Complete Tumor Regression Research Articles

S-1/irinotecan/oxaliplatinchemotherapy achieved a pathological complete remission in advanced pancreatic carcinoma.

Chemotherapy has been developed for many years for malignancies, including advanced pancreatic cancer, downsizing the primary site, thereby enabling complete cure with the combination of conversion surgery. Pathological complete remission from operation samples was usually identified as a promising indication for a good prognosis for many carcinomas. Several case reports consisting of pathological complete remission after chemotherapy application have been reported but no case of pathological complete remission that resulted from successful extensive resection by surgery after S-1, irinotecan, and oxaliplatin (SIROX) chemotherapy. A 48-year-old male patient was hospitalized due to abdominal pain which turned out to be a 25mm-sized advanced uncinate process of pancreatic cancer with possible duodenum invasion and hepatic metastasis. The tumor had decreased after administering 23 sessions of modified SIROX chemotherapy, and he underwent pylorus-preserving pancreaticoduodenectomy with portal vein resection. He was successfully managed with conservative treatment and discharged 12days postoperatively despite his postoperative weakness. He had been taking S-1 pills for 6months and until now, 3years postoperatively, with no relapse. The final pathology reported complete tumor regression. Therefore, we emphasize the oncologic significance of chemotherapy in the uncinate process of pancreatic cancer and the potential role of conversion surgery.

Oral reovirus reshapes the gut microbiome and enhances antitumor immunity in colon cancer

The route of oncolytic virotherapy is pivotal for immunotherapeutic efficacy in advanced cancers. In this preclinical study, an oncolytic reovirus (RC402) is orally administered to induce antitumor immunity. Oral reovirus treatment shows no gross toxicities and effectively suppresses multifocal tumor lesions. Orally administered reovirus interacts with the host immune system in the Peyer’s patch of the terminal ileum, increases IgA+ antibody-secreting cells in the lamina propria through MAdCAM-1+ blood vessels, and reshapes the gut microbiome. Oral reovirus promotes antigen presentation, type I/II interferons, and T cell activation within distant tumors, but does not reach or directly infect tumor cells beyond the gastrointestinal tract. In contrast to intratumoral reovirus injection, the presence of the gut microbiome, Batf3+ dendritic cells, type I interferons, and CD8+ T cells are indispensable for orally administered reovirus-induced antitumor immunity. Oral reovirus treatment is most effective when combined with αPD-1(L1) and/or αCTLA-4, leading to complete colon tumor regression and protective immune memory. Collectively, oral reovirus virotherapy is a feasible and effective immunotherapeutic strategy in preclinical studies.

A Caspase 3‐Hijacking Nanosystem Enhances Cancer Radiotherapy by Suppressing Tumor Repopulation

AbstractRadiotherapy is used in the treatment of ≈50% of patients with cancer. However, tumor repopulation is a major cause of treatment failure after radiotherapy. It is observed that apoptotic tumor following ionizing radiation (IR) accelerated the growth of surviving tumor cells. Here a Gasdermin E and Tannic acid‐based nanoassembly (GT) loaded with manganese tetroxide (Mn3O4) (termed as Mn3O4@GT) is developed to suppress tumor repopulation and improve the treatment outcome of radiotherapy. Mn3O4@GT enables an increase in the reactive oxygen species accumulation in tumor cells, enhancing radiotherapy‐mediated tumor killing. What's more, it can hijack activated caspase 3 to induce tumor pyroptosis, reversing apoptosis‐mediated tumor repopulation. In vivo results shows that Mn3O4@GT significantly reduced the IR induced tumor repopulation by 2.7 fold, resulting in 92% complete regression of tumors. In addition, Mn3O4@GT can sensitize tumors to anti‐PD‐L1 therapy by inducing immunogenic pyroptosis with 85% regression of distant tumors. The caspase 3‐hijacking nanosystem holds a great potential for improving the clinical benefits of radiotherapy.

Strongly quenched activatable theranostic nanogel for precision imaging-guided photodynamic therapy and enhanced immunotherapy

Immune checkpoint inhibitors (ICIs) are innovative immunotherapeutic agents for cancer. However, their low therapeutic efficacy in patients with large or rapidly growing tumors, along with their high cost, represents a notable limitation in their clinical applications. Therefore, new and safe strategies must be developed to enhance the therapeutic efficacy of ICIs in clinical settings. In this study, we developed a near-infrared (NIR) fluorescent dye-loaded activatable theranostic nanogel (NATNgel) for precision imaging-guided photodynamic therapy (PDT) and combined immunotherapy for rapidly growing tumors. Although NIR fluorescence and phototoxicity of NATNgel are strongly quenched, these can be selectively activated inside target tumor cells. A high tumor-to-background ratio (7.31 ± 1.40) in NIR fluorescence imaging could be achieved in NATNgel-treated mice, enabling real-time image-guided PDT. The combination of PDT and anti-PD-1 antibody therapy resulted in complete tumor regression. Histopathological evaluation of major organs and blood chemistry analysis revealed no side effects of the combined treatment regimen. In addition, the combination treatment completely suppressed the growth of rechallenged tumors. Overall, NATNgel is a safe and promising theranostic material for precision imaging-guided PDT and enhanced immunotherapy.

Dual targeting macrophages and microglia is a therapeutic vulnerability in models of PTEN-deficient glioblastoma.

Tumor-associated macrophages and microglia (TAMs) are critical for tumor progression and therapy resistance in glioblastoma (GBM), a type of incurable brain cancer. We previously identified lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) as essential macrophage and microglia chemokines, respectively, in GBM. Here, single-cell transcriptomics and multiplex sequential immunofluorescence followed by functional studies demonstrate that macrophages negatively correlate with microglia in the GBM tumor microenvironment. LOX inhibition in PTEN-deficient GBM cells upregulates OLFML3 expression via the NF-κB-PATZ1 signaling pathway, inducing a compensatory increase of microglia infiltration. Dual targeting macrophages and microglia via inhibition of LOX and the CLOCK-OLFML3 axis generates potent anti-tumor effects and offers a complete tumor regression in more than 60% of animals when combined with anti-PD1 therapy in PTEN-deficient GBM mouse models. Thus, our findings provide a translational triple therapeutic strategy for this lethal disease.

Combined KRAS inhibition and immune therapy generates durable complete responses in an autochthonous PDAC model.

Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy. In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. Here, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust anti-tumor regression in iKPC mice bearing large autochthonous tumors. While untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in 36% of mice at 6 months. Mechanistic analyses revealed enhanced T cell infiltration and activation, depletion of immunosuppressive myeloid cells, and increased antigen cross-presentation by dendritic cells within the tumor core. These findings highlight the promise of KRAS* inhibitors alongside immunotherapy as a potential PDAC treatment avenue, warranting clinical investigation.

Anti-metabolite chemotherapy increases LAG-3 expressing tumor-infiltrating lymphocytes which can be targeted by combination immune checkpoint blockade

BackgroundAntibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein/ligand 1 (PD-1/PD-L1) are approved for treatment of multiple cancer types. Chemotherapy is often...

Abstract C011: Targeting STAT3 overcomes PDAC resistance to EGFR/RAF1 inhibition leading to complete and durable tumor regression

Abstract Pancreatic ductal adenocarcinoma (PDAC) belongs to the tumors with worst prognosis due to the lack of effective treatment. It was previously demonstrated that combined elimination of EGFR and RAF1, two main mediators of the KRAS signaling, induces complete regression of a limited subset of small tumors in a genetically engineered mouse model (Blasco et al., 2019). In the current study, we show that resistance of PDACs with big sizes to the elimination of RAF1 and EGFR is mediated by STAT3. Indeed, combined genetic ablation of EGFR, RAF1 and STAT3 both in vitro and in vivo, results in complete and irreversible regression of more than 40 independent mouse PDAC tumors driven by Kras/Trp53 mutations. Importantly, all PDACs were characterized by increased initial tumor size and highly heterogeneous molecular profile similar to that of Basal human tumors. Moreover, we have validated the efficacy of this novel therapeutic strategy using pharmacological agents, such as EGFR inhibitors approved for clinical use and the STAT3 PROTAC degrader SD-36. Finally, inhibition of RAF1, EGFR and STAT3 expression effectively blocked in vitro and in vivo tumor progression in ten independent patient-derived organoid (PDO) and patient-derived xenograft (PDX) cultures carrying KRAS and TP53 mutations. These results open the door to the development of novel targeted therapies for PDAC patients. Citation Format: Vasiliki Liaki, Mariano Barbacid, Carmen Guerra. Targeting STAT3 overcomes PDAC resistance to EGFR/RAF1 inhibition leading to complete and durable tumor regression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C011.

Abstract A052: Silencing MICAL2 Expression in Pancreatic Cancer Cells rewires the tumor microenvironment through the IL1-a/p38 MAP kinase/STAT-3 axis and Sensitizes Tumors to Immune Checkpoint Blockade therapy

Abstract Introduction: PDAC is marked by a fibroinflammatory stroma and thrives on interactions between cancer cells and their microenvironment, including CAFs and immune cells, driving disease progression and treatment resistance. Using ChIP-seq on resected human PDAC samples, we identified MICAL2 as a super-enhancer-associated gene and its role in tumor progression. MICAL2 is a flavin monooxygenase that promotes actin depolymerization and SRF transcription. Here, we evaluated how tumor cell-expressed MICAL2 rewires the PDAC microenvironment through the IL1-a/p38 MAP kinase/STAT3 axis. Methods: KPC-Shcontrol (ShCNT) and MICAL2 (M2KD) were orthotopically injected to assess tumor growth. Sc-RNA seq, immunophenotyping, and immunohistochemistry were performed on ShCNT and M2KD tumors. Atomic force microscopy was done to assess tissue stiffness. CD8+ specific antibodies were used for T-cell depletion. Adoptive transfer of CD8+ T cells enriched from M2KD tumors was performed by tail vein injection. Anti-PD1 and anti-IL-1a antibodies were injected IP. RNA-Seq analysis was performed on human PDAC cells (AsPC-1 ShCNT and M2KD) and validation of IL-1α and IL-1R expression was done in human and mouse pancreas control, KD, OE cancer cell lines, and PSCs by q-PCR. We exposed PSCs to conditioned media from cancer cells with and without MICAL2 and checked the expression of genes related to inflammation and fibrosis by qPCR. Results: Orthotopic injections of KPC-M2KD cells led to decreased tumor growth compared to ShCNT (0.26 gm vs. 1 gm, p = 0.008). Sc-RNA and immunohistochemistry revealed reduced PDPN+ and a-SMA+ CAFs in M2KD tumors. We also observed less collagen and fibronectin deposition in M2KD tumors resulting in reduced tissue stiffness as measured by atomic force microscopy. Flow cytometry and immunofluorescence showed increased intertumoral infiltration of cytotoxic and effector CD8+T cells in M2KD tumors. CD8+T cell depletion reversed growth inhibition in M2KD tumors. Adoptive transfer of CD8+T cells enriched from M2KD tumors impeded control tumor growth. RNA-seq revealed decreased IL1-α expression in M2KD cells (p<0.05). IL1R expression was reduced on PSCs when cocultured with M2KD vs. control cell media. PSCs co-cultured with M2KD cancer cells also showed significant downregulation of genes including IL-6, Cxcl1, and LIF changes that were rescued by adding recombinant IL-1α in M2KD cells. Western blot showed MICAL2 regulates the phosphorylation of p38 MAP kinase which in turn regulates the expression of IL1-α and STAT3 activation confirmed by treating dox-inducible ShCNT and ShM2KD cancer cells with p38 inhibitor. Treating M2KD tumors with immune checkpoint blockade PD-1 alone significantly reduced tumor size and 50% of M2KD tumor-bearing mice had complete tumor regression after treatment with PD-1 and neutralizing IL-1a antibodies. Conclusion: MICAL2 mediates tumor-stromal crosstalk through the IL1-a/p38/STAT3 axis and creates an immunosuppressive environment in PDAC. MICAL2 may be a potential immunomodulatory target for pancreatic cancer therapy. Citation Format: Bharti Garg, Evangeline Mose, Edgar Esparaza, Jay Patel, Rithika Medari, Alexei Martsinkovskiy, Carrie Bishop, Gissele Gonzalez, Adam Engler, Parag Katira, Herve Tiriac, Andrew M Lowy. Silencing MICAL2 Expression in Pancreatic Cancer Cells rewires the tumor microenvironment through the IL1-a/p38 MAP kinase/STAT-3 axis and Sensitizes Tumors to Immune Checkpoint Blockade therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A052.

A multifunctional mesoporous silica drug delivery nanosystem that ameliorates tumor hypoxia and increases radiotherapy efficacy

Radiotherapy (RT) is a widely used treatment with strong therapeutic effects, but overcoming challenges related to hypoxia-induced tumor resistance and ineffective antitumor immune responses is crucial for optimal outcomes. In this study, we developed a versatile nanosystem using mesoporous silica nanoparticles (MSNs), R837, and a small quantity of manganese peroxide (Mn/ZnO2). The synthesized MSN@R837-Mn/ZnO2 nanoparticles exhibited precise tumor targeting and accumulation, controlled drug release under acidic conditions, and increased sensitivity in magnetic resonance imaging. These attributes collectively augmented the therapeutic efficacy of RT by alleviating hypoxia and immunosuppression. Tumor cells treated with RT combined with these nanoparticles displayed reduced oxidative stress, alleviated hypoxia, and normalized blood vessel formation. Notably, all mice in the RT + PD-1 + MSN@R837-Mn/ZnO2 group achieved complete tumor regression with extended survival. Safety assessments confirmed the absence of MSN@R837-Mn/ZnO2 toxicity, highlighting its potential as a promising approach with dual functionality for the diagnostic imaging and treatment of cancer.

The association between exosomal proteins and the efficacy of thermoradiochemotherapy in overweight/obese rectal cancer patients: a pilot prospective cohort study

Background: Overweight and especially obesity are associated with the risk of the development and progression of colorectal cancer. It can be assumed that there are multifaceted interactions between the tumor and adipose tissue during anti-tumor treatment. Cancer cells secrete exosomes, extracellular vesicles affecting the microenvironment of the tumor and promoting its progression or regression. The presence of transcription/translation/folding factors (heat shock proteins (HSPs), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in exosomes secreted by irradiated cells and cells exposed to hyperthermia, indicates the cell adaptation to the thermal and radiation stress. Aim: To analyze the MMPs, TIMP1, and HSPs on CD9-positive (CD9+) exosomes, as well as on exosomes of adipocytic origin (FABP4+) in rectal cancer patients with overweight/obesity under thermoradiochemotherapy (TRCT) and their association with the immediate treatment efficacy. Methods: Since 2021, 20 patients (of those 8 men; median age 59.0 [52.0; 63.0] years, median body mass index 29.6 [28.5; 33.1] kg/m2) with morphologically verified rectal cancer (T3-4N0M0 and T3-4N1M0, differentiation grade G1–G3) have been participating in the study. They were treated with TRCT: external gamma therapy (2 Gy, 1 fraction/day, 5 days/week, total focal dose 54 Gy), chemotherapy with capecitabine (825 mg/m2 twice daily) combined with local hyperthermia (42–44 °C, 60 min, 3 times/week, 10 sessions). The TRCT efficacy was assessed by RECIST 1.1 and ESGAR criteria. Blood samples for exosomes were taken from the patients at baseline (point 1), in the middle of the treatment course (point 2), at 6 to 10 weeks after the end of TRCT (point 3), and at 6 months after point 1 (point 4). Small extracellular vesicles were isolated from plasma by ultrafiltration with double ultracentrifugation. The isolated exosomes were characterized by transmission electronic microscopy, flow cytometry and nanoparticle trajectory analysis (NTA). Results: TRCT resulted in complete tumor regression in 13/20 of the rectal cancer patients and partial regression or stabilization in 7/20. Four subpopulations of CD9+ and FABP4+ exosomes associated with the TRCT efficacy were identified (CD9+MMP2+, СD9+MMP2+9+TIMP1+, СD9+MMP2+9+TIMP1-, and FABP4+MMP2+9-TIMP1+). Compared to the CD9+ exosomes, the adipocytic vesicles had higher MMP2 expression (p = 0.026); however, the adipocyte vesicles subpopulation were virtually free of vesicles with combined MMP2 and MMP9 gelatinase expression. The HSPs expression by circulating exosomes at various TRCT steps was associated neither with direct treatment efficacy nor with the vesicle type. Conclusion: The expression of MMPs and TIMP1 on CD9+ and FABP4+ exosomes is associated with TRCT efficacy. In the future, vesicular markers could be used to build prognostic models, to identify patient groups with an unfavorable prognosis, and to personalize treatment and follow-up.

Imaging-Guided Metabolic Radiosensitization of Pediatric Rhabdoid Tumors.

Tumor hypoxia leads to increased resistance to radiation therapy (RT), resulting in markedly worse clinical outcomes in the treatment and management of pediatric malignant rhabdoid tumors (MRT). To alleviate hypoxia in MRT, we repurposed an FDA approved, mitochondrial oxidative phosphorylation (OXPHOS) inhibitor, Atovaquone (AVO), to inhibit oxygen consumption and thereby enhance the sensitivity of tumor cells to low dose RT in MRT by hypoxia alleviation. Additionally, to better understand the tumor response induced by AVO and optimize the combination with RT, we employed an emerging, noninvasive imaging modality, known as multispectral optoacoustic tomography (MSOT), to monitor and evaluate real-time dynamic changes in tumor hypoxia and vascular perfusion. Oxygen-Enhanced (OE)-MSOT could measure the change of tumor oxygenation in the MRT xenograft models after AVO and RT treatments, indicating its potential as a response biomarker. OE-MSOT showed that treating MRT mouse models with AVO resulted in a transient increase in oxygen saturation (ΔsO 2 ) in tumors when the mice were subjected to oxygen challenge, while RT or saline treated groups produced no change. In AVO+RT combination groups, the tumors showed an increase in ΔsO 2 after AVO administration followed by a significant decrease after RT, that correlated with a strong anti-tumor response, demarcated by complete regression of tumors, with no relapse on long-term monitoring. These observations were histologically validated. In MRT models of acquired AVO resistance, combination therapy failed to alleviate tumoral hypoxia and elicit any therapeutic benefit. Together, our data highlights the utility of repurposing anti-malarial AVO as an anticancer adjuvant for enabling low dose RT for pediatric patients.

NAD+ Metabolism Reprogramming Mediates Irradiation-Induced Immunosuppressive Polarization of Macrophages

Purposeradiotherapy stands as an important complementary treatment for head and neck squamous cell carcinoma (HNSCC), yet it does not invariably result in complete tumor regression. The infiltration of immunosuppressive macrophages is believed to mediate the radiotherapy resistance, which mechanism remains largely unexplored. This study aimed to elucidate the role of immunosuppressive macrophages during radiotherapy and the associated underlying mechanisms. Materials and MethodsMale C3H mice bearing syngeneic SCC-VII tumor were received irradiation (2 × 8Gy). The impact of irradiation on tumor-infiltrating macrophages were assessed. Bone marrow derived macrophages were evaluated in differentiation, proliferation, migration, and inflammatory cytokines after treatment of irradiated tumor culture medium (irCM) and irradiated tumor derived extracellular vesicles (irTEVs). A comprehensive metabolomics profiling of the irTEVs was conducted using liquid chromatography-mass spectrometry, while key metabolites were investigated the mechanism in macrophage in vitro and in vivo. ResultsRadiotherapy on SCC-VII syngeneic graft tumors increased polarization of both M1 and M2 macrophages in tumor microenvironment and drove infiltrated macrophages towards an immunosuppressive phenotype. Irradiation-induced polarization and immunosuppression of macrophages were dependent on irTEVs which delivered an increased amount of nicotinamide (NAM) to macrophages. NAM directly bound to the NF-κB transcriptional activity regulator USP7, through which NAM reduced translocation of NF-κB into the nucleus, thereby decreasing the release of cytokines IL6 and IL8. Increased enzyme activity of nicotinamide phosphoribosyl transferase (NAMPT) which is the rate-limiting enzyme of NAD+ metabolism, contributed to the irradiation-induced accumulation levels of NAM in irradiated HNSCC and irTEVs. Inhibition of NAMPT decreased NAM levels in irTEVs and increased radiotherapy sensitivity through alleviating immunosuppressive function of macrophages. ConclusionsRadiotherapy could induce NAD+ metabolic reprogramming of HNSCC cells, which regulate macrophage towards an immunosuppressive phenotype. Pharmacological targeting NAD+ metabolism might be a promising strategy for radiotherapy sensitization of HNSCC.

Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2

ObjectiveThe hallmark oncogene MYC drives the progression of most tumours, but direct inhibition of MYC by a small-molecule drug has not reached clinical testing. MYC is a transcription factor that...

Long-term Outcomes of Regressed or “Burnt Out” Primary Testicular Germ Cell Tumors

ObjectiveTo review the presentation and long-term oncologic outcomes of patients with regressed (“burnt out”) primary testicular germ cell tumors (GCT). Certain testicular GCT can present with complete regression of the primary tumor. It is not well established if this is associated with more aggressive disease or worse oncologic outcomes. MethodsWe queried our prospectively maintained testicular cancer clinical database at a tertiary cancer center and identified patients without prior chemotherapy who had regressed primary GCT at radical orchiectomy from 1990–2023. All specimens were reviewed by a genitourinary pathologist at diagnosis. Long-term clinical outcomes were reported by Kaplan-Meier method. ResultsFifty-six patients met inclusion criteria; at diagnosis, 17 had no evidence of extra-testicular disease and 39 had advanced (clinical stage [CS] II+) GCT. All CSx (no viable disease or germ cell neoplasia in situ at orchiectomy, and no evidence of advanced disease) and CS0 patients were managed with surveillance and had 5-year recurrence-free survival (RFS) of 88% (95% CI: 39%, 98%). All patients with CS II+ disease underwent primary treatment with surgery (n=5) or first-line chemotherapy (n=34). Two- and 5-year RFS for patients with CSII+ disease was 94% (95% CI: 78%, 98%) and 90% (95% CI: 72%, 97%), respectively. ConclusionPatients with regressed primary testicular GCT often present with advanced disease, possibly due to lack of early clinical signs from the primary tumor. Our analysis shows excellent long-term oncologic outcomes similar to those reported in the literature for patients with viable primary testicular GCT.

Factors influencing pathological complete response and tumor regression in neoadjuvant radiotherapy and chemotherapy for high-risk breast cancer

BackgroundPathological complete response (pCR) is a well-established prognostic factor in breast cancer treated with neoadjuvant systemic therapy (naST). The determining factors of pCR are known to be intrinsic subtype, proliferation index, grading, clinical tumor and nodal stage as well as type of systemic therapy. The addition of neoadjuvant radiotherapy (naRT) to this paradigm might improve response, freedom from disease, toxicity and cosmetic outcome compared to adjuvant radiotherapy. The factors for pCR and primary tumor regression when neoadjuvant radiation therapy is added to chemotherapy have not been thoroughly described.MethodsWe performed a retrospective analysis of 341 patients (cT1-cT4/cN0-N+) treated with naRT and naST between 1990 and 2003. Patients underwent naRT to the breast and mostly to the supra-/infraclavicular lymph nodes combined with an electron or brachytherapy boost. NaST was given either sequentially or simultaneously to naRT using different regimens. We used the univariate and multivariate regression analysis to estimate the effect of different subgroups and treatment modalities on pCR (ypT0/Tis and ypN0) as well as complete primary tumor response (ypT0/Tis; bpCR) in our cohort. Receiver operating characteristic (ROC) analysis was performed to evaluate the interval between radiotherapy (RT) and resection (Rx) as well as radiotherapy dose.ResultsOut of 341 patients, pCR and pbCR were achieved in 31% and 39%, respectively. pCR rate was influenced by resection type, breast cancer subtype, primary tumor stage and interval from radiation to surgery in the multivariate analysis. Univariate analysis of bpCR showed age, resection type, breast cancer subtype, clinical tumor stage and grading as significant factors. Resection type, subtype and clinical tumor stage remained significant in multivariate analysis. Radiation dose to the tumor and interval from radiation to surgery were not significant factors for pCR. However, when treatment factors were added to the model, a longer interval from radiotherapy to resection was a significant predictor for pCR.ConclusionsThe factors associated with pCR following naST and naRT are similar to known factors after naST alone. Longer interval to surgery might to be associated with higher pCR rates. Dose escalation beyond 60 Gy did not result in higher response rates.

Radiotherapy-triggered reduction of platinum-based chemotherapeutic prodrugs in tumours.

Pt(II) drugs are a widely used chemotherapeutic, yet their side effects can be severe. Here we show that the radiation-induced reduction of Pt(IV) complexes to cytotoxic Pt(II) drugs is rapid, efficient and applicable in water, that it is mediated by hydrated electrons from water radiolysis and that the X-ray-induced release of Pt(II) drugs from an oxaliplatin prodrug in tumours inhibits their growth, as we show with nearly complete tumour regression in mice with subcutaneous human tumour xenografts. The combination of low-dose radiotherapy with a Pt(IV)-based antibody-trastuzumab conjugate led to the tumour-selective release of the chemotherapeutic in mice and to substantial therapeutic benefits. The radiation-induced local reduction of platinum prodrugs in the reductive tumour microenvironment may expand the utility of radiotherapy.

Non-Invasive 3D Breast Tumor Localization: A Viable Alternative to Invasive Tumor Marking.

Background: We present a detailed description and the preliminary results of our original technique for non-invasive three-dimensional tumor localization in the breast, which was created as an alternative to standard invasive tumor marking before neoadjuvant systemic therapy (NAST), aiming to enable adequate surgery after complete tumor regression. Methods: A detailed description of the technique is provided in the main text. The technique's feasibility and precision were assessed in a single-arm, prospective study based on the histological parameters of the adequacy and rationality of the excision of completely regressed tumor beds. Results: Out of 94 recruited patients, 15 (16%) were deemed unsuitable, mainly due to the tumors' inadequate ultrasound visibility. Among the 79 processed patients, 31 (39%) had complete clinical regression after NAST and were operated on using our technique. The histological parameters of surgical precision (signs of tumor regression: 24/31; microscopic cancer residues: 7/31) were verified in all excised specimens (100% precision). There were no positive margins in seven cases with microscopic residues, indicating our technique's capacity to enable oncologically safe post-NAST surgery. Conclusions: The proposed technique is feasible and satisfactorily accurate in determining the location of regressed tumors, thus representing an alternative to invasive tumor marking, especially in surgical centers lacking trained staff and equipment for invasive marking. The technique's limitations are mainly related to the inadequate ultrasound visibility of the tumor.

Efficacy of topical 5-Fluorouracil in the management of ocular surface squamous neoplasia: a study of 101 eyes.

To study the efficacy and side-effect profile of topical 5-Fluorouracil (5-FU) in the treatment of ocular surface squamous neoplasia (OSSN). Retrospective study of 101 eyes of 100 patients treated with 5-FU with one week on and 3weeks off regimen. Of the 100 patients (101 eyes), the mean age at diagnosis of OSSN was 49 (median, 52years; range, 11-87years). History of prior intervention was noted in 6 (6%) eyes. Tumor epicenter included bulbar conjunctiva (n = 54; 53%), limbus (n = 27; 27%), and cornea (n = 20;20%). Mean number of cycles of topical 5-FU administered was 3 (median, 3; range, 1-8). Complete tumor regression was achieved with topical 5-FU in 89 (88%) eyes with a mean number of 2 cycles (median, 2; range, 1-6) of 5-FU. The remaining 12 (12%) lesions underwent additional treatment including excisional biopsy (n = 7), extended enucleation (n = 3), and topical Interferon alpha 2b (n = 2) for complete tumor control. Over a mean follow-up period of 6months (median, 5months; range, 1-36months) following treatment, tumor recurrence was noted in 2 (2%) patients, and side-effects were noted in 7 (7%) eyes including conjunctival hyperemia (n = 1), punctal stenosis (n = 1), sterile keratitis (n = 4), and limbal stem cell deficiency (n = 1). Topical 5-FU is an effective non-invasive therapy for OSSN with a minimal side-effect profile.

CDK4/6 inhibition augments anti-tumor efficacy of XPO1 inhibitor selinexor in natural killer/T-cell lymphoma

XPO1 is an attractive and promising therapeutic target frequently overexpressed in multiple hematological malignancies. The clinical use of XPO1 inhibitors in natural killer/T-cell lymphoma (NKTL) is not well documented. Here, we demonstrated that XPO1 overexpression is an indicator of poor prognosis in patients with NKTL. The compassionate use of the XPO1 inhibitor selinexor in combination with chemotherapy showed favorable clinical outcomes in three refractory/relapsed (R/R) NKTL patients. Selinexor induced complete tumor regression and prolonged survival in sensitive xenografts but not in resistant xenografts. Transcriptomic profiling analysis indicated that sensitivity to selinexor was correlated with deregulation of the cell cycle machinery, as selinexor significantly suppressed the expression of cell cycle-related genes. CDK4/6 inhibitors were identified as sensitizers that reversed selinexor resistance. Mechanistically, targeting CDK4/6 could enhance the anti-tumor efficacy of selinexor via the suppression of CDK4/6-pRb-E2F-c-Myc pathway in resistant cells, while selinexor alone could dramatically block this pathway in sensitive cells. Overall, our study provids a preclinical proof-of-concept for the use of selinexor alone or in combination with CDK4/6 inhibitors as a novel therapeutic strategy for patients with R/R NKTL.