-killing mechanisms that act specifically on cancer cells. In antibody-drug conjugates, such nonspecific cytotoxic agents are combined with exquisitely specific monoclonal antibodies that bind to tumour-associated antigens and, thus, get endowed with new pharmacological characteristics. Not only is their activity newly targeted towards tumours and tumour cells, which hopefully renders them more tumour-specific, but they also acquire much of the pharmacokinetic behaviour of the monoclonal antibody component. With the structural composition of a macromolecular protein (the antibody), a small chemical cytotoxic agent and a linker to chemically connect these two molecules, antibody-drug conjugates are some of the most complex pharmacological agents ever developed. Their development over the last 20 years or so owes much to sophisticated in vitro and in vivo preclinical testing. This review attempts to summarise and exemplify many of the factors that had to be considered during the development, with special emphasis on the in vivo pharmacology of these agents.

Pharmacokinetics and biodistribution of the antitumor immunoconjugate, cantuzumab mertansine (huC242-DM1), and its two components in mice.

The humanized monoclonal antibody maytansinoid conjugate, cantuzumab mertansine (huC242-DM1) that contains on average three to four linked drug molecules per antibody molecule was evaluated in CD-1 mice for its pharmacokinetic behavior and tissue distribution, and the results were compared with those of the free antibody huC242. The pharmacokinetics in blood were similar for (125)I-labeled conjugate and antibody with terminal half-lives of 154 and 156 h, respectively. Pharmacokinetic analysis using an enzyme-linked immunosorbent assay (ELISA) method, which measures intact conjugate in plasma samples revealed a faster clearance for the conjugate corresponding to a half-life of 42.2 h. This faster clearance is explained as the result of clearance from circulation and concomitant clearance of drug from circulating conjugate through linker cleavage. An antibody-specific ELISA allowed the determination of the clearance rate of the antibody component from circulation. The drug clearance rate from circulating conjugate was then calculated as the difference between the clearance of the conjugate and the clearance of the antibody component and found to be about three times that of the antibody component. The above results were confirmed with a conjugate, huC242-[(3)H]DM1, where the linked DM1 drugs carried a stable tritium label. Tissue distribution studies with (125)I-labeled conjugate and antibody showed antibody-like behavior for the conjugate; the antibody of the conjugate did not distribute or bind significantly to any solid tissue.

GTI-2040, an antisense agent targeting the small subunit component (R2) of human ribonucleotide reductase, shows potent antitumor activity against a variety of tumors.

GTI-2040 is a 20-mer oligonucleotide that is complementary to a coding region in the mRNA of the R2 small subunit component of human ribonucleotide reductase. In vitro studies using a number of human tumor cell lines have demonstrated that GTI-2040 decreases mRNA and protein levels of R2 in a sequence- and target-specific manner. In vivo studies have shown that GTI-2040 significantly inhibits growth of human colon tumors (adenocarcinoma), pancreatic tumors (adenocarcinoma), liver tumors, lung tumors, breast tumors (adenocarcinoma), renal tumors, ovarian tumors (adenocarcinoma), melanoma, brain glioblastoma-astrocytoma, prostatic tumors, and cervical tumors in nude and/or severe combined immunodeficient mice. Antitumor effects were not observed with an oligonucleotide containing four mismatches to the R2 sequence or with a scrambled sequence containing the same base content but not complementary to R2. This suggests that an antisense mechanism is responsible for the in vivo observations. In addition to tumor growth assays, GTI-2040 was tested in a murine model of human lymphoma. Treatment of severe combined immunodeficient mice bearing Burkitt's lymphoma with GTI-2040, but not control oligonucleotides, greatly extended the survival of mice, and survival extended well beyond the treatment period. Finally, GTI-2040 specifically inhibits metastasis of human melanoma cells to the lungs in nude mice. Taken together, the results of these studies indicate that GTI-2040 can act as a selective and specific anticancer agent against a broad range of human tumors.

Tumor-specific novel taxoid-monoclonal antibody conjugates.

Taxoids bearing methyldisulfanyl(alkanoyl) groups for taxoid-antibody immunoconjugates were designed, synthesized and their activities evaluated. A highly cytotoxic C-10 methyldisulfanylpropanoyl taxoid was conjugated to monoclonal antibodies recognizing the epidermal growth factor receptor (EGFR) expressed in human squamous cancers. These conjugates were shown to possess remarkable target-specific antitumor activity in vivo against EGFR-expressing A431 tumor xenografts in severe combined immune deficiency mice, resulting in complete inhibition of tumor growth in all the treated mice.