Total Tumor Regression Research Articles

Significance of Nutritional-Inflammatory Index as Predictors for Total Neoadjuvant Therapy-Induced Tumor Regression in Locally Advanced Rectal Cancer Patients.

To evaluate the predictive capacity of the nutritional-inflammatory index and clinicopathological characteristics in patients with locally advanced rectal cancer (LARC) receiving total neoadjuvant therapy (TNT). Data from 127 patients with LARC receiving TNT from January 2017 to January 2021 were retrospectively analyzed. Clinicopathological characteristics with different TNT-induced responses were compared. The Chi-square test and the Mann-Whitney test were used to analyze the association between pre-TNT factors and TNT-induced responses. Multivariable logistic regression analysis was used to construct a predictive model. In the cohort of 127 patients with LARC who underwent total neoadjuvant therapy (TNT), the mean age was 54.1 ± 11.4 years; 88 (69.3%) were male. Seventy patients (55.1%) exhibited a favorable response to TNT, while 57 patients (44.9%) demonstrated a poor response. Tumor characteristics, including diameter, distance from the anal verge, pre-TNT lymphocyte, pre-TNT hemoglobin, CA199, PLR, and HALP, exhibit correlations with TNT-induced tumor regression. Multivariate logistic regression analysis identified large tumor diameters (> 5.0 cm; p = 0.005, HR 2.958; 95% CI 1.382-6.335) and low HALP (≤ 40; p = 0.002, HR 0.261; 95% CI 0.111-0.612) as predictors of TNT-induced poor responses. Additionally, low levels of HALP were associated with an increased risk of recurrence in patients with LARC with TNT, but this was not statistically significant (p = 0.087, HR 2.008, 95% CI 0.906-4.447). A large tumor diameter and low HALP predict poor tumor regression induced by the CAPOX-based TNT regimen in patients with LARC.

<b>First case report of fibropapillomatosis tumor regression identified through photoidentification and histopathology in a <i>Chelonia mydas</i> in Itapirubá, Santa Catarina, Brazil</b>

Background: Fibropapillomatosis (FP) is a tumor disease primarily affecting juvenile sea turtles, often characterized by external growths that can regress spontaneously. This study reports the first documented case of total tumor regression in a free-living green turtle (Chelonia mydas) with fibropapillomatosis in southern Brazil. Case Description: A juvenile green sea turtle (Chelonia mydas) was captured and recaptured on Itapirubá Beach, Santa Catarina, Brazil, showing sing of tumor regression with a period of 302 days between captures. At the first capture, photographs of the head and other regions were taken for photoidentification, along with documentation of fibropapilloma sites and tumor scoring. Tumor samples from the initial capture were histopathologically confirmed as fibropapillomas. At the recapture, the turtle showed a slight increase in carapace length, remaining classified as a juvenile. Tumors observed during the first capture were absent at recapture, with only scars remaining in the affected areas. Photoidentification confirmed the recapture, facilitating case monitoring. Tumor regression in this turtle is likely linked to various environmental and ecological factors. Conclusion: Spontaneous regression of fibropapillomatosis (FP) tumors remains a crucial indicator in the health monitoring of sea turtle populations. This is the first documented case of FP regression in this region of Brazil, suggesting that the turtle's increasing age and reduced exposure to anthropogenic pressure may have contributed to the tumor's regression. Although clinical follow-up of free-living sea turtles is challenging, reports of FP tumor regression are vital for understanding the health dynamics of sea turtle populations.

Effects of the Intake of Deuterium Depleted Water During Cancer Therapy: A Narrative Review

Drinking water has a deuterium (2H) concentration of 150 ppm. The intake of deuteriumdepleted water (DDW) provides a series of effects on the improvement of the state of health, contributing to the prevention of various diseases, as well as the delay in the evolution of certain types of cancer. The objective of this review is to verify the influence of DDW intake on the regression and survival rate of different types of cancer in living beings. The intake of DDW in patients with chronic lymphocytic leukemia, lung, prostate and breast cancer, as well as the antitumor effects of the intake of DDW in living beings, were analyzed. In conclusion, commenting that the intake of DDW has beneficial effects on the increase in the average survival time of cancer patients, favors the inhibition of cancer cell growth, increases the probability of total or partial regression of malignant tumors, as well as the delay in the multiplication of various types of tumor cells (PC-3, MDA, HT-29 and M14) and contributes to the decrease in PSA values in patients with prostate cancer.

Abstract 696: Sensitizing breast cancers to immune checkpoint inhibitors through CD27 agonism and vaccination against tumor-associated antigen

Abstract Project objective: Despite the recent revolution in immune checkpoint inhibitors (ICIs), only modest improvement in overall survival and likely caused by not enough potent cellular immunity among BC patients. Our lab has been focus on inducing cellular immunity against HER2+ BC through vaccination against the tumor-associated antigen HER2. Approximately 20 years ago, we performed an experimental pilot study by administrating HER2 peptide and recombinant protein pulsed dendritic cells (DC vaccine) to six patients with refractory HER2+ advanced or metastatic (stage II (≥ 6 +LN), III, or stage IV) BC. We followed the patients on 2019 found that all of the six patients were still alive, 18 years after vaccination. Their blood sample were analyzed with cytometry by time-of-flight (CyTOF) and found there is a significantly increased presence of CD27 expressing memory T cells in response to HER2 peptide stimulation. Recent report on the SARS-CoV2 mRNA vaccine also suggested that CD27 expressing memory T cells plays a critical role in long-lasting cellular immunity against SARS-CoV2 infection. Therefore, we hypothesized that CD27 plays a critical role in cellular immunity against BC, and the stimulation of CD27 expressing T cells with mAb targeting CD27 significantly increase the cellular immunity triggered by vaccination against tumor-associated antigen. Results: We recapitulate the rise of CD27+ antigen specific T cells among the vaccinated patients using a transgenic mouse model expressing human CD27. When combined the adenoviral-vector based HER2 (Ad-HER2) vaccination with a single dose of human aCD27 antibody (Varlilumab), we found there is a robust increase in the HER2 specific T cells compared to vaccination alone, especially CD27+CD44+ memory CD4 T cells, even after 120 days post vaccination. Using an ICI-insensitive syngeneic HER2+ BC models, we found 50% of mice in the combination group of aCD27 antibody plus Ad-HER2 showed total tumor regression by the end of study. When combined with anti-PD1 antibody, the combination of AdHER2 and Varlilumab leads to total tumor regression in 90% of tumor bearing mice with syngeneic HER2+ BC, indicating that the vaccination against tumor associated antigen HER2 plus anti-CD27 antibody sensitized ICI-insensitive HER2+ BC toward ICI. Conclusions: Our data demonstrates that the administration of anti-CD27 antibody significantly increase the long term presence of CD27+ antigen specific memory T cells after vaccination against tumor associated antigen HER2. As consequence, combination of anti-CD27 with HER2 sensitized the immune unresponsive breast cancer toward anti-PD1 antibody. Our study suggests that the vaccination against tumor-associated antigen with mAb targeting CD27 leads to the robust cellular immunity, which is required for successful ICIs against breast cancer. Citation Format: Bin-Jin Hwang, Erika Crosby, Timothy Trotter, Li-Chung Tsao, Tao Wang, Xiao Yang, Herbert Kim Lyerly, Zachary Hartman. Sensitizing breast cancers to immune checkpoint inhibitors through CD27 agonism and vaccination against tumor-associated antigen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 696.

THERAPEUTIC MODALITIES FOR BROWN TUMOR OF THE JAWS

<h3>Objectives</h3> The objective was to establish a more appropriate correlation between clinical context and treatment modality for brown tumor of the jaws to determine the best approach. <h3>Study Design</h3> A literature review was made in the PubMed, SciELO, and Google Scholar databases considering mesh terms and Boolean terms "brown tumor AND hyperparathyroidism," "brown tumor AND jaws AND hyperparathyroidism," "central giant cell AND hyperparathyroidism." Inclusion criteria included clinical cases published from 2015 to July 2020 in English, Spanish, French, and German involving patients with brown tumor of the jaws and their therapeutic approaches. Exclusion criteria included case reports with patients without brown tumor of the jaws, without relation to the proposed theme, or with genetic investigation bias. <h3>Results</h3> Eighty-five relevant results were obtained. Among the therapeutic modalities, conservative approaches were found, such as parathyroidectomy and reconditioning of parathyroid hormone levels, with possible total or partial brown tumor regression, or corticosteroid infiltration, as well as curettage, enucleation, and invasive resections. <h3>Conclusions</h3> The best clinical approach results from the correct diagnosis of hyperparathyroidism and treatment of its cause. Given these points, a therapeutical approach for the jaws can be defined.

Long-Term Feasibility of 13.56 MHz Modulated Electro-Hyperthermia-Based Preoperative Thermoradiochemotherapy in Locally Advanced Rectal Cancer.

Simple SummaryWe demonstrated that a 13.56 MHz modulated electro-hyperthermia (mEHT) boost is feasible in neoadjuvant treatment for rectal cancer. Herein, we attempted to present the long-term results for this phase 2 trial. Although there are many reports on the usefulness of thermoradiochemotherapy for loco-regional control, so far, only a few cases of survival benefit exist. Thus, this study assessed whether this limitation of hyperthermia could be overcome through the mEHT method featuring an applied energy variable. Following a median follow-up of 58 months for 60 patients, mEHT boost showed comparable results with conventional hyperthermia; potential therapeutic effects were also observed. Moreover, mEHT could be considered a useful tool in combination treatment with radiotherapy owing to its low thermotoxicity and improved treatment compliance.We evaluated the effect of 13.56 MHz modulated electro-hyperthermia (mEHT) boost in neoadjuvant treatment for cT3-4- or cN-positive rectal cancer. Sixty patients who completed the mEHT feasibility trial (ClinicalTrials.gov Identifier: NCT02546596) were analyzed. Whole pelvis radiotherapy of 40 Gy, mEHT boost twice a week during radiotherapy, and surgical resection 6–8 weeks following radiotherapy were performed. The median age was 59. The median follow-up period was 58 (6–85) months. Total/near total tumor regression was observed in 20 patients (33.3%), including nine cases of complete response. T- and N-downstaging was identified in 40 (66.6%) and 53 (88.3%) patients, respectively. The 5-year overall and disease-free survival were 94.0% and 77.1%, respectively. mEHT energy of ≥3800 kJ potentially increased the overall survival (p = 0.039). The ypN-stage and perineural invasion were possible significant factors in disease-free (p = 0.003 and p = 0.005, respectively) and distant metastasis-free (p = 0.011 and p = 0.034, respectively) survival. Tumor regression, resection margin status, and other molecular genetic factors showed no correlation with survival. Although a limited analysis of a small number of patients, mEHT was feasible considering long-term survival. A relatively low dose irradiation (40 Gy) plus mEHT setting could ensure comparable clinical outcomes with possible mEHT-related prognostic features.

A monoclonal antibody against annexin A2 targets stem and progenitor cell fractions in tumors

The involvement of cancer stem cells (CSCs) in driving tumor dormancy and drug resistance is well established. Most therapeutic regimens however are ineffective in targeting these regenerative populations. We report the development and evaluation of a monoclonal antibody, mAb150, which targets the metastasis associated antigen, Annexin A2 (AnxA2) through recognition of a N-terminal epitope. Treatment with mAb150 potentiated re-entry of CSCs into the cell cycle that perturbed tumor dormancy and facilitated targeting of CSCs as was validated by in vitro and in vivo assays. Epigenetic potentiation further improved mAb150 efficacy in achieving total tumor regression by targeting regenerative populations to achieve tumor regression, specifically in high-grade serous ovarian adenocarcinoma.

Burned-out testicular tumor: Two case reports

Spontaneous regression of a testicular tumor or burned-out testicular tumor is a rare phenomenon in patients with testicular germ cell tumors. The condition is characterized by tumor metastases, suspicious findings of the testicular tumor on ultrasound imaging, and partial or total histological regression of the primary testicular tumor after orchiectomy without treatment. Clinically, patients present with a disseminated tumor with symptoms related to the metastatic site without a palpable testicular tumor. Patients may also present with elevated levels of tumor biomarkers, depending on the histology. The etiopathogenesis of this phenomenon remains unclear and may involve immunologic factors as well as necrosis due to tumor growth beyond the available blood supply. We report here two clinical cases of patients treated at our center, both presenting with symptoms caused by retroperitoneal lymph node dissemination but different histologiesas well as a different clinical course. Keywords: germ cell tumor; testicular cancer; spontaneous regression.

A Hybrid Organo-Nanotheranostic Platform of Superlative Biocompatibility for Near-Infrared-Triggered Fluorescence Imaging and Synergistically Enhanced Ablation of Tumors.

The quest for an all-organic nanosystem with negligible cytotoxicity and remarkable in vivo tumor theranostic capability is inescapably unending. Hitherto, the landscape of available photothermal agents is dominated by metal-based nanoparticles (NPs) with attendant in vivo negatives. Here, an all-organic-composed theranostic nanosystem with outstanding biocompatibility for fluorescence image-guided tumor photothermal therapy, and as a potential alternative to metal-based photothermal agents is developed. This is rationally achieved by compartmentalizing indocyanine green (ICG) in glycol chitosan (GC)-polypyrrole (PP) nanocarrier to form hybrid ICG@GC-PP NPs (≈65nm). The compartmentalization strategy, alongside the high photothermal conversion ability of PP jointly enhances the low photostability of free ICG. Advantageously, ICG@GC-PP is endowed with an impeccable in vivo performance by the well-known biocompatibility track records of its individual tri organo-components (GC, PP, and ICG). As a proof of concept, ICG@GC-PP NPs enables a sufficiently prolonged tumor diagnosis by fluorescence imaging up to 20 h post-injection. Furthermore, owing to the complementary heating performances of PP and ICG, ICG@GC-PP NPs-treated mice by one-time near-infrared irradiation exhibit total tumor regression within 14 days post-treatment. Therefore, leveraging the underlying benefits of this study will help to guide the development of new all-organic biocompatible systems in synergism, for safer tumor theranostics.

Therapeutic Efficiency of Multiple Applications of Magnetic Hyperthermia Technique in Glioblastoma Using Aminosilane Coated Iron Oxide Nanoparticles: In Vitro and In Vivo Study.

Magnetic hyperthermia (MHT) has been shown as a promising alternative therapy for glioblastoma (GBM) treatment. This study consists of three parts: The first part evaluates the heating potential of aminosilane-coated superparamagnetic iron oxide nanoparticles (SPIONa). The second and third parts comprise the evaluation of MHT multiple applications in GBM model, either in vitro or in vivo. The obtained heating curves of SPIONa (100 nm, +20 mV) and their specific absorption rates (SAR) stablished the best therapeutic conditions for frequencies (309 kHz and 557 kHz) and magnetic field (300 Gauss), which were stablished based on three in vitro MHT application in C6 GBM cell line. The bioluminescence (BLI) signal decayed in all applications and parameters tested and 309 kHz with 300 Gauss have shown to provide the best therapeutic effect. These parameters were also established for three MHT applications in vivo, in which the decay of BLI signal correlates with reduced tumor and also with decreased tumor glucose uptake assessed by positron emission tomography (PET) images. The behavior assessment showed a slight improvement after each MHT therapy, but after three applications the motor function displayed a relevant and progressive improvement until the latest evaluation. Thus, MHT multiple applications allowed an almost total regression of the GBM tumor in vivo. However, futher evaluations after the therapy acute phase are necessary to follow the evolution or tumor total regression. BLI, positron emission tomography (PET), and spontaneous locomotion evaluation techniques were effective in longitudinally monitoring the therapeutic effects of the MHT technique.

Does total regression of primary rectal cancer after preoperative chemoradiotherapy represent "no tumor" status?

PurposeInsistence that total regression of primary tumor would not represent long-term oncologic outcomes has been raised. Therefore, this study aimed to evaluate the outcomes of these patients after preoperative chemoradiotherapy (PCRT) and radical surgery and to evaluate the associated risk factors.MethodsWe included 189 patients with rectal cancer who showed total regression of the primary tumor after PCRT, followed by radical resection, between 2001 and 2012. Recurrence-free survival (RFS) was calculated using the Kaplan-Meier method, and the results were compared with 77 patients with Tis rectal cancer who received only radical resection. Factors associated with RFS were evaluated using Cox regression analysis.ResultsSphincter-saving resection was performed for 146 patients (77.2%). Adjuvant chemotherapy was administered to 168 patients (88.9%). During the follow-up period, recurrence occurred in 17 patients (9%). The 5-year RFS was 91.3%, which was significantly lower than that of patients with Tis rectal cancer without PCRT (P = 0.005). In univariate analysis, preoperative CEA and histologic differentiation were associated with RFS. However, no factors were found to be associated with RFS.ConclusionRFS was lower in patients with total regression of primary rectal cancer after PCRT than in those with Tis rectal cancer without PCRT, and it would not be considered as the same entity with early rectal cancer or “disappeared tumor” status.

Association of immunologic markers from complete blood counts with the response to preoperative chemoradiotherapy and prognosis in locally advanced rectal cancer.

We investigated retrospectively whether immunologic markers from a complete blood count (CBC) are associated with the responsiveness to preoperative chemoradiotherapy (PCRT) and oncologic outcomes in 984 patients with locally advanced rectal cancer (LARC) who also underwent radical surgery from 2005 to 2013. CBC parameters including the neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and platelet to lymphocyte ratio (PLR) were recorded. Pathologic responses to PCRT were evaluated in the resected specimens using the tumor regression grade system. The cut-off values of the immunologic markers were calculated to analyze their association with recurrence-free survival (RFS). One hundred ninety-five patients achieved total regression of their primary tumor. By receiver operating characteristic analysis, NLR, PLR, and LMR could not distinguish total regression from residual disease after PCRT. The NLR, LMR and PLR cut-off values were 1.7, 6.8 and 92.88, respectively. By univariate analysis, low NLR (≤1.7), high LMR (>6.8) and high PLR (>92.88) were indicators of a favorable RFS outcome. By multivariate analysis, high PLR was associated with an improved RFS (HR, 0.649; 95% CI, 0.473-0.89; P=0.007). High NLR (>1.7) was an independent negative prognostic factor for RFS in stage II (HR, 1.868; 95% CI, 1.08-3.109; P=0.025) and high PLR was a positive prognostic factor in stage III (HR, 0.675; 95% CI, 0.421-0.957; P=0.03). Immunologic markers derived from CBCs are independently associated with the RFS outcome in LARC patients treated with PCRT followed by radical resection. However, these markers are not predictive of total primary tumor regression after PCRT.

Combining antiangiogenic therapy with neoadjuvant chemotherapy increases treatment efficacy in stage IIIA (N2) non-small cell lung cancer without increasing adverse effects.

To evaluate the safety and efficacy of combining Endostar antiangiogenic therapy with neoadjuvant chemotherapy for the treatment of stage IIIA (N2) NSCLC, we conducted a randomized, controlled, open-label clinical study of 30 NSCLC patients. Patients were randomly assigned to the test or control groups, which received either two cycles of an NP neoadjuvant chemotherapy regimen combined with Endostar or the NP regimen alone, respectively, at a 2:1 ratio. Efficacy was assessed after 3 weeks, and surgical resection occurred within 4 weeks, in the 26 patients who successfully completed treatment. While total response rates (RR) and clinical benefit rates (CBR) did not differ between the experimental groups, total tumor regression rates (TRR) were higher in the test group than in the control group. Median DFS and OS also did not differ between the test and control groups. Clinical perioperative indicators, including intraoperative blood loss, number of dissected lymph node groups, duration of postoperative indwelling catheter use, and time to postoperative discharge, were comparable in the test and control groups. Finally, hematological and non-hematological toxicities and postoperative pathological indicators, including down-staging ratio, complete resection ratio, and metastatic lymph node ratio, also did not differ between the groups. Overall, combining Endostar with NP neoadjuvant chemotherapy increased therapeutic efficacy without increasing adverse effects in stage IIIA-N2 NSCLC patients. This study is registered with ClinicalTrials.gov (number NCT02497118).

Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2.

BackgroundProstate cancer ranks as the second most lethal malignancy in the Western world. Previous targeting of prostate-specific antigen and human kallikrein-related peptidase 2, two related enzymes abundantly expressed in prostatic malignancies, with radioimmunoconjugates intended for diagnostic purposes, have proven successful in rodent prostate cancer (PCa) models. In this study, we investigated the uptake and therapeutic efficacy of 177Lu-m11B6, a human kallikrein-related peptidase 2 (hK2)-targeting radioimmunoconjugate in a pre-clinical setting.MethodsThe murine 11B6 antibody, m11B6, with high affinity for hK2, was labeled with 177Lu. Therapy planning was done from a biokinetic study in LNCaP xenografts, and therapeutic activities of 177Lu-m11B6 were administered to groups of mice. Body weight and general conditions of the mice were followed over a period of 120 days.ResultsThe tumor uptake in LNCaP xenografts was 30 ± 8.2 % injected activity per gram 1 week post-injection. In vivo targeting was hK2-specific as verified by a 2.5-fold decrease in tumor uptake in pre-dosed xenografts or by a fourfold lower tumor accumulation in hK2-negative DU 145 xenografts. Therapy showed a dose-dependent efficacy in LNCaP xenografts treated with 177Lu-m11B6. No therapeutic effect was seen in the control groups. The median survival for the lowest given activity of 177Lu-m11B6 was 88 days compared to that of 38 days in mice given labeled non-specific IgG. For the higher administrated activities, total tumor regression was seen with minimal normal organ toxicity.ConclusionsWe have proven the possibility of radioimmunotherapy targeting hK2 in subcutaneous prostate cancer xenografts. 177Lu-m11B6 exhibited high therapeutic efficacy, with low observed toxicity. Additionally, an evaluation of the concept of pre-therapy planning using a dosimetry model was included in this radioimmunotherapy study.

Abstract C102: Combination of immune checkpoints DNA vaccines and radiation enhances melanoma control

Abstract Background: We intend to develop DNA-based vaccines targeting immune checkpoint proteins in order to enhance immune response to tumors. Ionizing radiation, similar to some conventional chemotherapy, possesses immunomodulatory properties. Therefore, we reason that in combination with radiation, which may expose tumor-related antigens to the T cells, these immune-modulating DNA vaccines may reverse tumor-induced immune evasion and create a sustainable anti-tumor immunity. Materials and methods: The DNA sequences encoding murine CTLA-4 or PD1 were PCR amplified using a cDNA library obtained respectively from leukocyte of mouse and human as template. The resulting PCR products were fused with a transmembrane domain sequence of placental alkaline phosphatase (PLAP) into a mammalian expression plasmid, pVAC-1, forming CTLA-4 and PD1 DNA vaccines. These c57BL/6 mice (5 mice/group) were injected with DNA vaccine or control plasmid intramuscularly with the aid of electroporation weekly for 3 times. One week after the last vaccination, sera from the immunized mice was subjected to ELISA assay for detection of antibody titers against the respective immune checkpoint protein. B16F10 murine melanoma tumors were established on the c57BL/6 mice. The radiation regimen used (when applicable) was 2 weekly fractions of 5 Gy after the tumors were established. The mice were divided into groups, each treated with either radiation, radiation plus CTLA-4 vaccine, radiation plus PD1 vaccine, radiation plus CTLA-4 and PD1 vaccines, or no treatment (control group). Results: The mice vaccinated with the CTLA-4 or PD1 DNA vaccines demonstrated increased antibody titers against respective proteins, compared with the control groups (p &amp;lt; 0.005). Compared with radiation alone, the addition of the CTLA-4 vaccine led to enhanced tumor regression (a 53.2% reduction of tumor volume relative to that of radiation alone group) 1 month after radiation started. However, immunization with PD1 vaccine did not significantly enhance the tumor suppression of radiation (a 14.7% reduction of tumor volume; p = 0.55). Interestingly, near total regression of B16 tumor was observed when the mice received radiation plus immunization with both CTLA-4 and PD1 vaccines, a 92.4% decrease of tumor volume relative to that of radiation alone group (p = 0.037). Conclusion: We have developed potent DNA vaccines targeting CTLA-4 and PD1 immune checkpoints, enhancing the tumor control effects of radiation in the melanoma animal model. These DNA-based vaccines have the advantages of being less expensive and easier to manipulate as opposed to the antibody-based reagents. The blockade of PD1 checkpoint alone is futile in aiding tumor control of radiation in the c57BL/6 melanoma model. The interplay of various aspects of immunity seems crucial in the effort to recruit its anti-tumor ability. Citation Format: Keng-Hsueh Lan, Ming-Feng Wei, Keng-Li Lan, Ann-Lii Cheng, Sung-Hsin Kuo. Combination of immune checkpoints DNA vaccines and radiation enhances melanoma control. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C102.

Influence of Preoperative Chemoradiotherapy on the Surgical Strategy According to the Clinical T Stage of Patients With Rectal Cancer

The aim of this study was to evaluate the pathologic responses and changes to surgical strategies following preoperative chemoradiotherapy (PCRT) in rectal cancer patients according to their clinical T stage (cT).The use of PCRT has recently been extended to less advanced disease.The authors enrolled 650 patients with cT2 to 4 mid and low rectal cancer who received both PCRT and surgical resection. The rate of total regression and the proportion of local excision were compared according to the cT category. The 3-year recurrence-free survival (RFS) rate was compared using the log-rank test according to patient cT category, pathologic stage, and type of surgical treatment.Patients with cT2 were older (P = 0.001), predominately female (P = 0.028), and had low-lying rectal cancer (P = 0.008). Pathologic total regression was achieved most frequently in cT2 patients (54% of cT2 versus 17.6% of cT3 versus 8.2% of cT4; P < 0.001). Local excision was performed on 42 cT2 (42%) and 24 cT3 (5.2%) patients (P < 0.001). The 3-year RFS rates differed according to both cT (P < 0.001) and ypT stage (P < 0.001). Among patients with ypT0 to 1 disease, the 3-year RFS did not differ according to the type of surgical treatment received (P = 0.5).Total regression of the primary tumor and a change in the surgical strategy after PCRT are most commonly seen in cT2 disease. Although PCRT is not generally indicated for cT2 rectal cancer, optimal surgical treatment may be achieved with the tailored use of PCRT.

The efficacy of photodynamic therapy for basal cell carcinoma with intralesional injection of radachlorine

The results of evaluation of the efficiency of photodynamic therapy with photosensitizer radachlorine for basal cell carcinoma are represented. The study included patients with primary and recurrent cancer, solitary and multiple foci of different histological subtypes. All tumors corresponded stages T1-2N0M0. The radachlorine solution was injected into pathological focus at dose of 1.75-3.50 mg/ cm2 of tumor 15 min before the onset of irradiation (wavelength of 662 nm, light dose of 300 J/cm2). The evaluation of efficiency by means of short-term and long-term outcomes was performed on the basis of clinical and cytological data. According to shortterm outcomes evaluation, the total tumor regression was in 43 (95,5%) patients for 47 (95,9%) tumors. The partial regression was achieved in 2 (4,5%) patients, who subsequently had one repeated course of photodynamic therapy with short-term outcome as total tumor regression. All patients with multiple, superficial and nodal forms of basal cell carcinoma had total tumor regression in 100% of cases, with ulcerated form – in 94,4%, with morphea-like form – in 83,3%. During follow-up in subjects, 44 (97,7%) patients had 5-year recurrence-free period. The relapse of tumor was detected in 1 (2,3%) patient after PDT for primary cancer of nasal ala stage Т2N0M0 of solid and adenoid histological subtype. Thus, photodynamic therapy with intralesional injection of radachlorine showed high efficiency for treating all existent clinical forms and histological subtypes of basal cell carcinoma.

Anti-Tumor Effects of Bak-Proteoliposomes against Glioblastoma.

Despite palliative treatments, glioblastoma (GBM) remains a devastating malignancy with a mean survival of about 15 months after diagnosis. Programmed cell-death is de-regulated in almost all GBM and the re-activation of the mitochondrial apoptotic pathway through exogenous bioactive proteins may represent a powerful therapeutic tool to treat multidrug resistant GBM. We have reported that human Bak protein integrated in Liposomes (LB) was able, in vitro, to activate the mitochondrial apoptotic pathway in colon cancer cells. To evaluate the anti-tumor effects of LB on GBM, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays and Western blot analysis were performed on GL26 murine cell line. LB treatment shows a dose-dependent inhibition of cell viability, followed by an up-regulation of Bax and a down-modulation of JNK1 proteins. In GL26-bearing mice, two different routes of administration were tested: intra-tumor and intravenous. Biodistribution, tumor growth and animal survival rates were followed. LB show long-lasting tumor accumulation. Moreover, the intra-tumor administration of LB induces tumor growth delay and total tumor regression in about 40% of treated mice, while the intravenous injection leads to a significant increased life span of mice paralleled by an increased tumor cells apoptosis. Our findings are functional to the design of LB with potentiated therapeutic efficacy for GBM.

Salmonella-Based Therapy Targeting Indoleamine 2,3-Dioxygenase Coupled with Enzymatic Depletion of Tumor Hyaluronan Induces Complete Regression of Aggressive Pancreatic Tumors.

Bacterial-based therapies are emerging as effective cancer treatments and hold promise for refractory neoplasms, such as pancreatic ductal adenocarcinoma (PDAC), which has not shown significant improvement in therapy for more than 25 years. Using a novel combination of shIDO-ST, a Salmonella-based therapy targeting the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO), with an enzyme, PEGPH20, which depletes extracellular matrix hyaluronan, we observed extended survival with frequent total regression of autochthonous and orthotopic PDAC tumors. This observation was associated with migration and accumulation of activated polymorphonuclear neutrophils (PMN) from spleens into tumors, which was not seen using a scrambled control (shScr-ST). Purified splenic PMNs from PEGPH20/shIDO-ST-treated mice exhibited significant IDO knockdown and were able to kill tumor targets ex vivo through mechanisms involving FasL and serine proteases. In addition, CD8(+) T cells were observed to contribute to late control of pancreatic tumors. Collectively, our data demonstrate that entry of shIDO-ST and PMNs into otherwise impermeable desmoplastic tumors is facilitated by PEGPH20-mediated HA removal, further highlighting an important component of effective treatment for PDAC.

IQGAP1 in rectal adenocarcinomas: Localization and protein expression before and after radiochemotherapy

Treatment of rectal adenocarcinoma includes total mesorectal excision, which is preceded by radiochemotherapy (RCT) in cases of advanced disease. The response to RCT varies from total tumor regression to no effect but this heterogeneous response is unexplained. However, both radiation and treatment with 5-fluorouracil may induce treatment resistance through upregulation of the mitogen-activated protein kinase (MAPK) cascade. IQGAP1 is a scaffold protein that appears to be essential to MAPK signaling in cancers. We have therefore studied IQGAP1 protein expression in rectal adenocarcinomas before and after RCT. We demonstrate that cancer cells show increased apical staining for IQGAP1 following RCT. Interestingly, this increase is significantly higher in patients showing poor RCT responses. Our results also suggest that low levels of apical IQGAP1-staining in biopsies may predict the RCT response. Together, these data suggest that both the level and localization of IQGAP1 may influence the treatment response.