Pathological Response and Outcomes in Patients With Metastatic Renal Cell Carcinoma (mRCC) Receiving Immunotherapy-Based Therapies and Undergoing Deferred Cytoreductive Nephrectomy (CN).

In this study we evaluated outcomes of patients with metastatic renal cell carcinoma who received immunotherapy before surgery. We found that receiving immunotherapy combinations before surgery can offer patients benefits in reducing tumor size and improving disease control. BACKGROUND: Immunotherapy (IO) has improved outcomes for patients with metastatic renal cell carcinoma (mRCC). However, the timing of surgical intervention for cytoreductive nephrectomy (CN) is still controversial for this group of patients. PATIENTS AND METHODS: We identified patients with mRCC receiving IO-based therapies and undergoing CN. Patients were divided into 2 cohorts: those who underwent upfront CN and those who underwent deferred CN. Pathologic and radiographic features along with clinical outcomes were systematically collected. Comparisons were performed using Chi-square test, paired t-Test or Mann-Whitney-U test. Progression Free survival (PFS) and Overall Survival (OS) were estimated using the Kaplan-Meier method. RESULTS: Fifty-one patients with mRCC were included, with a median follow-up of 21 months. 38 (74.5%) patients received IO-based therapies prior to CN, while 13 (25.5%) patients underwent up-front CN. IO-based therapies reduced median tumor size from pretreatment 10 cm to 8.6 cm post-treatment when given prior to CN. IO-TKI had a trend toward higher tumor shrinkage (-2.3 vs -1.2 cm). Pathologic T downstaging occurred in 42% (n=16) of patients, 11% (n=4) of whom had pT0 disease. Thrombus downstaging occurred in 13% (n=6) of patients, all with either partial response (PR) or complete response (CR) in metastases. PFS (HR=0.7, 95% CI 0.29-1.98, p=0.58) and OS (HR 0.4, 95% CI 0.13-1.57, p=0.21) were not statistically significant between 2 cohorts. CONCLUSIONS: IO-based therapies, particularly IO-TKIs, resulted in pathologic necrosis and reductions in tumor size prior to deferred CN. PFS and OS were similar for patients who received either upfront IO-based therapy or after CN.

Correction: Co-delivery of all-trans-retinoic acid enhances the anti-metastasis effect of albumin-bound paclitaxel nanoparticles.

Correction for 'Co-delivery of all-trans-retinoic acid enhances the anti-metastasis effect of albumin-bound paclitaxel nanoparticles' by Hai Huang et al., Chem. Commun., 2017, 53, 212-215, https://doi.org/10.1039/C6CC08146K.

Erratum: Addition and Correction to "High-Performance Concurrent Chemo-Immuno-Radiotherapy for the Treatment of Hematologic Cancer through Selective High-Affinity Ligand Antibody Mimic-Functionalized Doxorubicin-Encapsulated Nanoparticles".

[This corrects the article DOI: 10.1021/acscentsci.8b00746.].

Vocal learning-associated convergent evolution in mammalian proteins and regulatory elements.

Vocal production learning ("vocal learning") is a convergently evolved trait in vertebrates. To identify brain genomic elements associated with mammalian vocal learning, we integrated genomic, anatomical, and neurophysiological data from the Egyptian fruit bat (Rousettus aegyptiacus) with analyses of the genomes of 215 placental mammals. First, we identified a set of proteins evolving more slowly in vocal learners. Then, we discovered a vocal motor cortical region in the Egyptian fruit bat, an emergent vocal learner, and leveraged that knowledge to identify active cis-regulatory elements in the motor cortex of vocal learners. Machine learning methods applied to motor cortex open chromatin revealed 50 enhancers robustly associated with vocal learning whose activity tended to be lower in vocal learners. Our research implicates convergent losses of motor cortex regulatory elements in mammalian vocal learning evolution.

Prospective Characterization of Circulating Tumor Cell Kinetics in Patients With Oligometastatic Disease Receiving Definitive Intent Radiation Therapy.

PURPOSE: There are currently no predictive molecular biomarkers to identify patients with oligometastatic disease (OMD) who will benefit from definitive-intent radiation therapy (RT). We prospectively characterized circulating tumor cell (CTC) kinetics in patients with OMD undergoing definitive-intent RT. METHODS: This prospective correlative biomarker study included patients with any solid malignancy ≤5 metastatic sites in ≤3 anatomic organ systems undergoing definitive-intent RT to all disease sites. Circulating tumor cells (CTCs) were captured and enumerated using a biomimetic cell rolling and nanotechnology-based assay functionalized with antibodies against epithelial cell adhesion molecule, against human epidermal growth factor receptor 2, and against epidermal growth factor receptor before and during RT and at follow-up visits up to 2 years post-RT. RESULTS: We enrolled 43 patients with a median follow-up of 14.3 months. The pretreatment CTC level (cells captured/mL) was not associated with the number of disease sites (median one metastatic site/patient, range 1-5) or metastasis location (bone, brain, visceral) on Wilcoxon signed-rank test, P > .05. Post-RT, 56% of patients received systemic therapy, and 72% of patients experienced subsequent local or systemic progression. For 90% of patients, a CTC level <15 within 130 days post-RT corresponded to a durable control of irradiated lesions. Patients with a favorable versus an unfavorable clearance profile experienced significantly longer progression-free survival after RT (median 13 v 4 months, log-rank test, P = .0011). On logistic regression, CTC level >15 at a given time point was associated with clinical disease progression within the subsequent 6 months (odds ratio 3.31, P = .007). In 26% of patients with disease progression, a CTC level >15 preceded radiographic or clinical progression. CONCLUSION: CTCs may serve as a biomarker for disease control in OMD and may predict disease progression before standard assessments for patients receiving diverse cancer-directed therapies.

An injectable subcutaneous colon-specific immune niche for the treatment of ulcerative colitis.

As a chronic autoinflammatory condition, ulcerative colitis is often managed via systemic immunosuppressants. Here we show, in three mouse models of established ulcerative colitis, that a subcutaneously injected colon-specific immunosuppressive niche consisting of colon epithelial cells, decellularized colon extracellular matrix and nanofibres functionalized with programmed death-ligand 1, CD86, a peptide mimic of transforming growth factor-beta 1, and the immunosuppressive small-molecule leflunomide, induced intestinal immunotolerance and reduced inflammation in the animals' lower gastrointestinal tract. The bioengineered colon-specific niche triggered autoreactive T cell anergy and polarized pro-inflammatory macrophages via multiple immunosuppressive pathways, and prevented the infiltration of immune cells into the colon's lamina propria, promoting the recovery of epithelial damage. The bioengineered niche also prevented colitis-associated colorectal cancer and eliminated immune-related colitis triggered by kinase inhibitors and immune checkpoint blockade.

Genitourinary cancers updates: highlights from ASCO 2023.

Significant scientific advances in immunotherapy and targeted therapy approaches have improved clinical outcomes and increased treatment options for patients with genitourinary (GU) malignancies. We highlight the clinical trial developments released at the ASCO 2023 annual meeting, including PARP inhibitors for prostate cancer, antibody drug conjugates and fibroblast growth factor receptor inhibitors for urothelial cancer, and HIF2a inhibitors for renal cell carcinoma. Novel agents such as bispecific antibodies, chimeric antigen receptor T-cells, and radiopharmaceuticals are currently in early phase development and also have high potential impact for the GU cancer landscape. With more treatment options, the field will need to define best treatment sequencing to optimize outcomes for each patient.

Chemotherapy-Induced Neoantigen Nanovaccines Enhance Checkpoint Blockade Cancer Immunotherapy.

Chemotherapeutics have the potential to increase the efficacy of cancer immunotherapies by stimulating the production of damage-associated molecular patterns (DAMPs) and eliciting mutations that result in the production of neoantigens, thereby increasing the immunogenicity of cancerous lesions. However, the dose-limiting toxicity and limited immunogenicity of chemotherapeutics are not sufficient to induce a robust antitumor response. We hypothesized that cancer cells in vitro treated with ultrahigh doses of various chemotherapeutics artificially increased the abundance, variety, and specificity of DAMPs and neoantigens, thereby improving chemoimmunotherapy. The in vitro chemotherapy-induced (IVCI) nanovaccines manufactured from cell lysates comprised multiple neoantigens and DAMPs, thereby exhibiting comprehensive antigenicity and adjuvanticity. Our IVCI nanovaccines exhibited enhanced immune responses in CT26 tumor-bearing mice, with a significant increase in CD4+/CD8+ T cells in tumors in combination with immune checkpoint inhibitors. The concept of IVCI nanovaccines provides an idea for manufacturing and artificial enhancement of immunogenicity vaccines to improve chemoimmunotherapy.

Chemotherapy-induced nanovaccines implement immunogenicity equivalence for improving cancer chemoimmunotherapy.

Several chemoimmunotherapies have been approved by the FDA for the treatment of various cancers. Chemotherapy has the potential to improve the efficacy of immunotherapy by inducing immunogenic cell death (ICD) of tumor cells, promoting the release of tumor associated antigens (TAAs), tumor specific antigens (TSAs) and damage associated molecular patterns (DAMPs), and disrupting immunosuppressive microenvironments by tumor debulking. Unfortunately, systemic administration of chemotherapeutics carries side effects of blunting anti-cancer immune response through systemic immunosuppression, which deserves to be explored as an inner contradiction in chemoimmunotherapy. Here, we proposed the hypothesis of "immunogenicity equivalence" in chemoimmunotherapy that chemotherapeutics-induced immunogenic antigens and DAMPs in vitro that can subsequently be incorporated into nanovaccines, which will possess comparable immunostimulatory potential when compared to tumors treated with systemic chemotherapy in vivo. The proteomic analysis confirmed that our nanovaccines contained TAAs, TSAs and DAMPs. Improvement in treatment outcomes in tumor-bearing mice receiving anti-PD-1 and chemotherapy-induced nanovaccines was then observed. Furthermore, we demonstrated the feasibility of replacing long-term chemotherapy with nanovaccines in chemoimmunotherapy. Our nanovaccine strategy would be a general choice for formulating cancer vaccines in personalized medicine.

Outcomes of surgical resection and intraoperative electron radiotherapy for patients with para-aortic recurrences of gastrointestinal and gynecologic malignancies.

BACKGROUND: Para-aortic lymph node (PALN) metastases from primary pelvic malignancies are often treated with resection, but recurrence is common. We report toxicity and oncologic outcomes for patients with PALN metastases from gastrointestinal and gynecologic malignancies treated with resection and intraoperative electron radiotherapy (IORT). METHODS: We retrospectively identified patients with recurrent PALN metastases who underwent resection with IORT. All patients were included in the local recurrence (LR) and toxicity analyses. Only patients with primary colorectal tumors were included in the survival analysis. RESULTS: There were 26 patients with a median follow up of 10.4 months. The rate of para-aortic local control (LC) was 77% (20/26 patients) and the rate of any cancer recurrence was 58% (15/26 patients). Median time from surgery and IORT to any recurrence was 7 months. The LR rate for those with positive/close margins was 58% (7/12 patients) versus 7% (1/14 patients) for those with negative margins (p = 0.009). 15% (4/26 patients) developed surgical wound and/or infectious complications, 8% (2/26 patients) developed lower extremity edema, 8% (2/26 patients) experienced diarrhea, and 19% (5/26 patients) developed an acute kidney injury. There were no reported nerve injuries, bowel perforations, or bowel obstructions. For patients with primary colorectal tumors (n = 19), the median survival (OS) was 23 months. CONCLUSIONS: We report favorable LC and acceptable toxicity for patients receiving surgical resection and IORT for a population that has historically poor outcomes. Our data show disease control rates similar to literature comparisons for patients with strong risk factors for LR, such as positive/close margins.

Effects of Bioactive Glasses (BGs) on Exosome Production and Secretion: A Critical Review.

There is an increasing trend toward the application of bioactive glasses in different areas of biomedicine, including tissue engineering and oncology. The reason for this increase is mostly attributed to the inherent properties of BGs, such as excellent biocompatibility, and the ease of tailoring their properties by changing, for example, the chemical composition. Previous experiments have demonstrated that the interactions between BGs and their ionic dissolution products, and mammalian cells, can affect and change cellular behaviors, and thereby govern the performance of living tissues. However, limited research exists on their critical role in the production and secretion of extracellular vesicles (EVs) such as exosomes. Exosomes are nanosized membrane vesicles that carry various therapeutic cargoes such as DNA, RNA, proteins, and lipids, and thereby can govern cell-cell communication and subsequent tissue responses. The use of exosomes is currently considered a cell-free approach in tissue engineering strategies, due to their positive roles in accelerating wound healing. On the other hand, exosomes are known as key players in cancer biology (e.g., progression and metastasis), due to their capability to carry bioactive molecules between tumor cells and normal cells. Recent studies have demonstrated that the biological performance of BGs, including their proangiogenic activity, is accomplished with the help of exosomes. Indeed, therapeutic cargos (e.g., proteins) produced in BG-treated cells are transferred by a specific subset of exosomes toward target cells and tissues, and lead to a biological phenomenon. On the other hand, BGs are suitable delivery vehicles that can be utilized for the targeted delivery of exosomes to cells and tissues of interest. Therefore, it seems necessary to have a deeper understanding of the potential effects of BGs in the production of exosomes in cells that are involved in tissue repair and regeneration (mostly mesenchymal stem cells), as well as in those that play roles in cancer progression (e.g., cancer stem cells). This review aims to present an updated report on this critical issue, to provide a roadmap for future research in the fields of tissue engineering and regenerative medicine.

Nanostructured bioactive glasses: A bird's eye view on cancer therapy.

Bioactive glasses (BGs) arewell known for their successful applications in tissue engineering and regenerative medicine. Recent experimental studies have shown their potential usability in oncology, either alone or in combination with other biocompatible materials, such as biopolymers. Direct contact with BG particles has been found to cause toxicity and death in specific cancer cells (bone-derived neoplastic stromal cells) in vitro. Nanostructured BGs (NBGs) can be doped with anticancer elements, such as gallium, to enhance their toxic effects against tumor cells. However, the molecular mechanisms and intracellular targets for anticancer compositions of NBGs require further clarification. NBGs have been successfully evaluated for use in various well-established cancer treatment strategies, including cancer hyperthermia, phototherapy, and anticancer drug delivery. Existing results indicate that NBGs not only enhance cancer cell death, but can also participate in the regeneration of lost healthy tissues. However, the application of NBGs in oncology is still in its early stages, and numerous unanswered questions must be addressed. For example, the impact of the composition, biodegradation, size, and morphology of NBGs on their anticancer efficacy should be defined for each type of cancer and treatment strategy. Moreover, it should be more clearly assessed whether NBGs can shrink tumors, slow/stop cancer progression, or cure cancer completely. In this regard, the use of computational studies (in silico methods) is highly recommended to design the most effective glass formulations for cancer therapy approaches and to predict, to some extent, the relevant properties, efficacy, and outcomes. This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Circulating tumor cell abundance in head and neck squamous cell carcinoma decreases with successful chemoradiation and cetuximab treatment.

Head and neck squamous cell carcinoma (HNSCC) is a common and deadly cancer. Circulating tumor cell (CTC) abundance may a valuable, prognostic biomarker in low- and intermediate-risk patients. However, few technologies have demonstrated success in detecting CTCs in these populations. We prospectively collected longitudinal CTC counts from two cohorts of patients receiving treatments at our institution using a highly sensitive device that purifies CTCs using biomimetic cell rolling and dendrimer-conjugated antibodies. In patients with intermediate risk human papillomavirus (HPV)-positive HNSCC, elevated CTC counts were detected in 13 of 14 subjects at screening with a median of 17 CTC/ml (range 0.2-2986.5). A second cohort of non-metastatic, HPV- HNSCC subjects received cetuximab monotherapy followed by surgical resection. In this cohort, all subjects had elevated baseline CTC counts median of 73 CTC/ml (range 5.4-332.9) with statistically significant declines during treatment. Interestingly, two patients with recurrent disease had elevated CTC counts during and following treatment, which also correlated with growth of size and ki67 expression in the primary tumor. The results suggest that our device may be a valuable tool for evaluating the success of less intensive treatment regimens.

Nanotechnology and machine learning enable circulating tumor cells as a reliable biomarker for radiotherapy responses of gastrointestinal cancer patients.

A highly sensitive, circulating tumor cell (CTC)-based liquid biopsy was used to monitor gastrointestinal cancer patients during treatment to determine if CTC abundance was predictive of disease recurrence. The approach used a combination of biomimetic cell rolling on recombinant E-selectin and dendrimer-mediated multivalent immunocapture at the nanoscale to purify CTCs from peripheral blood mononuclear cells. Due to the exceptionally high numbers of CTCs captured, a machine learning algorithm approach was developed to efficiently and reliably quantify abundance of immunocytochemically-labeled cells. A convolutional neural network and logistic regression model achieved 82.9% true-positive identification of CTCs with a false positive rate below 0.1% on a validation set. The approach was then used to quantify CTC abundance in peripheral blood samples from 27 subjects before, during, and following treatments. Samples drawn from the patients either prior to receiving radiotherapy or early in chemotherapy had a median 50 CTC ml-1 whole blood (range 0.6-541.6). We found that the CTC counts drawn 3 months post treatment were predictive of disease progression (p = .045). This approach to quantifying CTC abundance may be a clinically impactful in the timely determination of gastrointestinal cancer progression or response to treatment.

Post-irradiation intratumoral heterogeneity modulates response to immune checkpoint inhibition therapy in a murine melanoma model.

PURPOSE: The underlying mechanism for radiation as a potentiator of immune checkpoint inhibition (ICI) is unclear. We developed a novel murine model to investigate the effects of post-irradiation intratumoral heterogeneity (ITH) on response to ICI. EXPERIMENTAL DESIGN: Parental mouse melanoma B16F10 cells were irradiated in vitro (5Gy x 3 fractions), then an a priori determined number of resulting colonies were implanted in C57BL/6J immunocompetent mice creating syngeneic models of unirradiated (parental) and irradiated tumors with low (irradiated-L) and high (irradiated-H) ITH. Mice were treated with placebo, α-PD-L1, α-CTLA-4 or dual ICI. Murine tumors underwent whole exome sequencing (WES). Clinically correlated paired pre- and post-irradiation patient rectal adenocarcinoma samples underwent WES. RESULTS: Irradiated-L tumors showed increased tumor mutational burden (TMB) and a sustained decrease in ITH. Irradiated-L tumors were predicted to express five neoantigens with high variant allele frequency/clonal distribution. Mice with irradiated-L and irradiated-H versus parental B16F10 tumors demonstrated longer overall survival with dual ICI. Only mice with irradiated-L tumors experienced an overall survival benefit with single agent ICI. Clinically correlated rectal adenocarcinoma samples showed similarly increased TMB and decreased ITH following irradiation. CONCLUSIONS: Post-irradiation ITH modulates ICI response in a murine melanoma model. Irradiation may offer a mechanism to widen the therapeutic window of ICI.

Preliminary Evaluation of PTV Margins for Online Adaptive Radiation Therapy of the Prostatic Fossa.

PURPOSE: In modern trials, traditional planning target volume (PTV) margins for postoperative prostate radiation therapy have been large (7-10 mm) to account for both daily changes in patient positioning and target deformation. With daily adaptive radiation therapy, these interfractional changes could be minimized, potentially reducing the margins required for treatment and improving adjacent normal-tissue dosimetry. METHODS AND MATERIALS: A single-center retrospective study was conducted from March 2021 to November 2021. Patients receiving conventionally fractionated postoperative radiation therapy (PORT) for prostate cancer with pretreatment and posttreatment cone beam computed tomography (CBCT) imaging (pre-CBCT and post-CBCT, respectively) were included (248 paired images). Pretreatment and posttreatment clinical target volumes (pre-CTVs and post-CTVs) were contoured by a single observer on all CBCTs and verified by a second observer. Motion was calculated from pre-CTV to that of the post-CTV, and predicted margins were calculated with van Herk's formula. Adequate coverage of the proposed planning target volume (PTV) margin expansions (pre-PTV) were verified by determining overlap with post-CTV. In a smaller cohort (25 paired images), dosimetric changes with the proposed online adaptive margins were compared with conventional plans in the Ethos emulator environment. RESULTS: The estimated margins predicted to achieve ≥95% CTV coverage for 90% of the population were 1.6 mm, 2.0 mm, and 2.2 mm (x-, y-, and z -xes, respectively), with 95% of the absolute region of interest displacement being within 1.9 mm, 2.8 mm, and 2.1 mm. After symmetrically expanding all pre-CTVs by 3 mm, the percentage of paired images achieving ≥95% CTV coverage was 97.1%. When comparing adaptive plans (3-mm margins) with scheduled plans (7-mm margins), rectum dosimetry significantly improved, with an average relative reduction in V40Gy[cc] of 59.2% and V65Gy[cc] of 79.5% (where V40Gy and V65Gy are defined as the volumes receiving 40 Gy and 65 Gy or higher dose, respectively). CONCLUSIONS: Online daily adaptive radiation therapy could significantly decrease PTV margins for prostatic PORT and improve rectal dosimetry, with a symmetrical expansion of 3 mm achieving excellent coverage in this cohort. These results need to be validated in a larger prospective cohort.

Biocompatible Nanocomposites for Postoperative Adhesion: A State-of-the-Art Review.

To reduce and prevent postsurgical adhesions, a variety of scientific approaches have been suggested and applied. This includes the use of advanced therapies like tissue-engineered (TE) biomaterials and scaffolds. Currently, biocompatible antiadhesive constructs play a pivotal role in managing postoperative adhesions and several biopolymer-based products, namely hyaluronic acid (HA) and polyethylene glycol (PEG), are available on the market in different forms (e.g., sprays, hydrogels). TE polymeric constructs are usually associated with critical limitations like poor biocompatibility and mechanical properties. Hence, biocompatible nanocomposites have emerged as an advanced therapy for postoperative adhesion treatment, with hydrogels and electrospun nanofibers among the most utilized antiadhesive nanocomposites for in vitro and in vivo experiments. Recent studies have revealed that nanocomposites can be engineered to generate smart three-dimensional (3D) scaffolds that can respond to different stimuli, such as pH changes. Additionally, nanocomposites can act as multifunctional materials for the prevention of adhesions and bacterial infections, as well as tissue healing acceleration. Still, more research is needed to reveal the clinical potential of nanocomposite constructs and the possible success of nanocomposite-based products in the biomedical market.