Percutaneous Ethanol Intratumoral Injection for Treatment of Small Primary Liver Cancer：Summary of 240 Cases

Objective To evaluate the therapeutic effects of percutaneous ethanol intratumoral injection (PEIT) for treatment of small primary liver cancer (SPLC).Methods 240 patients with surgically or pathologically proved SPLC ( < 3 cm in diameter) were treated by PEIT ( under the guidance of B-ultrasound) . Of the" 240 patients, 163 had recurrent liver cancer, 55 had inoperable liver cancer because of cardiac, pulmonary, hepatic and renal dysfunctions or due to the close proximity of tumor to the major vessels, and 22 refused to receive surgical resection. In 40 patients who received surgical resection after PEIT treatment, the resected tumors were pathologically evaluated for necrotic status and the patients were followed up postoperatively.Results Postoperative 1-, 2- and 3-year survival rate of the 240 patients was 94.9% , 84.2% and 66.3% respectively. Conclusion PEIT can be used as a non-invasive treatment for SPLC, and preoperative PEIT appears to be helpful in reducing recurrence of postoperative liver cancer.

In vivo assessment of intratumoral aspirin injection to treat hepatic tumors

AIM: To study the antineoplastic efficacy of 10% aspirin intralesional injection on VX2 hepatic tumors in a rabbit model. METHODS: Thirty-two male rabbits (age: 6-9 wk; body weight: 1700-2500 g) were inoculated with VX2 hepatic tumor cells (104 cells/rabbit) via supraumbilical median laparotomy. On day 4 post-implantation, when the tumors were about 1 cm in diameter, the rabbits were randomly divided into the following groups (n = 8 each group) to assess early (24 h) and late (7 d) antineoplastic effects of intratumoral injection of 10% bicarbonate aspirin solution (experimental groups) in comparison to intratumoral injection of physiological saline solution (control groups): group 1, 24 h control; group 2, 24 h experimental; group 3, 7 d control; group 4, 7 d experimental. The serum biochemistry profile (measurements of glycemia, alkaline phosphatase, gamma-glutamyl transferase, aspartateaminotransferase, and alanine aminotransferase) and body weight measurements were obtained for all animals at the following time points: D0, before tumor implant; D4, day of treatment; D5, day of sacrifice for groups 1 and 2; D11, day of sacrifice for groups 3 and 4. Gross assessments of the abdominal and thoracic cavities were carried out upon sacrifice. The resected liver tissues, including hepatic tumors, were qualitatively (general morphology, signs of necrosis) and quantitatively (tumor area) assessed by histopathological analysis. RESULTS: Gross examination showed no alterations, besides the left hepatic lobe tumors, had occurred in the thoracic and abdominal cavities of any animal at any time point evaluated. However, the features of the tumor foci were distinctive between the groups. Compared to the control groups, which showed normal unabated tumor progression, the aspirin-treated groups showed imprecise but limited tumor boundaries and a general red-white coloration (indicating hemorrhaging) at 24 h post-treatment, and development of yellow-white areas of a cicatricial aspect at 7 d after treatment. At all time points evaluated, all except one biochemical parameters tested within the reference range (P > 0.05); a significant increase was detected in the alkaline phosphatase level of the control group 3 on D11 (P < 0.05). At 24 h post-treatment, the aspirintreated groups showed extensive coagulation necrosis accompanied by a remarkable absence of viable tumor foci; at 7 d after treatment, the tumors had completely disappeared in these animals and fibrous necrotic nod- ules had developed. In contrast, throughout the study course, the tumors of the control groups remained unchanged, showing tumor nodules without necrosis at the time point corresponding to 24 h post-treatment and increased amounts of tumor nodules at the time point corresponding to 7 d post-treatment. Quantitative analysis of the remaining tumor area revealed that the aspirin-treated groups had significantly smaller tumor foci at 24 h post-treatment (8.5% ± 0.7%) andat 7 d after treatment (11.0% ± 4.2%), compared to those in the control groups (24 h: 98.5% ± 1.5% and 7 d: 94.0% ± 2.7%; both,P < 0.005). CONCLUSION: Intralesional injection of a 10% aspirin solution causes destruction of VX2 hepatic tumors in rabbits without evidence of relapse at 7 d after treat- ment administration.

Evaluation of micelles incorporated into thermosensitive hydrogels for intratumoral delivery and controlled release of docetaxel:A dual approach for in situ treatment of tumors

The in situ gelling hybrid hydrogel system has been reported to effectively concentratechemotherapeutic drugs at the tumor site and sustain their release for a long period. DTX-micelles(docetaxel-loaded mixed micelles) are able to increase the solubility of DTX inwater, and then a high drug loading rate of hydrogels can be achieved by encapsulatingthe docetaxel-loaded mixed micelles into the hydrogels. The thermosensitive nature ofDTX-MM-hydrogels(thermosensitive hydrogels incorporated with docetaxel-loaded mixedmicelles) can accelerate the formation of a depot of this drug-loaded system at the siteof administration. Therefore, the hydrogels provide a much slower release compared withDTX-micelles and DTX-injection. An in vivo retention study has demonstrated that the DTX-MM-hydrogels can prolong the drug retention time and in viv o trials have shown that theDTX-MM-hydrogels have a higher antitumor efficacy and systemic safety. In conclusion, theDTX-MM-hydrogels prepared in this study have considerable potential as a drug deliverysystem, with higher tumor inhibition effects and are less toxic to normal tissues.

Magnetic Particle Imaging for Magnetic Hyperthermia Treatment: Visualization and Quantification of the Intratumoral Distribution and Temporal Change of Magnetic Nanoparticles in Vivo

Purpose: Magnetic hyperthermia treatment (MHT) is a strategy for cancer therapy using the tem-perature rise of magnetic nanoparticles (MNPs) under an alternating magnetic field (AMF). Re-cently, a new imaging method called magnetic particle imaging (MPI) has been introduced. MPI allows imaging of the spatial distribution of MNPs. The purpose of this study was to investigate the feasibility of visualizing and quantifying the intratumoral distribution and temporal change of MNPs and predicting the therapeutic effect of MHT using MPI. Materials and Methods: Colon-26 cells (1 × 106 cells) were implanted into the backs of eight-week-old male BALB/c mice. When the tumor volume reached approximately 100 mm3, mice were divided into untreated (n = 10) and treated groups (n = 27). The tumors in the treated group were directly injected with MNPs (Resovist?) with iron concentrations of 500 mM (A, n = 9), 400 mM (B, n = 8), and 250 mM (C, n = 10), respectively, and MHT was performed using an AMF with a frequency of 600 kHz and a peak amplitude of 3.5 kA/m. The mice in the treated group were scanned using our MPI scanner immediately before, immediately after, 7 days, and 14 days after MHT. We drew a region of interest (ROI) on the tumor in the MPI image and calculated the average, maximum, and total MPI values and the number of pixels by taking the threshold value for extracting the contour as 40% of the maximum MPI value (pixel value) within the ROI. These parameters in the untreated group were taken as zero. We also measured the relative tumor volume growth (RTVG) defined by (V-V0)/V0, where V0 and V are the tumor volumes immediately before and after MHT, respectively. Results: The average, maximum, and total MPI values decreased up to 7 days after MHT and remained almost constant thereafter in all groups, whereas the number of pixels tended to increase with time. The RTVG values in Groups A and B were significantly lower than those in the control group 3 days or more and 5 days or more after MHT, respectively. The above four parameters were significantly inversely correlated with the RTVG values 5, 7, and 14 days after MHT. Conclusion: MPI can visualize and quantify the intratumoral distribution and temporal change of MNPs before and after MHT. Our results suggest that MPI will be useful for predicting the therapeutic effect of MHT and for the treatment planning of MHT.

Observation of intratumoral injection of radiosensitizer

The present study made in 92 mice showed that hydrogen peroxide com-pound injected directly into the tumor could to some extent sensitize the hypoxiccells of S180 solid tumor to radiate,for example,both the tumor regression rateand the mouse survival rate 40d after radiation in the hydrogen peroxide com-pound group were significantly greater than those in the radiation alone group.The increasing rate of tumor diameter in 10d was 77.10%,47.09%,and 47.47%-10.4% in groups of control,radiation alone,radiosensitizer alone,radiationand hydrogen peroxide compound,respectively.Some of the problems aboutthe intratumoral injection of radiosensitizer were discussed.

Beyond the Gut:The intratumoral microbiome’s influence on tumorigenesis and treatment response

The intratumoral microbiome(TM)refers to the microorganisms in the tumor tissues,including bacteria,fungi,viruses,and so on,and is distinct from the gut microbiome and circulating microbiota.TM is strongly associated with tumorigenesis,progression,metastasis,and response to therapy.This paper highlights the current status of TM.Tract sources,adjacent normal tissue,circulatory system,and concomitant tumor co-metastasis are the main origin of TM.The advanced techniques in TM analysis are comprehensively summarized.Besides,TMis involved in tumor progression through several mechanisms,including DNA damage,activation of oncogenic signaling pathways(phosphoinositide 3-kinase[PI3K],signal transducer and activator of transcription[STAT],WNT/β-catenin,and extracellular regulated protein kinases[ERK]),influence of cytokines and induce inflammatory responses,and interaction with the tumor microenvironment(anti-tumor immunity,pro-tumor immunity,and microbial-derived metabolites).Moreover,promising directions of TM in tumor therapy include immunotherapy,chemotherapy,radiotherapy,the application of probiotics/prebiotics/synbiotics,fecal microbiome transplantation,engineered microbiota,phage therapy,and oncolytic virus therapy.The inherent challenges of clinical application are also summarized.This review provides a comprehensive landscape for analyzing TM,especially the TM-related mechanisms and TM-based treatment in cancer.

Photodynamic eradication of intratumoral microbiota with bacteria-targeted micelles overcomes gemcitabine resistance of pancreatic cancer

Increasing evidence suggests that intratumoral microbiota plays a pivotal role in tumor progression,immunosurveillance,metastasis,and chemosensitivity.Particularly,in pancreatic ductal adenocarcinoma,tumor-resident Gammaproteobacteria could transform the chemotherapeutic drug gemcitabine(Gem)into its inactive form,thus rendering chemotherapy ineffective.Herein,a strategy for selectively eradicating intratumoral bacteria was described for overcoming Gem resistance in a pancreatic cancer animal model.An antimicrobial peptide was linked with photosensitizer through a poly(ethylene glycol)chain,which can self-assemble into micelles with a diameter of∼20 nm.The micelles could efficiently kill bacteria under light irradiation by inducing membrane depolarization,thereby inhibiting Gem metabolism.In a bacteria-resident pancreatic cancer animal model,the selective photodynamic eradication of intratumoral bacteria was demonstrated to efficiently reverse Gem resistance.This research highlights antibacterial photodynamic therapy as a promising adjuvant strategy for cancer therapy by modulating intratumoral microbiota.

Light-triggered nitric oxide release and structure transformation of peptide for enhanced intratumoral retention and sensitized photodynamic therapy

Tumor-targeted delivery of nanomedicine is of great importance to improve therapeutic efficacy of cancer and minimize systemic side effects.Unfortunately,nowadays the targeting efficiency of nanomedicine toward tumor is still quite limited and far from clinical requirements.In this work,we develop an innovative peptide-based nanoparticle to realize light-triggered nitric oxide(NO)release and structural transformation for enhanced intratumoral retention and simultaneously sensitizing photodynamic therapy(PDT).The designed nanoparticle is self-assembled from a chimeric peptide monomer,TPP-RRRKLVFFK-Ce6,which contains a photosensitive moiety(chlorin e6,Ce6),aβ-sheet-forming peptide domain(Lys-Leu-Val-Phe-Phe,KLVFF),an oligoarginine domain(RRR)as NO donor and a triphenylphosphonium(TPP)moiety for targeting mitochondria.When irradiated by light,the constructed nanoparticles undergo rapid structural transformation from nanosphere to nanorod,enabling to achieve a significantly higher intratumoral accumulation by 3.26 times compared to that without light irradiation.More importantly,the conversion of generated NO and reactive oxygen species(ROS)in a light-responsive way to peroxynitrite anions(ONOO)with higher cytotoxicity enables NO to sensitize PDT in cancer treatment.Both in vitro and in vivo studies demonstrate that NO sensitized PDT based on the well-designed transformable nanoparticles enables to eradicate tumors efficiently.The light-triggered transformable nanoplatform developed in this work provides a new strategy for enhanced intratumoral retention and improved therapeutic outcome.

iRGD-reinforced, photo-transformable nanoclusters toward cooperative enhancement of intratumoral penetration and antitumor efficacy

Insufficient intratumoral penetration greatly hurdles the anticancer performance of nanomedicine. To realize highly efficient tumor penetration in a precisely and spatiotemporally controlled manner, far-red light-responsive nanoclusters (NCs) capable of size shrinkage and charge conversion were developed and co-administered with iRGD to synergistically improve the intratumoral penetration and the anticancer efficacy. The NCs were constructed using the singlet oxygen-sensitive (SOS) polyethylene glycolpolyurethane-polyethylene glycol (PEG-(1O2)PU-PEG) triblock copolymer to encapsulate the doxorubicin (DOX)-loaded, chlorin e6 (Ce6)-conjugated polyamindoamine (PAMAM) dendrimer (DCD) via the double-emulsion method. Co-administration of iRGD notably increased the permeability of NCs within tumor vasculature and tumor tissues. In addition, upon far-red light irradiation (660 nm) of tumors at low optical density (10 mW/cm2), the generated 1O2 could disintegrate the NCs and release the DCD with positive surface charge and ultra-small size (~ 5 nm), which synergized with iRGD to enable deep intratumoral penetration. Consequently, the local 1O2 at lethal concentrations along with the released DOX efficiently and cooperatively eradicated tumor cells. This study provides a convenient approach to spatiotemporally promote the intratumoral penetration of nanomedicine and mediate programmed anticancer therapy.

Chemo-photothermal immunotherapy for eradication of orthotopic tumors and inhibition of metastasis by intratumoral injection of polydopamine versatile hydrogels

Cancer remains one of the leading causes of death globally and metastasis always leads to treatment failure.Here,we develop a versatile hydrogel loading photothermal agents,chemotherapeutics,and immune-adjuvants to eradicate orthotopic tumors and inhibit metastasis by combinational therapy.Hydrogel networks were synthesized via the thiol-Michael addition of polydopamine(PDA)with thiolated hyaluronic acid.PDA acted as a cross-linking agent and endowed the hydrogel with excellent photothermal property.Meanwhile,a chemotherapeutic agent,doxorubicin(DOX),was loaded in the hydrogel viaπ-πstacking with PDA and an immune-adjuvant,CpG-ODN,was loaded via electrostatic interaction.The release of DOX from the hydrogel was initially slow but accelerated due to near infrared light irradiation.The hydrogels showed remarkably synergistic effect against 4T1 cancer cells and stimulated plenty of cytokines secreting from RAW264.7 cells.Moreover,the hydrogels eradicated orthotopic murine breast cancer xenografts and strongly inhibited metastasis after intratumoral injection and light irradiation.The high anticancer efficiency of this chemo-photothermal immunotherapy resulted from the strong synergistic effect of the versatile hydrogels,including the evoked host immune response.The combinational strategy of chemo-photothermal immunotherapy is promising for highly effective treatment of breast cancer.

Metal-polyphenol-network coated CaCO_(3)as pH-responsive nanocarriers to enable effective intratumoral penetration and reversal of multidrug resistance for augmented cancer treatments

Construction of multifunctional stimuli-responsive nanotherapeutics enabling improved intratumoral penetration of therapeutics and reversal of multiple-drug resistance(MDR)is potent to achieve effective cancer treatment.Herein,we report a general method to synthesize pH-dissociable calcium carbonate(CaCO_(3))hollow nanoparticles with amorphous CaCO_(3)as the template,gallic acid(GA)as the organic ligand,and ferrous ions as the metallic center via a one-pot coordination reaction.The obtained GA–Fe@CaCO_(3)exhibits high loading efficiencies to both oxidized cisplatin prodrug and doxorubicin,yielding drug loaded GA-Fe@CaCO_(3)nanotherapeutics featured in pH-responsive size shrinkage,drug release,and Fenton catalytic activity.Compared to nonresponsive GA-Fe@silica nanoparticles prepared with silica nanoparticles as the template,such GA-Fe@CaCO_(3)confers significantly improved intratumoral penetration capacity.Moreover,both types of drug-loaded GA–Fe@CaCO_(3)nanotherapeutics exhibit synergistic therapeutic efficacies to corresponding MDR cancer cells because of the GA–Fe mediated intracellular oxidative stress amplification that could reduce the efflux of engulfed drugs by impairing the mitochondrial-mediated production of adenosine triphosphate(ATP).As a result,it is found that the doxorubicin loaded GA-Fe@CaCO_(3)exhibits superior therapeutic effect towards doxorubicin-resistant 4T1 breast tumors via combined chemodynamic and chemo-therapies.This work highlights the preparation of pH-dissociable CaCO_(3)-based nanotherapeutics to enable effective tumor penetration for enhanced treatment of drug-resistant tumors.

Pediatric gliomatosis cerebri presenting with intratumoral hemorrhage leading to poor outcome

Gliomatosis cerebri(GC)is an uncommon disease,defined as diffuse infiltration of neoplastic glial cells involving at least three cerebral lobes.GCs in young population are rare.We described a case of 14-year-old woman with GC who did not receive any recommended treatment,because the patient’s family refused.The patient had a rapid deterioration in 5 months after first symptoms due to intratumoral bleeding.This is the first case report of intratumoral bleeding after diagnosis of GC is made,resulting in poor outcome.GC may acquire possibility of intratumoral hemorrhage through its development.

Preoperatively predicting vessels encapsulating tumor clusters in hepatocellular carcinoma:Machine learning model based on contrast-enhanced computed tomography

BACKGROUND Recently,vessels encapsulating tumor clusters(VETC)was considered as a distinct pattern of tumor vascularization which can primarily facilitate the entry of the whole tumor cluster into the bloodstream in an invasion independent manner,and was regarded as an independent risk factor for poor prognosis in hepatocellular carcinoma(HCC).AIM To develop and validate a preoperative nomogram using contrast-enhanced computed tomography(CECT)to predict the presence of VETC+in HCC.METHODS We retrospectively evaluated 190 patients with pathologically confirmed HCC who underwent CECT scanning and immunochemical staining for cluster of differentiation 34 at two medical centers.Radiomics analysis was conducted on intratumoral and peritumoral regions in the portal vein phase.Radiomics features,essential for identifying VETC+HCC,were extracted and utilized to develop a radiomics model using machine learning algorithms in the training set.The model’s performance was validated on two separate test sets.Receiver operating characteristic(ROC)analysis was employed to compare the identified performance of three models in predicting the VETC status of HCC on both training and test sets.The most predictive model was then used to constructed a radiomics nomogram that integrated the independent clinical-radiological features.ROC and decision curve analysis were used to assess the performance characteristics of the clinical-radiological features,the radiomics features and the radiomics nomogram.RESULTS The study included 190 individuals from two independent centers,with the majority being male(81%)and a median age of 57 years(interquartile range:51-66).The area under the curve(AUC)for the combined radiomics features selected from the intratumoral and peritumoral areas were 0.825,0.788,and 0.680 in the training set and the two test sets.A total of 13 features were selected to construct the Rad-score.The nomogram,combining clinicalradiological and combined radiomics features could accurately predict VETC+in all three sets,with AUC values of 0.859,0.848 and 0.757.Decision curve analysis revealed that the radiomics nomogram was more clinically useful than both the clinical-radiological feature and the combined radiomics models.CONCLUSION This study demonstrates the potential utility of a CECT-based radiomics nomogram,incorporating clinicalradiological features and combined radiomics features,in the identification of VETC+HCC.

Clinicopathological and prognostic implications of endoglin (CD105) expression in hepatocellular carcinoma and its adjacent non-tumorous liver

AIM: The expression pattern of endoglin (CD105) in hepatocellular carcinoma (HCC) has not been reported so far. We hypothesized that CD105 could differentially highlight a subset of microvessels in HCC, and intratumoral microvessel density (IMVD) by CD105 immunostaining (IMVD-CD105) could provide better prognostic information than IMVD by CD34 immunostaining (IMVD-CD34).METHODS: Paraffin blocks of tumor and adjacent nontumorous liver tissues from 86 patients who underwent curative resection of HCC were used for this study. Serial sections were stained for CD105 and CD34, respectively,to highlight the microvessels. IMVD was counted according to a standard protocol.RESULTS: In the HCC tissues, CD105 was either negatively or positively stained only in a subset of microvessels. In contrast, CD34 showed positive and more extensive microvessel staining in all cases examined. However, in the adjacent non-tumorous liver sections, CD105 showed a diffuse pattern of microvessel staining in 20 of 86 cases,while CD34 showed negative or only focal staining of the sinusoids around portal area. Correlation with clinicopathological data demonstrated that lower scores of IMVD-CD105 were found in larger sized tumors [mean 41.4/0.74 mm2 (＞5 cm tumor) vs 65.9/0.74 mm2(≤ 5 cm tumor), P = 0.043] and more aggressive tumors,as indicated by venous infiltration [36.8/0.74 mm2 (present)vs 64.2/0.74 mm2 (absent), P = 0.020], microsatellite nodules [35.1/0.74 mm2 (present) vs 65.9/0.74 mm2(absent), P = 0.012], and advanced TNM tumor stage [38.8/0.74 mm2 (stage 3 or 4) vs 68.3/0.74 mm2 (stage 1or 2), P = 0.014]. No prognostic significance was observed when median values were used as cut-off points using either IMVD-CD105 or IMVD-CD34. However, the presence of the diffuse pattern of CD105 expression in the adjacent non-tumorous liver tissues predicted a poorer disease-free survival (median 8.6 vs 21.5 mo, P = 0.026).CONCLUSION: Our data demonstrate that a lower IMVDCD105 is associated with larger and more aggressive tumors. In this study, IMVD-CD105 did not provide significant prognostic information. However, active angiogenesis as highlighted by diffuse CD105 staining of the microvessels in the adjacent non-tumorous liver tissues is predictive of early recurrence.

Knockdown of liver-intestine cadherin decreases BGC823 cell invasiveness and metastasis in vivo

AIM:To assess BGC823 gastric cancer(GC) cell metastasis after knockdown of liver-intestine cadherin(CDH17) and the therapeutic value of CDH17-RNAilentivirus in vivo.METHODS:We evaluated primary tumor growth and assessed local infiltration and systemic tumor dissemination using an orthotopic implantation technique.The therapeutic value of CDH17 knockdown was examined by intratumoral administration of CDH17-RNA interference(RNAi)-lentivirus in an established GC tumor xenograft mouse model.Furthermore,a comparative proteomic approach was utilized to identify differentially expressed proteins in BGC823 and lenti-CDH17-miRneg cells following CDH17 knockdown.RESULTS:Metastases in the liver and lung appeared earlier and more frequently in animals with tumors derived from BGC823 or lenti-CDH17-miR-neg cells than in tumors derived from lenti-CDH17-miR-B cells.Average tumor weight and volume in the CDH17-RNAi-lentivirus-treated group were significantly lower than those in the control group(tumor volume:0.89 ± 0.04 cm 3 vs 1.16 ± 0.06 cm 3,P < 0.05;tumor weight:1.15 ± 0.58 g vs 2.09 ± 0.08 g,P < 0.05).Fifteen differentially expressed proteins were identified after CDH17 silencing in BGC823 cells,including a variety of cytoskeletal and chaperone proteins as well as proteins involved in metabolism,immunity/defense,cell proliferation and differentiation,cell cycle,and signal transduction.CONCLUSION:Our data establish a foundation for future studies of the comprehensive protein expression patterns and effects of CDH17 in GC.

Impact of gut microbiome in the development and treatment of pancreatic cancer:Newer insights

The gut microbiome plays an important role in the variation of pharmacologic response.This aspect is especially important in the era of precision medicine,where understanding how and to what extent the gut microbiome interacts with drugs and their actions will be key to individualizing therapy.The impact of the composition of the gut microbiome on the efficacy of newer cancer therapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell treatment has become an active area of research.Pancreatic adenocarcinoma(PAC)has a poor prognosis even in those with potentially resectable disease,and treatment options are very limited.Newer studies have concluded that there is a synergistic effect for immunotherapy in combination with cytotoxic drugs,in the treatment of PAC.A variety of commensal microbiota can affect the efficacy of conventional chemotherapy and immunotherapy by modulating the tumor microenvironment in the treatment of PAC.This review will provide newer insights on the impact that alterations made in the gut microbial system have in the development and treatment of PAC.

Mechanisms of acquired resistance of BRCA1/2-driven tumors to platinum compounds and PARP inhibitors

Molecular pathogenesis of tumors arising in BRCA1/2 germ-line mutation carriers usually includes somatic inactivation of the remaining allele of the involved gene.Consequently,BRCA1/2-driven cancers are sensitive to platinum-based therapy and poly(ADP-ribose)polymerase inhibitors(PARPi).Long-term exposure to these drugs may result in the emergence of secondary BRCA1/2 mutations,which restore the open-reading frame of the affected allele.This platinum/PARPi crossresistance mechanism applies both for BRCA1 and BRCA2 genes and has been repeatedly validated in various laboratory models and multiple clinical studies.There are some other routes associated with the partial rescue of BRCA1/2 function or the development of BRCA1/2-independent pathways for genomic maintenance;however,their actual clinical relevance remains to be established.In addition,studies on the short-term neoadjuvant therapy for ovarian cancer revealed that even chemonaive BRCA1-driven tumors contain a small proportion of BRCA1-proficient cells.These pre-existing cells with retained BRCA1 heterozygosity rapidly repopulate the tumor mass during platinum exposure,but become outcompeted by BRCA1-deficient cells during therapy holidays.Understanding of the platinum/PARPi resistance pathways has led to the development of novel therapeutic approaches,which aim to improve the management of BRCA1/2-related cancers and are currently undergoing preclinical and clinical evaluation.

Endoscopic ultrasound guided interventions in the management of pancreatic cancer

There has been a growing interest in developing endoscopic ultrasound(EUS)-guided interventions for pancreatic cancer,some of which have become standard of care.There are two main factors that drive these advancements to facilitate treatment of patients with pancreatic cancer,ranging from direct locoregional therapy to palliation of symptoms related to inoperable pancreatic cancer.Firstly,an upper EUS has the capability to access the entire pancreas–lesions in the pancreatic head and uncinate process can be accessed from the duodenum,and lesions in the pancreatic body and tail can be accessed from the stomach.Secondly,there has been a robust development of devices that allow through-theneedle interventions,such as placement of fiducial markers,brachytherapy,intratumoral injection,gastroenterostomy creation,and ablation.While these techniques are rapidly emerging,data from a multicenter randomized controlled trial for some procedures are awaited prior to their adoption in clinical settings.

Biodistribution and Anti-tumor Activities of the ^(131)I-labeled Rituximab in Nude Mice Bearing Human Burkitt's lymphoma

OBJECTIVE To explore the biodistribution and anti-tumoractivity of ^(131)I labeled rituximab injected intratumorally orintraperitoneally in vivo in nude mice bearing Raji human Burkitt's lymphoma xenografts.METHODS The rituximab and the mouse IgG were labeled withNa^(131)I using the IODO-GEN method.BALB/C nude mice werexenografted with ^(131)I-Rituximab or ^(131)I-IgG and killed on the 1st,3rd,7th,and 15th day after injection.The tumor/non-tumor ratio(T/NT)and the dose injected in each gram of the tissue(%ID/g)from12 organs or tissues of interest,e.g.tumor,blood,were calculated.The long and short axes of each tumor were measured by calipersat 2-3-day intervals after treatment,and the growth inhibition ofthe tumor was calculated using the MIRD formula.RESULTS When comparing intraperitoneal injection(IP)andintratumoral injection(IT)of ^(131)I-IgG,intratumoral injection of^(131)I-rituximab produced a significantly higher tumor/non-tumorratio in all tissues and organs of interest on the 1st,3rd,and 7thday,respectively(P<0.05).The %ID/g of tumor was 1.4-1.7-foldand 1.5-3.7-fold in the IP and IgG IT groups,respectively,but the%ID/g of non-tumors was significantly lower in the IP group andIgG IT group.Similarly,the tumor growth was greatly inhibitedby intratumoral injection of the ^(131)I-rituximab,whereas it wasless inhibited by other forms of the treatment(P<0.05).However^(131)I-rituximab injected intratumorally inhibited tumor growth ina dose-dependent manner.The inhibition rate was less with alow dose(75μCi)and greater with a high dose(150μCi),yet thedifference was not significant(P>0.05).CONCLUSION Tumors can absorb the highest amount of theradiolabelled antibodies,and the tumor/non-tumor ratios in thegroup with intratumoral injection of the ^(131)I-rituximab resulted inthe optimal anti-tumor activity.