Areas Of Solid Tumors Research Articles

Challenges to Overcome in Clinical Research on Meningiomas

In contrast to other cancer research areas, the development of chemotherapy and radiotherapy for meningiomas has been challenging, lacking standardized criteria for assessing treatment response and progression. Although efforts by RANO have proposed evaluation criteria, a consensus on effective evaluation parameters for meningiomas remains elusive. This paper underscores the importance of establishing efficacy endpoints in clinical trials, compares efficacy assessment in meningioma research with other solid tumor areas, and outlines the challenges ahead in meningioma research. Recent analyses revealed the absence of consensus on efficacy endpoints in meningioma trials, complicating trial design and hindering cross-trial comparisons. The unique anatomical constraints and histological variability of meningiomas pose challenges in determining appropriate efficacy measures. To address these challenges, future research must focus on accumulating prognostic data, standardizing evaluation criteria, and considering multiple endpoints in trial designs. Akin to other cancer areas, investigating targeted therapies and establishing international consensus on efficacy endpoints are crucial steps forward.

The success of volumetric means ADC in predicting MGMT promoter hypermethylation in glioblastomas

Aims: This study aimed to investigate the relationship between volumetric mean ADC values and MGMT promoter hypermethylation status in glioblastoma (GB) patients segmented into perilesional edema area, solid tumor area, and necrosis area.
 Methods: The 212 GB patients in the University of California San Francisco Preoperative Diffuse Glioma MRI (UCSF-PDGM) dataset were retrieved from the Cancer Imaging Archive (TCIA). The mean volumetric ADC value was calculated in patients with shared segmentation data in the UCSF-PDGM dataset. The difference in mean volumetric ADC value was investigated in patients divided into groups based on MGMT promoter hypermethylation (MGMT+/ MGMT-).
 Results: Of the patients in our study, 125 (59.0%) were male. The median age of the patients was 62 years (26-94). MGMT promoter hypermethylation was observed in 152 (71.7%) patients. Mean Survival was calculated as 574.14±345.57 days in the MGMT+ group and 484.68±301.71 days in MGMT- group. According to volumetric mean ADC values, a difference was observed in the solid tumor and perilesional edema areas according to MGMT promoter hypermethylation (p1.14 in ADC measurements from the edema area with 72% sensitivity and 90% specificity. MGMT+ group could be determined with a sensitivity of 88% and specificity of 69% with a cut-off value of >1.01 in ADC measurements from the solid tumor area.
 Conclusion: Volumetric ADC measurements from the perilesional edema and solid tumor areas revealed higher ADC values in the MGMT+ group.

The Rate of Cisplatin Dosing Affects the Resistance and Metastatic Potential of Triple Negative Breast Cancer Cells, Independent of Hypoxia

To best control tumor growth and/or metastasis in triple negative breast cancer (TNBC), it may be useful to understand the effect(s) of chemotherapy delivery (i.e., the rate and pattern of exposure to the drug) on cell sub-populations that have experienced different levels of hypoxia (and/or acidosis). In this spirit, MDA-MB-231 TNBC cells, and their hypoxia-reporter counterparts, were characterized for their sensitivity to cisplatin. When in the form of multicellular spheroids, that capture the diffusion-limited transport that generates hypoxic and acidic subregions within the avascular areas of solid tumors, the effects of the rate and pattern of exposure to cisplatin on cell viability and motility/migration potential were evaluated for each cell sub-population. We demonstrated that cell sensitivity to cisplatin was not dependent on acidosis, but cell resistance increased with exposure to hypoxia. In spheroids, the increase of the rates of cell exposure to cisplatin, at a constant cumulative dose, increased sensitivity to chemotherapy and lowered the cells’ metastatic potential, even for cells that had experienced hypoxia. This effect was also shown to be caused by nanocarriers engineered to quickly release cisplatin which deeply penetrated the spheroid interstitium, resulting in the fast and uniform exposure of the TNBC tumors to the agent. This rate and dosing-controlled model may effectively limit growth and/or metastasis, independent of hypoxia. This mode of chemotherapy delivery can be enabled by engineered nanocarriers.

Bacteria-mediated tumor-targeted delivery of tumstatin (54-132) significantly suppresses tumor growth in mouse model by inhibiting angiogenesis and promoting apoptosis.

Tumor growth is an angiogenesis-dependent process and accompanied by the formation of hypoxic areas. Tumstatin is a tumor-specific angiogenesis inhibitor that suppresses the proliferation and induces the apoptosis of tumorous vascular endothelial cells. VNP20009, an attenuated Salmonella typhimurium strain, preferentially accumulates in the hypoxic areas of solid tumors. In this study, a novel Salmonella-mediated targeted expression system of tumstatin (VNP-Tum5) was developed under the control of the hypoxia-induced J23100 promoter to obtain anti-tumor efficacy in mice. Treatment with VNP-Tum5 effectively suppressed tumor growth and prolonged survival in the mouse model of B16F10 melanoma. VNP-Tum5 exhibited a higher efficacy in inhibiting the proliferation and inducing the necrosis and apoptosis of B16F10 cells in vitro and in vivo compared with VNP (control). VNP-Tum5 significantly inhibited the proliferation and migration of mouse umbilical vascular endothelial cells to impede angiogenesis. VNP-Tum5 downregulated the expression of anti-vascular endothelial growth factor A, platelet endothelial cell adhesion molecule-1, phosphorylated phosphoinositide 3 kinase, and phosphorylated protein kinase B and upregulated the expression of cleaved-caspase 3 in tumor tissues. This study is the first to use tumstatin-transformed VNP20009 as a tumor-targeted system for treatment of melanoma by combining anti-tumor and anti-angiogenic effects.

Activated aggregation strategies to construct size-increasing nanoparticles for cancer therapy.

The development of novel therapeutic strategies and modalities for tumors is still one of the important areas of current scientific research. Low permeability and short residence time of drugs in solid tumor areas are important reasons for the low efficiency of existing therapeutic strategies. Typically, nanoparticles with large size displayed enhanced residence time but low permeability. Therefore, to prolong the retention time of materials in solid tumors, size-increasing strategies have been developed to directly generate large-scale nanoparticles using small molecular compounds or increase the size of small nanoparticles in solid tumor areas. In this review, we summarize recently reported activatable aggregation systems that could be activated by cancer-related substances for cancer therapy and classify them by the mechanisms that lead to aggregation. In the end, we propose some potential challenges briefly from the view of our opinion. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Application of diffusion kurtosis imaging to the study of edema in solid and peritumoral areas of glioma

ObjectiveWhen gliomas grow in an infiltrative form, high-grade malignant glioma tissue extends beyond the contrast-enhancing tumor boundary, and this diffuse non-enhancing tumor infiltration is not visible on conventional MRI. The purpose of this study was to evaluate the of diffusion kurtosis imaging (DKI)-derived parameters in a group of patients with pre-operative gliomas, evaluating changes in the solid tumor and peritumoral edema area, and investigating their use for evaluating the recurrence and prognosis of gliomas. MethodsIn this retrospective study, 51 patients with gliomas who underwent biopsy or surgery underwent DKI scans before surgery. DKI scans were performed to generate DKI parameter maps of the solid tumor and peritumoral edema areas. In the solid tumor area, the kurtosis parameters showed the highest area under the curve (AUC), sensitivity, and specificity for distinguishing high- and low-grade gliomas (all P < 0.01). ResultsIn the peritumoral edema area, significant differences were found between groups with grade III and IV gliomas (P < 0.05). DKI parameters were found to correlate with clinical Ki-67 scores within the solid tumor area (MK: R2 = 0.288, P < 0.001; Kr: R2 = 0.270, P < 0.001; Ka: R2 = 0.274, P < 0.001; MD: R2 = 0.223, P < 0.001; FA: R2 = 0.098, P < 0.01). No significant correlations were found between Ki-67 and kurtosis parameters of peritumoral edema. ConclusionsIn this study, DKI showed potential utility for studying solid tumor and peritumoral edema of high grade gliomas.

Glioma associated microglia/macrophages distribution is conserved in glioblastoma regrowth: a morphometric study

We compared the morphological aspect of glioblastoma associated microglia/macrophages cells in 15 paired recurrent glioblastomas to check the ability of glioblastoma to recreate its microenvironment. The absolute number of GAMs is lower in normal tissue (21/mm2) than in the isolated tumor cells area (100-112/mm2) than in the solid tumor area (212-220/mm2) (p < 0.01). The morphology of GAMs remained the same in each tumor area with a reduced covered area by cell processes (196 to 216/mm2) than in normal tissue (708/mm2) (p < 0.01). In paired tumors, GAMs morphology remained the same in successive resections and was not modified by the treatments.

High-Resolution Diffusion-Weighted Imaging of C6 Glioma on a 7T BioSpec MRI Scanner: Correlation of Tumor Cellularity and Nuclear-to-Cytoplasmic Ratio with Apparent Diffusion Coefficient

To determine the association of the apparent diffusion coefficient (ADC) with quantitative cellularity and the nuclear-to-cytoplasmic ratio in C6 glioma. Animal models bearing C6 gliomas underwent MR scans with T1 rapid acquisition with relaxation enhancement (RARE), T2 RARE, and high-resolution diffusion-weighted imaging sequences. For each model, three consecutive sections were used to draw regions of interest (ROIs) and measure ADC values; the middle section was localized in the plane with the maximal solid tumor area. The minimal, mean, and maximal ADC values were recorded for each ROI. GFAP-immunostained sections coregistered with ADC measurements were used to calculate tumor cellularity and the nuclear-to-cytoplasmic (N/C) ratio. Spearman's correlation was used to assess the relationship between ADC values and quantitative tumor cellularity as well as N/C ratios with a significance level of p < 0.05. Thirty-three sections from 11 glioma-bearing rats were analyzed. The median values of the minimal, mean, and maximal ADC were 0.443 × 10-3, 0.744 × 10-3, and 1.140 × 10-3 mm2/s, respectively. The median cellularity and N/C ratio were 2151.234 per 0.025 mm2 and 0.857, respectively. The minimal, mean, and maximal ADCs were all significantly associated with cellularity, with correlation coefficients of -0.712 (p < 0.001), -0.631 (p < 0.001), and -0.460 (p = 0.007), respectively. The minimal and mean ADC had significant negative relationships with the N/C ratio, with correlation coefficients of -0.565 (p = 0.001) and -0.426 (p = 0.013), respectively. The minimal ADC correlated well with cellularity and N/C ratios in C6 glioma and may be used as a biomarker of these two pathological features.

Mannan-Based Nanodiagnostic Agents for Targeting Sentinel Lymph Nodes and Tumors.

Early detection of metastasis is crucial for successful cancer treatment. Sentinel lymph node (SLN) biopsies are used to detect possible pathways of metastasis spread. We present a unique non-invasive diagnostic alternative to biopsy along with an intraoperative imaging tool for surgery proven on an in vivo animal tumor model. Our approach is based on mannan-based copolymers synergistically targeting: (1) SLNs and macrophage-infiltrated solid tumor areas via the high-affinity DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) receptors and (2) tumors via the enhanced permeability and retention (EPR) effect. The polymer conjugates were modified with the imaging probes for visualization with magnetic resonance (MR) and fluorescence imaging, respectively, and with poly(2-methyl-2-oxazoline) (POX) to lower unwanted accumulation in internal organs and to slow down the biodegradation rate. We demonstrated that these polymer conjugates were successfully accumulated in tumors, SLNs and other lymph nodes. Modification with POX resulted in lower accumulation not only in internal organs, but also in lymph nodes and tumors. Importantly, we have shown that mannan-based polymer carriers are non-toxic and, when applied to an in vivo murine cancer model, and offer promising potential as the versatile imaging agents.

Mesoporous silica and polymer hybrid nanogels for multistage delivery of an anticancer drug

Effective treatment of cancer has always been a major medical problem. Although some nanoformulations can guide chemotherapeutic drugs to reach the tumor sites, their large size (~ 100 nm) is still the bottleneck for the treatment of solid tumors through deep penetration. In this study, we develop a kind of biodegradable hybrid nanogels to multistage delivery of anticancer drug. The nanogels can effectively encapsulate an anticancer drug (doxorubicin hydrochloride) and accelerate its release under redox and acidic conditions mimicking tumor and intracellular situations as well as controlling its release using a remote heating approach. Furthermore, the nanogels can enter the narrow space between the cells by diminishing their sizes to 40–60 nm drug-carrying mesoporous silica nanoparticles at solid tumor area, eventually entering the tumor cells and functioning in the nucleus. The drug-loaded nanogels present higher intracellular drug accumulation capacity, resulting in a two-fold enhancement in anticancer cytotoxicity as compared to free drug, suggesting their high potential as a good nanoplatform for delivery of therapeutic agents.

Improved Biopsy Accuracy in Retroperitoneal Dedifferentiated Liposarcoma.

Biopsy sensitivity in retroperitoneal dedifferentiated liposarcoma (DDLPS) is variable. Patients with grade 3 DDLPS face a significant risk of metastatic disease and may potentially benefit from neoadjuvant therapy, making highly accurate pretherapy diagnosis essential. Our study aimed to establish whether diagnostic sensitivity could be improved by targeting solid areas of tumor on percutaneous biopsy. Between 2016 and 2019, data on patients with suspected primary retroperitoneal sarcoma who underwent a biopsy were collected, and diagnostic accuracy was calculated. These data were compared with our previously reported series from 2005 to 2016. For DDLPS tumors, comparisons were then made between biopsies that targeted the solid component and those that did not. Data were available for 121 patients in the current series and 238 from the previous study. The proportion of biopsies returning a histological subtype concordant with postoperative pathology was 83% in the current series, marking a significant improvement over our previous study (67%, p = 0.001). For diagnosis of DDLPS, biopsy sensitivity improved from 40 to 74% (p < 0.001), with an increase from 13 to 50% (p = 0.006) where grade 3 DDLPS was treated as a separate disease. Within the current series, targeted biopsy yielded a sensitivity of 100% for identifying DDLPS, compared with 10% in nontargeted biopsy (p < 0.001). Systematic targeting of solid areas of tumor within suspected retroperitoneal liposarcoma has improved sensitivity for detection of both DDLPS and grade 3 DDLPS on biopsy. This approach minimizes the risk of underdiagnosis of patients with DDLPS who could benefit from neoadjuvant chemotherapy.

Mouse bone marrow mesenchymal stem cells with distinct p53 statuses display differential characteristics.

Mesenchymal stem cells (MSCs) affect diverse aspects of tumor progression, such as angiogenesis, tumor growth and metastasis. Bone marrow MSCs (BM-MSCs) are fibroblast-like cells with multipotent differentiation ability, that localize to areas of tissue damage, including wounds and solid tumors. The tumor suppressor gene, p53, is functionally involved in cell cycle control, apoptosis and genomic stability, and is mutated and inactivated in most human cancers. The present study aimed to investigate the role of p53 in the biology of BM-MSCs. In the present study, p53 wild-type (p53+/+), knockdown (p53+/−) and knockout (p53−/−) mouse BM-MSCs (mBM-MSCs) were observed to be similar in appearance and in the expression of cell surface biomarkers, but expressed differential p53 protein levels. The p53+/− and p53−/− mBM-MSCs demonstrated an increased proliferation rate compared with mBM-MSCs derived from p53+/+ mice. mBM-MSCs from all three groups, representing distinct p53 statuses, were unable to form tumors over a 3-month period in vivo. The adipogenic and osteogenic differentiation of mBM-MSCs was increased in the absence of p53. The colony formation and migratory abilities of p53+/− and p53−/− mBM-MSCs were markedly enhanced, and the expression levels of stem cell-associated proteins were significantly increased compared with p53+/+. The expression levels of microRNA (miR)-3152 and miR-337 were significantly increased in p53+/− and p53−/− mBM-MSCs, whereas the expression levels of miR-221, miR-155, miR-1288 and miR-4669 were significantly decreased. The expression levels of tumor necrosis factor-α and interferon-γ-inducible protein-10 were significantly upregulated in the supernatant of p53+/− and p53−/− mBM-MSCs. Ubiquitin protein ligase E3 component n-recognin 2, RING-finger protein 31 and matrix metalloproteinase 19 were highly expressed in p53+/− and p53−/− mBM-MSCs. The results of the present study indicated that p53 may serve an important role in the biology of mBM-MSCs, and may provide novel insights into the role of cells with different p53 statuses in cancer progression.

CTNNB1 and APC mutations in odontogenic carcinoma with dentinoid

The purpose of the present study is to report 2 cases of odontogenic carcinoma with dentinoid, a rare low-grade odontogenic carcinoma associated with facial deformity and bone loss, and to investigate the presence of pathogenic mutations in these samples. By using a next-generation sequencing approach, we sequenced a panel of 50 oncogenes and tumor suppressor genes commonly mutated in human cancer. Microscopic features of both cases revealed solid areas of malignant odontogenic tumor with a large amount of dentinoid material. We identified pathogenic mutations in the genes CTNNB1 and APC, both of which are part of the Wnt-signaling pathway. Consistent with Wnt-signaling activation, both tumors showed strong β-catenin accumulation in the cytoplasm and in the nuclei. The molecular profile of odontogenic carcinoma with dentinoid may help in its diagnosis, as well as in the identification of potential molecular targets for therapy in the future.

Intestinal probiotics E. coli Nissle 1917 as a targeted vehicle for delivery of p53 and Tum-5 to solid tumors for cancer therapy

Traditional cancer therapies, such as surgery treatment, radiotherapy, and chemotherapy, often fail to completely eliminate tumor cells in an anaerobic microenvironment of tumor regions.In contrast to these traditional cancer therapies, the use of targeted delivery vectors to deliver anticancer genes or antitumor drugs to hypoxic areas in tumors is the most clinically promising cancer treatment with rapid development in recent years. In this study, E.coli Nissle 1917 (EcN), an intestinal probiotic, was utilized as a targeted transport vector to deliver p53 and Tum-5 protein to tumor hypoxic regions. The tumor-targeting characteristics of EcN were investigated using luciferase LuxCDABE operon, and the results demonstrated that EcN could specifically accumulate in the solid tumor areas of SMMC-7721 tumor-bearing BALB/c nude mice. The Tum 5-p53 bifunctional proteins were initially constructed and then delivered to solid tumor regions by using the targeted transporter EcN for cancer therapy. The antitumor effect and safety of three engineered bacteria, namely, EcN (Tum-5), EcN (p53), and EcN (Tum 5-p53), were also examined. The calculated tumor volume and tumor weight indicated that these three engineered bacteria could inhibit the growth of human hepatoma SMMC-7721 cells, and the antitumor effect of EcN (Tum 5-p53) expressing the Tum 5-p53 fusion protein was significantly better than those of EcN (Tum-5) and EcN (p53) alone. Immunofluorescence demonstrated that the expression of Ki-67, a nuclear proliferation-related protein, was inhibited in the tumor areas of the groups treated with the engineered bacteria, whereas the expression of caspase-3 was upregulated. The expression trends of Ki-67 and caspase-3 were consistent with the different antitumor efficacies of these three engineered bacteria. EcN did not elicit obvious side effects on mice. This research not only provids a foundation for tumor-targeted therapy but also contributes greatly to the development of antitumor agents and anticancer proteins.

HIF-1 transcription activity: HIF1A driven response in normoxia and in hypoxia

BackgroundHIF1A (Hypoxia-Inducible-Factor 1A) expression in solid tumors is relevant to establish resistance to therapeutic approaches. The use of compounds direct against hypoxia signaling and HIF1A does not show clinical efficiency because of changeable oxygen concentrations in solid tumor areas. The identification of HIF1A targets expressed in both normoxia and hypoxia and of HIF1A/hypoxia signatures might meliorate the prognostic stratification and therapeutic successes in patients with high-risk solid tumors.MethodsIn this study, we conducted a combined analysis of RNA expression and DNA methylation of neuroblastoma cells silenced or unsilenced for HIF1A expression, grown in normoxia and hypoxia conditions.ResultsThe analysis of pathways highlights HIF-1 (heterodimeric transcription factor 1) activity in normoxia in metabolic process and HIF-1 activity in hypoxia in neuronal differentiation process. HIF1A driven transcriptional response in hypoxia depends on epigenetic control at DNA methylation status of gene regulatory regions. Furthermore, low oxygen levels generate HIF1A-dependent or HIF1A-independent signatures, able to stratify patients according to risk categories.ConclusionsThese findings may help to understand the molecular mechanisms by which low oxygen levels reshape gene signatures and provide new direction for hypoxia targeting in solid tumor.

Differentiation between glioblastomas and brain metastases and regarding their primary site of malignancy using dynamic susceptibility contrast MRI at 3T

BackgroundDifferentiation between glioblastoma and brain metastasis may be challenging in conventional contrast-enhanced MRI. PurposeTo investigate if perfusion-weighted MRI is able to differentiate glioblastoma from metastasis and, as a second aim was to see if it was possible in the latter group, to predict the primary site of neoplasm. Material and methodsHundred and fourteen patients with newly discovered tumor lesion (76 metastases and 38 glioblastomas) underwent conventional contrast-enhanced MRI including dynamic susceptibility contrast perfusion sequence. The calculated relative cerebral blood volumes were analyzed in the solid tumor area, peritumoral area, area adjacent to peritumoral area, and normal appearing white matter in contralateral semioval center. The Student t-test was used to detect statistically significant differences in relative cerebral blood volume between glioblastomas and metastases in the aforementioned areas. Furthermore, the metastasis group was divided in four sub groups (lung-, breast-, melanoma-, and gastrointestinal origin) and using one-way ANOVA test. P-values < 0.05 were considered significant. ResultsRelative cerebral blood volume (rCBV) in the peritumoral edema was significantly higher in glioblastomas than in metastases (mean 3.2 ± 1.4 and mean 0.9 ± 0.7), respectively, (P < 0.0001). No significant differences in the solid tumor area or the area adjacent to edema were found, (P = 0.28 and 0.21 respectively). There were no significant differences among metastases in the four groups. ConclusionIt is possible to differentiate glioblastomas from metastases by measuring the CBV in the peritumoral edema.It is not possible to differentiate between brain metastases from different primaries (lung-, breast-, melanoma or gastrointestinal) using CBV-measurements in the solid tumor area, peritumoral edema or area adjacent to edema.

Learning from Clostridium novyi-NT: How to defeat cancer.

Side effects associated with conventional anticancer therapies have prompted the new idea of solid tumor treatment strategy. One of them is using bacteria explored as potential antitumor agents over more than one century. Notably, the ideal therapy is a specifical target to tumors with limited toxicity. Here, we take "Clostridium novyi" for the search keyword in the PubMed from 2000 to 2015 and describe that C. novyi-NT spores act as "Trojan horse" for bacteriolytic therapy. This therapy is based on the fact that the live and attenuated obligate anaerobic bacteria are capable of binary fission selectively in anoxic areas of solid tumors and direct tumoricidal effects. Our succinct review mainly concentrates on the potential mechanisms of combination bacteriolytic therapy, an effective and safe tumor therapy with the help of C. novyi-NT. Importantly, C. novyi-NT spores were shown to induce solid tumor regression and exhibit the property to initiate an immune response. Therefore, C. novyi-NT spores should be an effective and safe tumor therapy.

Multifunctional Protocells for Enhanced Penetration in 3D Extracellular Tumoral Matrices

The high density of the extracellular matrix in solid tumors is an important obstacle to nanocarriers for reaching deep tumor regions and has severely limited the efficacy of administrated nanotherapeutics. The use of proteolytic enzymes prior to nanoparticle administration or directly attached to the nanocarrier surface has been proposed to enhance their penetration, but the low in vivo stability of these macromolecules compromises their efficacy and strongly limits their application. Herein, we have designed a multifunctional nanocarrier able to transport cytotoxic drugs to deep areas of solid tumors and once there, to be engulfed by tumoral cells causing their destruction. This system is based on mesoporous silica nanocarriers encapsulated within supported lipid bilayers (SLBs). The SLB avoids premature release of the housed drug while providing high colloidal stability and an easy to functionalize surface. The tumor penetration property is provided by attachment of engineered polymeric nanocapsules th...

Autophagy in advanced low- and high-grade tubular adenocarcinomas of the stomach: An ultrastructural investigation

ABSTRACTAutophagy represents a catabolic process in which cellular protein and organelles are engulfed into autophagosomes, digested in lysosomes and reutilized for the cellular metabolism. In neoplastic conditions, autophagy may act either as a tumour suppressor avoiding the accumulation of damaged proteins and organelles or as a mechanism of cell survival promoting the tumour growth. Although enhanced autophagy has been reported in hypoxic areas of solid tumors, there are only few ultrastructural reports concerning the relationships between autophagy and tumor grade.In the present study, we have performed an ultrastructural investigation aimed to document autophagy in a cohort of advanced gastric carcinomas of tubular type, correlating the observed findings with low and high tumor grade. Among 71 surgically resected cases of advanced gastric carcinomas, we have selected twelve low-grade and thirteen high-grade tubular adenocarcinomas.Autophagic vacuoles (AV) were only occasionally found in low-grade tubular carcinomas, while they constituted a frequent finding in high-grade ones (p < 0.01). Moreover, in high-grade tubular adenocarcinomas, our data revealed a morphologic association between autophagy and nuclear changes, such as multinucleation, micronucleation and nuclear buds, largely considered as ultrastructural aspects of mitotic instability. However, an increased autophagy was associated with organelle-poor cytoplasm or a senescent phenotype, characterized by lipofuscin granules and cytoplasmic vacuoles.In the light of our observations, it may be suggested that autophagy should be considered a phenomenon mainly related to the cellular differentiation and tumor progression.

Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting.

Diffusion limitations on the penetration of nanocarriers in solid tumors hamper their therapeutic use when labeled with α-particle emitters. This is mostly due to the α-particles' relatively short range (≤100μm) resulting in partial tumor irradiation and limited killing. To utilize the high therapeutic potential of α-particles against solid tumors, we designed non-targeted, non-internalizing nanometer-sized tunable carriers (pH-tunable liposomes) that are triggered to release, within the slightly acidic tumor interstitium, highly-diffusive forms of the encapsulated α-particle generator Actinium-225 (225Ac) resulting in more homogeneous distributions of the α-particle emitters, improving uniformity in tumor irradiation and increasing killing efficacies. On large multicellular spheroids (400μm-in-diameter), used as surrogates of the avascular areas of solid tumors, interstitially-releasing liposomes resulted in best growth control independent of HER2 expression followed in performance by (a) the HER2-targeting radiolabeled antibody or (b) the non-responsive liposomes. In an orthotopic human HER2-negative mouse model, interstitially-releasing 225Ac-loaded liposomes resulted in the longest overall and median survival. This study demonstrates the therapeutic potential of a general strategy to bypass the diffusion-limited transport of radionuclide carriers in solid tumors enabling interstitial release from non-internalizing nanocarriers of highly-diffusing and deeper tumor-penetrating molecular forms of α-particle emitters, independent of cell-targeting.