First-line hepatic arterial infusion chemotherapy plus lenvatinib and PD-(L)1 inhibitors versus systemic chemotherapy alone or with PD-(L)1 inhibitors in unresectable intrahepatic cholangiocarcinoma.

PURPOSE: Limited treatment options exist for unresectable intrahepatic cholangiocarcinoma (ICC), with systemic chemotherapy (SC) serving as the primary approach. This study aimed to assess the effectiveness of first-line hepatic arterial infusion chemotherapy (HAIC) in combination with lenvatinib and PD-(L)1 inhibitors (HLP) compared to SC combined with PD-(L)1 inhibitors (SCP) or SC alone in treating unresectable ICC. METHODS: Patient with unresectable ICC who underwent first-line treatment with HLP, SCP or SC from January 2016 to December 2022 were retrospectively analyzed. The study evaluated and compared efficacy and safety outcomes across the three treatment groups. RESULTS: The study comprised 42, 49, and 50 patients in the HLP, SCP, and SC groups, respectively. Median progression-free survival (PFS) times were 30.0, 10.2, and 6.5 months for HLP, SCP, and SC groups. While the SC group had a median overall survival (OS) time of 21.8 months, the HLP and SCP groups hadn't reached median OS. The HLP group demonstrated significantly superior PFS (p < 0.001) and OS (p = 0.014) compared to the others. Moreover, the HLP group exhibited the highest objective response rate (ORR) at 50.0% and the highest disease control rate (DCR) at 88.1%, surpassing the SC group (ORR, 6.0%; DCR, 52.0%) and SCP group (ORR, 18.4%; DCR, 73.5%) (p < 0.05). Generally, the HLP group reported fewer grades 3-4 adverse events (AEs) compared with others. CONCLUSION: In contrast to systemic chemotherapy with or without PD-(L)1 inhibitors, the triple combination therapy incorporating HAIC, lenvatinib, and PD-(L)1 inhibitors showcased favorable survival benefits and manageable adverse events for unresectable ICC.

Surgically-relevant quality of life thresholds for the Short Inflammatory Bowel Disease Questionnaire in Crohn's disease.

BACKGROUND: Despite growing interest in patient-reported outcome measures to track the progression of Crohn's disease, frameworks to apply these questionnaires in the preoperative setting are lacking. Using the Short Inflammatory Bowel Disease Questionnaire (sIBDQ), this study aimed to describe the interpretable quality of life thresholds and examine potential associations with future bowel resection in Crohn's disease. METHODS: Adult patients with Crohn's disease completing an sIBDQ at a clinic visit between 2020 and 2022 were eligible. A stoplight framework was adopted for sIBDQ scores, including a "Resection Red" zone suggesting poor quality of life that may benefit from discussions about surgery as well as a "Nonoperative Green" zone. Thresholds were identified with both anchor- and distribution-based methods using receiver operating characteristic curve analysis and subgroup percentile scores, respectively. To quantify associations between sIBDQ scores and subsequent bowel resection, multivariable logistic regression models were fit with covariates of age, sex assigned at birth, body mass index, medications, disease pattern and location, resection history, and the Harvey Bradshaw Index. The incremental discriminatory value of the sIBDQ beyond clinical factors was assessed through the area under the receiver operating characteristics curve (AUC) with an internal validation through bootstrap resampling. RESULTS: Of the 2003 included patients, 102 underwent Crohn's-related bowel resection. The sIBDQ Nonoperative Green zone threshold ranged from 61 to 64 and the Resection Red zone from 36 to 38. When adjusting for clinical covariates, a worse sIBDQ score was associated with greater odds of subsequent 90-day bowel resection when considered as a 1-point (odds ratio [OR] [95% CI], 1.05 [1.03-1.07]) or 5-point change (OR [95% CI], 1.27 [1.14-1.41]). Inclusion of the sIBDQ modestly improved discriminative performance (AUC [95% CI], 0.85 [0.85-0.86]) relative to models that included only demographics (0.57 [0.57-0.58]) or demographics with clinical covariates (0.83 [0.83-0.84]). CONCLUSION: In the decision-making process for bowel resection, disease-specific patient-reported outcome measures may be useful to identify patients with Crohn's disease with poor quality of life and promote a shared understanding of personalized burden.

Endoscopic ultrasonography-related diagnostic accuracy and clinical significance on small rectal neuroendocrine neoplasms.

This research aimed to examine the diagnostic accuracy and clinical significance of endoscopic ultrasonography (EUS) in the context of small rectal neuroendocrine neoplasms (NENs). A total of 108 patients with rectal subepithelial lesions (SELs) with a diameter of < 20 mm were included in the analysis. The diagnosis and depth assessment of EUS was compared to the histology findings. The prevalence of NENs in rectal SELs was 78.7% (85/108). The sensitivity of EUS in detecting rectal NENs was 98.9% (84/85), while the specificity was 52.2% (12/23). Overall, the diagnostic accuracy of EUS in identifying rectal NENs was 88.9% (96/108). The overall accuracy rate for EUS in assessing the depth of invasion in rectal NENs was 92.9% (78/84). Therefore, EUS demonstrates reasonable diagnostic accuracy in detecting small rectal NENs, with good sensitivity but inferior specificity. EUS may also assist physicians in assessing the depth of invasion in small rectal NENs before endoscopic excision.

Incidence of Cutaneous Immune-Related Adverse Events and Outcomes in Immune Checkpoint Inhibitor-Containing Regimens: A Systematic Review and Meta-Analysis.

Immune checkpoint inhibitors (ICIs) are used to treat many cancers, and cutaneous immune-related adverse events (cirAEs) are among the most frequently encountered toxic effects. Understanding the incidence and prognostic associations of cirAEs is of importance as their uses in different settings, combinations, and tumor types expand. To evaluate the incidence of cirAEs and their association with outcome measures across a variety of ICI regimens and cancers, we performed a systematic review and meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) ICIs, both alone and in combination with chemotherapy, antiangiogenic agents, or other ICIs in patients with melanoma, renal cell carcinoma, non-small cell lung cancer, and urothelial carcinoma. Key findings of our study include variable cirAE incidence among tumors and ICI regimens, positive association with increased cirAE incidence and response rate, as well as significant association between increased vitiligo incidence and overall survival. Across 174 studies, rash, pruritis, and vitiligo were the most reported cirAEs, with incidences of 16.7%, 18.0%, and 6.6%, respectively. Higher incidence of cirAEs was associated with ICI combination regimens and with CTLA-4-containing regimens, particularly with higher doses of ipilimumab, as compared to PD-1/L1 monotherapies. Outcome measures including response rate and progression-free survival were positively correlated with incidence of cirAEs. The response rate and incidence of pruritis, vitiligo, and rash were associated with expected rises in incidence of 0.17% (p = 0.0238), 0.40% (p = 0.0010), and 0.18% (p = 0.0413), respectively. Overall survival was positively correlated with the incidence of pruritis, vitiligo, and rash; this association was significant for vitiligo (p = 0.0483). Our analysis provides benchmark incidence rates for cirAEs and links cirAEs with favorable treatment outcomes at a study level across diverse solid tumors and multiple ICI regimens.

A novel prognostic prediction model of cuprotosis-related genes signature in hepatocellular carcinoma.

Background: Cuprotosis is a recently discovered copper-dependent cell death mechanism that relies on mitochondrial respiration. However, the role of cuprotosis-related genes (CRGs) in hepatocellular carcinoma (HCC) and their prognostic significances remain unknown. Methods: Based on the recently published CRGs, the LASSO Cox regression analysis was applied to construct a CRGs risk model using the gene expression data from the International Cancer Genome Consortium as a training set, followed by validation with datasets from The Cancer Genome Atlas and the Gene Expression Omnibus (GSE14520). Functional enrichment analysis of the CRGs was performed by single-sample gene set enrichment analysis. Results: Five of the 13 previously published CRGs were identified to be associated with prognosis in HCC. Kaplan-Meier analysis suggested that patients with high-risk scores have a shorter overall survival time than patients with low-risk scores. ROC curves indicated that the average AUC was more than 0.7, even at 4 years, and at least 0.5 at 5 years. Moreover, addition of this CRG risk score can significantly improve the efficiency of predicting overall survival compared to using traditional factors alone. Functional analysis demonstrated increased presence of Treg cells in patients with high-risk scores, suggesting a suppressed immune state in these patients. Finally, we point to the possibility that novel immunotherapies such as inhibitors of PDCD1, TIGIT, IDO1, CD274, CTLA4, and LAG3 may have potential benefits in high-risk patients. Conclusion: We constructed a better prognostic model for liver cancer by using CRGs. The CRG risk score established in this study can serve as a potentially valuable tool for predicting clinical outcome of patients with HCC.

Efficacy and safety of immune checkpoint inhibitors in young adults with metastatic melanoma.

BACKGROUND: The integration of immune checkpoint inhibitors (ICI) for the treatment of melanoma has resulted in remarkable and durable responses. Given the potential role of immunosenescence, age may contribute to differential ICI efficacy and toxicity. While older patients have been studied in detail, outcomes from ICI in young patients (≤40 years) are not well characterised. METHODS: We performed a multi-institutional, retrospective study of patients with advanced melanoma treated with anti-PD-1 monotherapy or ICI combination (ipilimumab and anti-PD-1). Response rates, survival, and toxicities were examined based on age comparing those under 40 years of age with older patients (age 41-70 and ≥ 71 years). RESULTS: A total of 676 patients were included: 190 patients (28%) aged ≤40 years, 313 (46%) between ages 41-70, and 173 patients (26%) aged ≥71. Patients ≤40 years had higher response rates (53% vs 38%, p = 0.035) and improved progression-free survival (median 13.7 vs 4.0 months, p = 0.032) with combination ICI compared to monotherapy. Progression-free survival was similar among groups while overall survival was inferior in patients >70 years, who had low response rates to combination therapy (28%). ICIs had a similar incidence of severe toxicities, though hepatotoxicity was particularly common in younger patients vs. patients >40 with monotherapy (9% vs. 2%, p = 0.007) or combination ICI (37% vs. 10%, p < 0.001). CONCLUSIONS: ICIs had comparable efficacy between younger and older patients, although outcomes were superior with combination ICI compared to monotherapy in patients aged ≤40 years. Toxicity incidence was similar across age groups, though organs affected were substantially different.

Comprehensive analysis of tumor necrosis factor-α-inducible protein 8-like 2 (TIPE2): A potential novel pan-cancer immune checkpoint.

Tumor necrosis factor-α-inducible protein 8-like 2 (TIPE2) is encoded by TNFAIP8L2 and is a newly identified negative regulator of natural and acquired immunity that plays a critical function in maintaining immune homeostasis. Recently, CAR-NK immune cell therapy has been a focus of major research efforts as a novel cancer therapeutic strategy. TIPE2 is a potential checkpoint molecule for immune cell maturation and antitumor immunity that could be used as a novel NK cell-based immunotherapeutic approach. In this study, we explored the expression of TNFAIP8L2 across various tumor types and found that TNFAIP8L2 was highly expressed in most tumor types and correlated with prognosis. Survival analysis showed that TNFAIP8L2 expression was predictive of improved survival in cervical-squamous-cell-carcinoma (CESC), sarcoma (SARC) and skin-cutaneous-melanoma (SKCM). Conversely, TNFAIP8L2 expression predicted poorer survival in acute myeloid leukemia (LAML), lower-grade-glioma (LGG), kidney-renal-clear-cell-carcinoma (KIRC) and uveal-melanoma (UVM). Analysis of stemness features and immune cell infiltration indicated that TNFAIP8L2 was significantly associated with cancer stem cell index and increased macrophage and dendritic cell infiltration. Our data suggest that TNFAIP8L2 may be a novel immune checkpoint biomarker across different tumor types, particularly in LAML, LGG, KIRC and UVM, and may have further utility as a potential target for immunotherapy.

Mechanism of Abnormal Coagulation Induced by Tigecycline in Cancer Patients.

Tigecycline is a broad-spectrum active intravenous antibiotic that is active against methicillin-resistant staphylococcus aureus. In Phase 3 and 4 clinical trials, increased all-cause mortality was observed in patients treated with tigecycline compared to patients in the control group. The reason for the increase is unclear. In this study, we found that tigecycline cause abnormal coagulation in tumor patients, especially in patients with hematological malignancies. The main manifestations were decreased fibrinogen and prolonged activated prothrombin time (APTT), thrombin time (TT), and D-dimer. In addition, through functional studies, we found that tigecycline inhibit platelet adhesion and aggregation, and the coagulation function of patients gradually recover after discontinuation. Gene sequencing results suggested that tigecycline significantly regulate the expression of genes related to platelet function pathways and increase the incidence of single nucleotide polymorphisms and the number of alternative splices in the Chinese hamster ovary (CHO) cells treated with tigecycline. An abnormal function and low numbers of platelets are common in patients with hematological malignancies. Our study can explain the mechanism of abnormal coagulation caused by tigecycline. Additionally, doctors who apply tigecycline to cure infections in tumor patients should be warned.

Spinal CCK1 Receptors Contribute to Somatic Pain Hypersensitivity Induced by Malocclusion via a Reciprocal Neuron-Glial Signaling Cascade.

Recent studies have shown that the incidence of chronic primary pain including temporomandibular disorders (TMD) and fibromyalgia syndrome (FMS) often exhibit comorbidities. We recently reported that central sensitization and descending facilitation system contributed to the development of somatic pain hypersensitivity induced by orofacial inflammation combined with stress. The purpose of this study was to explore whether TMD caused by unilateral anterior crossbite (UAC) can induce somatic pain hypersensitivity, and whether the cholecystokinin (CCK) receptor-mediated descending facilitation system promotes hypersensitivity through neuron-glia cell signaling cascade. UAC evoked thermal and mechanical pain hypersensitivity of the hind paws from day 5 to 70 that peaked at week 4 post UAC. The expression levels of CCK1 receptors, interleukin-18 (IL-18) and IL-18 receptors (IL-18R) were significantly up-regulated in the L4 to L5 spinal dorsal horn at 4 weeks post UAC. Intrathecal injection of CCK1 and IL-18 receptor antagonists blocked somatic pain hypersensitivity. IL-18 mainly co-localized with microglia, while IL-18R mainly co-localized with astrocytes and to a lesser extent with neurons. These findings indicate that the signaling transduction between neurons and glia at the spinal cord level contributes to the descending pain facilitation through CCK1 receptors during the development of the comorbidity of TMD and FMS. PERSPECTIVE: CCK1 receptor-dependent descending facilitation may mediate central mechanisms underlying the development of widespread somatic pain via a reciprocal neuron-glial signaling cascade, providing novel therapeutic targets for the clinical treatment of TMD and FMS comorbidities.

Multi-omics analyses of tumor-associated immune-infiltrating cells with the novel immune checkpoint protein tyrosine phosphatase 1B (PTP1B) in extracellular matrix of brain-lower-grade-glioma (LGG) and uveal-melanoma (UVM).

Immune checkpoint inhibitors represented by PD-1 have greatly changed the way cancer is treated. In addition to PD-1, new immune checkpoints are constantly excavated to better treat cancer. Recently, protein tyrosine phosphatase 1B (PTP1B) was identified as a new immune checkpoint and played a critical role in the treatment of tumors by inhibiting the proliferation and cytotoxicity of T cells induced by tumor antigen. To explore the targeting role of PTP1B in precision tumor therapy, we deeply analyzed the expression and prognosis of PTP1B in all tumors. Survival analysis results indicated that PTP1B was highly expressed in most tumor tissues and indicated poor prognosis in acute-myeloid-leukemia (LAML), brain-lower-grade-glioma (LGG), kidney-renal clear-cell-carcinoma (KIRC) and uveal-melanoma (UVM). The methylation status of PTP1B in these four tumors exhibited hypomethylation and mutation landscape showed that PTP1B had its specific characteristics in genomic instability and heterogeneity. The homologous recombination deficiency (HRD) and loss of heterozygosity (LOH) were positive related to PTP1B expression in liver-hepatocellular-carcinoma (LIHC) and kidney-chromophobe (KICH), while the immunescore and immune infiltration displayed a significant positive correlation with PTP1B expression in LGG and UVM. Drug sensitivity tests showed that the PTP1B inhibitor MSI-1436 had a sensitivity effect suppressing tumor cell viability and suggested it enhanced the efficacy of PD-1 inhibitors in cancers.

[Primary Study on Chronic Myeloid Leukemia in NCG Mice from Qinba Mushroom].

OBJECTIVE: The present study was to evaluate the anti-tumor effects of acidic RNA protein complex (FA-2-b-ß) extracted from the wild edible Qinba mushroom in inducing of apoptosis and immunoregulation of tumor cell. METHODS: Cell proliferation inducing rate of FA-2-b-ß to K562 cell was measured using CCK-8. Apoptosis rate was detected by using flow cytometry. Chronic myeloid leukemia model was developed by tail vein injection/subcutaneous inoculation of K562 cells in NCG mice. The tumor burden of mice was observed. The general condition of the mice was monitored twice daily. The peripherivcal full blood counts of mice was tested daily. RT-qPCR and Western blot was FA-2-b-ß performed to determine involvement of apoptotic-related gene and protenin, Immunofluorescence and immunohistochemistry was used to detected the expression of CD3, CD4 and CD8. RESULTS: The proliferation and apoptosis of K562 cell could be inhibitied and induced by FA-2-b-ß, there was 100% successful in the tumor formation in vivo, after treated by drug for 21 days there were significantly increased peripheral leucocytes, but decreased hemoglobin of mice treated by FA-2-b-ß as compared with those in control group. The CD3, CD4 and CD8 showed positive in mice, and the propotation was imbalance, but it showed reserved after treated by FA-2-b-ß. CONCLUSION: FA-2-b-ß is strong anti-leukemia effect in vitro and in vivo, suggesting the traditional Chinese medicine maybe contribute to the anti-cancer and immunoregulation research.

A comparative study of contrast-enhanced ultrasound and contrast-enhanced CT for the detection and characterization of renal masses.

This study aims to compare the value of contrast-enhanced ultrasound (CEUS) and contrast-enhanced CT (CECT) in the differential diagnosis of benign and malignant renal masses. Included in this retrospective study were 143 renal masses in 141 patients using histopathological findings as the gold standard. A comparison was made of the two modalities in image characteristics for their accuracy in the differential diagnosis of renal masses. CEUS and CECT were both used for 39 masses in 37 patients, with 31 (79.5%) being malignant and 8 (20.5%) benign. The differences between the benign and malignant groups in perfusion intensity, perfusion uniformity and entry and exit of the contrast agent were not statistically significant (P > 0.05). However, CEUS could better display the circular perfusion of renal cell carcinoma than CECT (P < 0.05). CECT alone detected 109 masses in 107 patients, with 93 (85.3%) being malignant and 16 (14.7%) benign. CEUS detected 73 masses in 71 patients, with 56 (76.7%) being malignant and 17 (23.3%) benign. No statistically significant differences were observed between CEUS and CECT in the diagnosis of renal cell carcinoma (92.8% vs. 90.3%), with a specificity of 52.9% vs. 31.2%, an accuracy of 83.5% vs. 81.6%, and a positive predictive value of 86.7% vs. 88.4% or a negative predictive value of 69.2% vs. 35.7% (P > 0.05 for all). These results suggested both CEUS and CECT are highly valuable in the differential diagnosis of renal masses, and CEUS can be used as an important supplement for CECT in diagnosis of renal cancer.

[Inhibitory Effects of Agaricus Blazei Murrill (FA-2-b-ß) on Proliferation of Chronic Myeloid Leukemia Cells in vivo and Its Mechanism].

OBJECTIVE: To investigated the anti-tumor in vivo effect and mechanism of the acid RNA protein complex (FA-2-b-ß) of Agaricus blazei Murrill extract. METHODS: CCK-8 method was used to detected the inhibitory effect of FA-2-b-ß on proliferation of primary CML cells from newly diagnosed CML patients, the CML mouse model was established by trail-venous injection of primary CML cells, and the survival time, blood cell count and body weight were observed, the immunoflouresence and immunehistochemistry analysis, RT-qPCR, Western bolt were used to detemine the expression of caspase-3 signal pathway-related apoptosis genes and proteins. RESULTS: The experiments in vitro showed that the proliferative inhibitory rate in drug-treated group increased with concentration- and time-dependent manner (r24=0.9092, r48=0.9442, r72=0.9546), the inter group comparison showed the statistical difference of results. The experiments in vitro showed that the survival time prolonged, blood cell count increased and body weight recovered in FA-2-b-ß-treated group and imatinib-treated group, despite the WBC count is still high. The RT-qPCR and Western blot showed that the expression of BAX and caspase-3 gene and protein were up-regulated, the expression of BCL-2, cytochroime C, caspase-8, caspase-9 and BCL-ABL gene and protein were down-regulated. CONCLUSION: The FA-2-b-ß can induce apoptosis of primary CML cells and prolong the survival time of CML model mouse, which may be related with the caspase-3 signal pathway related genes and proteins.

Identification of cancer stem cell characteristics in liver hepatocellular carcinoma by WGCNA analysis of transcriptome stemness index.

Cancer stem cells (CSCs) are characterized by self-renewal and -differential potential as compared to common cancer cells and play an important role in the development and therapeutic resistance of liver hepatocellular carcinoma (LIHC). However, the specific pathogenesis of LIHC stem cells is still unclear, and the genes involved in the stemness of LIHC stem cells are currently unknown. In this study, we investigated novel biomarkers associated with LIHC and explored the expression characteristics of stem cell-related genes in LIHC. We found that mRNA expression-based stemness index (mRNAsi) was significantly overexpressed in liver cancer tissues. Further, mRNAsi expression in LIHC increased with the tumor pathological grade, with grade 4 tumors harboring the greatest stem cell features. Upon establishing mRNAsi scores based on mRNA expression of every gene, we found an association with poor overall survival in LIHC. Moreover, modules of interest were determined based on weighted gene co-expression network analysis (WGCNA) inclusion criteria, and three significant modules (red, green, and brown) and 21 key genes (DCN, ECM1, HAND2, PTGIS, SFRP1, SRPX, COLEC10, GRP182, ADAMTS7, CD200, CDH11, COL8A1, FAP, LZTS1, MAP1B, NAV1, NOTCH3, OLFML2A, PRR16, TMEM119, and VCAN) were identified. Functional analysis of these 21 genes demonstrated their enrichment in pathways involved in angiogenesis, negative regulation of DNA-binding transcription factor activity, apoptosis, and autophagy. Causal relationship with proteins indicated that the Wnt, Notch, and Hypoxia pathways are closely related to LIHC tumorigenesis. To our knowledge, this is the first report of a novel CSC biomarker, mRNAsi, to predict the prognosis of LIHC. Further, we identified 21 key genes through mRNA expression network analysis, which could be potential therapeutic targets to inhibit the stemness of cancer cells in LIHC.

Layer-by-layer assembly of chitosan stabilized multilayered liposomes for paclitaxel delivery.

Paclitaxel (PTX) loaded multilayered liposomes were prepared using layer-by-layer assembly in an effort to improve the stabilization of the liposomal compositions for PTX delivery. Stearyl amine was used to provide positive charge to the PTX-liposomes, and subsequently coated with anionic polyacrylic acid (PAA) followed by cationic chitosan. Various process variables were optimized and the optimum formulation was found to have particle size of 215 ± 17 nm, zeta potential of +27.9 ± 3.4 mV and encapsulation efficiency of 70.93 ± 2.39%. The lyophilized chitosan-PAA-PTX-liposomes formulation was stable in simulated gastrointestinal fluids and at different environmental conditions (4 °C and 25 °C). In vitro drug release experiments demonstrated that chitosan-PAA-PTX-liposomes formulation exhibited obvious sustained release behaviors compared to PTX-liposomes. Furthermore, chitosan-PAA-PTX-liposomes formulation revealed enhanced PTX induced cytotoxicity in human cervical cancer cell culture experiments compared to PTX-liposomes. In conclusion, the approach presented herein will provide a promising solution for PTX delivery.

Theoretical modeling study of the necrotic field during high-intensity focused ultrasound surgery.

BACKGROUND: High-intensity focused ultrasound (HIFU) is a type of micro-invasive treatment of tumor. It is important to create a guideline for the volume and position of the necrotic field by means of a theoretical model, this being one of the key problems in the clinic application of HIFU. MATERIAL/METHODS: Based on cellular thermo-necrotic theory, a computational model of temperature distribution and, therefore, the necrotic field was developed. A multi-transducer system with non-interferential and self-focused property was devised to provide experimental verification of the theoretical model. RESULTS: The necrotic field resulting from the modeling simulation did not show any evident difference from that of the experiment. The necrotic field of the same heating duration (4 seconds) was found with both modeling and experiment to be spheroid, with its center at the system's geometric focus and a volume of 1x1x2 cm3. CONCLUSIONS: The model of this study may predict the practical volume of the necrotic field as well as the time needed for it to form.