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Cancer is a major threat to human health. Among various treatment methods, precision therapy has received significant attention since the inception, due to its ability to efficiently inhibit tumor growth, while curtailing common shortcomings from conventional cancer treatment, leading towards enhanced survival rates. Particularly, organelle-targeted strategies enable precise accumulation of therapeutic agents in organelles, locally triggering organelle-mediated cell death signals which can greatly reduce the therapeutic threshold dosage and minimize side-effects. In this review, we comprehensively discuss history and recent advances in targeted therapies on organelles, specifically including nucleus, mitochondria, lysosomes and endoplasmic reticulum, while focusing on organelle structures, organelle-mediated cell death signal pathways, and design guidelines of organelle-targeted nanomedicines based on intervention mechanisms. Furthermore, a perspective on future research and clinical opportunities and potential challenges in precision oncology is presented. Through demonstrating recent developments in organelle-targeted therapies, we believe this article can further stimulate broader interests in multidisciplinary research and technology development for enabling advanced organelle-targeted nanomedicines and their corresponding clinic translations.

The ability to manufacture ordered mesoporous materials using low-cost precursors and scalable processes is essential for unlocking their enormous potential to enable advancement in nanotechnology. While templating-based methods play a central role in the development of mesoporous materials, several limitations exist in conventional system design, including cost, volatile solvent consumption, and attainable pore sizes from commercial templating agents. This work pioneers a new manufacturing platform for producing ordered mesoporous materials through direct pyrolysis of crosslinked thermoplastic elastomer-based block copolymers. Specifically, olefinic majority phases are selectively crosslinked through sulfonation reactions and subsequently converted to carbon, while the minority block can be decomposed to form ordered mesopores. We demonstrate that this process can be extended to different polymer precursors for synthesizing mesoporous polymer, carbon, and silica. Furthermore, the obtained carbons possess large mesopores, sulfur-doped carbon framework, with tailorable pore textures upon varying the precursor identities. Scaled manufacturing of ordered mesoporous materials has been historically challenging. This work reports a simple and generalizable method to directly convert low-cost thermoplastic elastomers to mesoporous polymer, carbon, and silica, with controlled pore textures by altering precursor identity.

The current American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system does not have sufficient details to encompass the variety of soft-tissue sarcomas, and available prognostic methods need refinement. We aimed to develop and externally validate two prediction nomograms for overall survival and distant metastases in patients with soft-tissue sarcoma in their extremities. Consecutive patients who had had an operation at the Istituto Nazionale Tumori (Milan, Italy), from Jan 1, 1994, to Dec 31, 2013, formed the development cohort. Three cohorts of patient data from the Institut Gustave Roussy (Villejuif, France; from Jan 1, 1996, to May 15, 2012), Mount Sinai Hospital (Toronto, ON, Canada; from Jan 1, 1994, to Dec 31, 2013), and the Royal Marsden Hospital (London, UK; from Jan 1, 2006, to Dec 31, 2013) formed the external validation cohorts. We developed the nomogram for overall survival using a Cox multivariable model, and a Fine and Gray multivariable model for the distant metastases nomogram. We applied a backward procedure for variables selection for both nomograms. We assessed nomogram model performance by examining overall accuracy (Brier score), calibration (calibration plots and Hosmer–Lemeshow calibration test), and discrimination (Harrell C index). We plotted decision curves to evaluate the clinical usefulness of the two nomograms. 1452 patients were included in the development cohort, with 420 patients included in the French validation cohort, 1436 patients in the Canadian validation cohort, and 444 patients in the UK validation cohort. In the development cohort, 10-year overall survival was 72·9% (95% CI 70·2–75·7) and 10-year crude cumulative incidence of distant metastases was 25·0% (95% CI 22·7–27·5). For the overall survival nomogram, the variables selected applying a backward procedure in the multivariable Cox model (patient's age, tumour size, Fédération Française des Centres de Lutte Contre le Cancer [FNCLCC] grade, and histological subtype) had a significant effect on overall survival. The same variables, except for patient age, were selected for the distant metastases nomogram. In the development cohort, the Harrell C index for overall survival was 0·767 (95% CI 0·743–0·789) and for distant metastases was 0·759 (0·736–0·781). In the validation cohorts, the Harrell C index for overall survival and distant metastases were 0·698 (0·638–0·754) and 0·652 (0·605–0·699; French), 0·775 (0·754–0·796) and 0·744 (0·720–0·768; Canadian), and 0·762 (0·720–0·806) and 0·749 (0·707–0·791; UK). The two nomograms both performed well in terms of discrimination (ability to distinguish between patients who have had an event from those who have not) and calibration (accuracy of nomogram prediction) when applied to the validation cohorts. Our nomograms are reliable prognostic methods that can be used to predict overall survival and distant metastases in patients after surgical resection of soft-tissue sarcoma of the extremities. These nomograms can be offered to clinicians to improve their abilities to assess patient prognosis, strengthen the prognosis-based decision making, enhance patient stratification, and inform patients in the clinic. None.

Despite groundbreaking advances in the additive manufacturing of polymers, metals, and ceramics, scaled and accurate production of structured carbons remains largely underdeveloped. This work reports a simple method to produce complex carbon materials with very low dimensional shrinkage from printed to carbonized state (less than 4%), using commercially available polypropylene precursors and a fused filament fabrication-based process. The control of macrostructural retention is enabled by the inclusion of fiber fillers regardless of the crosslinking degree of the polypropylene matrix, providing a significant advantage to directly control the density, porosity, and mechanical properties of 3D printed carbons. Using the same printed plastic precursors, different mechanical responses of derived carbons can be obtained, notably from stiff to highly compressible. This report harnesses the power of additive manufacturing for producing carbons with accurately controlled structure and properties, while enabling great opportunities for various applications. This work reports a simple method to produce 3D printed complex carbon materials with low dimensional shrinkage (<4%) from printed to carbonized state, using commercially available carbon fiber-reinforced polypropylene precursors and a fused filament fabrication-based process.

Synovial sarcoma (SS) is a tumor known for its classic monophasic spindle cell or biphasic morphology. However, it exhibits a wide range of histologic variations, leading to diagnostic challenges. Here, we present four cases of molecularly confirmed, biphasic SS originating in the feet and displaying myoepithelial differentiation. The patients were two men and two women with an age range from 19 to 71 years (mean, 45 years). Each tumor showed foci with conventional spindle cell morphology. The epithelial components included areas with nests and cords of epithelioid cells set within a hyalinized and sclerotic stroma. The cytoplasm was clear to pale and eosinophilic. The nuclei were ovoid-round with fine chromatin and small to inconspicuous nucleoli. Mitotic figures were present (2–13 per 10 high-power fields; mean, 6.5). Immunohistochemical studies showed variable staining of the myoepithelial-like regions for low molecular weight keratins, EMA, p63, and S100 protein. Molecular studies confirmed the presence of SS18::SSX1/2 fusion in all four tumors. These cases highlight an unusual variant of synovial sarcoma with an apparent predilection for the distal lower extremity and suggest that differentiation of biphasic synovial sarcoma may be impacted by the anatomic site. Awareness of this variant is important to avoid misclassification and potential treatment and prognostic implications.

Background The potential for local recurrence and pulmonary metastasis after treatment of primary bone sarcomas necessitates careful patient followup; however, minimal data exist regarding the incidence and timing of these events, and therefore an evidence-based surveillance protocol has not been developed. Questions/purposes The purposes of this study were to (1) describe the frequency and timing of local recurrence by histologic grade over time; (2) describe the frequency and timing of metastasis by histologic grade and diagnosis over time; and (3) use these data to either justify current surveillance schedules and/or propose modifications that may improve the rate of new pulmonary metastatic events detected per examination. Methods A retrospective review was performed of all patients who underwent resection of a primary, nonmetastatic bone sarcoma (excluding chordoma) at a single tertiary oncology center from 1989 to 2010. Of the 680 patients identified, 15 were excluded for loss of followup in the first 2 years, leaving 665 eligible for study. Of these, 437 patients were alive with no evidence of disease at the conclusion of the study (mean followup, 136 months; range, 25–321 months). Cox regression analysis was performed to evaluate and control for patient age, tumor size, tumor location, and surgical margins. With patients stratified by sarcoma grade, Kaplan-Meier survival curves were constructed for the endpoints of local recurrence and metastasis, and log-rank tests were used to compare the rates of these events between grades and diagnoses. The number of new pulmonary metastatic events per patient-year was calculated for each sarcoma grade over the time intervals used in current surveillance protocols (0–2, 2–5, 5–10, and > 10 years) to facilitate development of a surveillance schedule that would maximize events detected per imaging study performed. In addition, to determine the effect of disease type, subset analysis was performed for osteosarcoma (OSA) and chondrosarcoma because these were the only diagnoses with sufficient numbers to support individual statistical analysis. Results With the numbers available for study, the overall local recurrence-free survival did not differ between sarcoma grades at any time points (p = 0.864). Metastasis-free survival curves differed between sarcoma grades (p < 0.001), and the pattern of Grade 2 OSA metastasis was more consistent with other Grade 3 sarcomas, so it was subsequently classified as high grade. No metastases of Grade 1 sarcomas occurred after 3 years, whereas Grade 2 and 3 sarcomas continued to metastasize until 10 years and rarely thereafter. According to the number of new pulmonary metastatic events per patient-year in each group, we propose that chest surveillance be performed according to the following schedule: annually only until 5 years for low-grade sarcomas; every 3 months for 2 years and annually from 2 to 10 years for intermediate-grade sarcomas; and every 3 months for 2 years, every 6 months from 2 to 5 years, and annually from 5 to 10 years for high-grade sarcomas. Conclusions Pulmonary screening beyond 5 years may not be necessary for Grade 1 tumors but should be continued until 10 years for Grade 2 and 3 bone sarcomas. The surveillance frequency listed here, which is based on the number of new pulmonary metastatic events per patient-year in each grade, would increase the number of such events detected per examination performed. Level of Evidence Level III, therapeutic study.

BackgroundUnlike other sarcoma subtypes, myxoid liposarcoma (MLS) has a propensity for extra-pulmonary metastases. Computed tomography (CT) scan of the chest, abdomen, and pelvis has become an accepted practice for surveillance. However, recent literature suggests that this may be inadequate. This study aimed to assess the ability of current imaging methods to detect metastases adequately in this population.MethodsThe study identified 169 patients with MLS diagnosed between 2000 and 2016. The timing and location of metastases, the reasons leading to the MLS diagnosis, and the imaging methods were recorded. The locations of metastases were classified into the following categories: pulmonary, soft tissue, bone, retroperitoneal, intraperitoneal, solid organ, and lymph node.ResultsAn initial diagnosis of metastasis was made at presentation with staging CT scan for 3 (10 %) of 31 patients, with a follow-up surveillance CT scan for 15 (48 %) of the patients or with subsequent imaging obtained in response to patient-reported symptoms for 13 (42 %) of the patients. The proportions of patients who had metastases in each location were as follows: soft tissue (84 %), pulmonary (68 %), intraabdominal (48 %), solid organ (48 %), bone (45 %), lymph node (32 %), and retroperitoneal (29 %). Although 14 patients had bone metastases, only 1 patient had a sclerotic/blastic presentation visualized on CT scan, and the diagnosis for the remaining 13 patients was determined by magnetic resonance imaging (MRI).ConclusionDue to metastatic disease identified outside surveillance imaging for 58 % of the patients, the diversity of locations, and the significant failure of CT and bone scan to identify bone metastases, this study questioned the adequacy of CT scan for surveillance of MLS. Consideration should be given to the use of whole-body MRI for detection of metastasis in MLS.

Dermat of ibrosarcoma protuberans (DFSP) is a soft-tissue sarcoma with a high risk of local recurrence, though typically never metastasizes. DFSP can transform into high-grade fibrosarcoma (DFSP-FS), which has a risk of metastasis. Currently, treatment for DFSP includes Moh's micrographic surgery (MMS); however, this is not recommended for DFSP-FS. Often, the transformation to DFSP-FS is not recognized until the final histological diagnosis. At that point, wide local excision (WLE) of a previous MMS site can be morbid. As such, we analyzed patient risk factors to allow identification of DFSP-FS transformation at presentation. We reviewed 368 (174 female, 194 male) patients with a mean age of 42 years from two sarcoma centers. A total of 319 (87%) patients had a history of DFSP and 49 (13%) had DFSP-FS. When comparing patients with a DFSP to those with a DFSP-FS, patients with a DFSP-FS were more likely (p<0.05) to be older, female and with larger tumors. A painful mass and rapidly enlarging mass were associated with DFSP-FS. Patients who presented with DFSP-FS were found to typically have a larger, painful, and growing mass. Patients with these features should be referred for WLE over MMS at presentation.

Background Peritumoral edema on staging magnetic resonance imaging (MRI) is associated with higher local recurrence in soft tissue sarcoma (STS). This may relate to the presence of satellite malignant cells that are difficult to distinguish from benign atypia, leading to over- or undertreatment. This study evaluated a novel targeted molecular approach to identify malignancy in STS peritumoral planes as a means to improve personalized care. Methods In the targeted molecular approach, whole-exome sequencing was employed to identify tumor-specific variants (TSVs), and peritumoral planes were assayed for malignancy, defined as two or more TSVs/plane, using droplet digital polymerase chain reaction (PCR). Feasibility was evaluated using a retrospective cohort ( n  = 8) in which planes with cellular atypia were tested. A prospective cohort ( n  = 8) then assayed all peritumoral planes with radiologic edema. Results The targeted molecular approach identified malignancy in three of eight cases with cellular atypia of unknown significance (37.5%) and five of eight cases with peritumoral edema on staging MRI (62.5%). Peritumoral regions were heterogeneous; in none of the malignant cases did all sampled planes have evidence of tumor. Malignancy was also identified in regions without cellular atypia. Both cases with a local recurrence had molecular evidence of malignancy outside the main mass despite R0 margins. Conclusion This study describes a novel personalized approach to detect malignancy in peritumoral regions in STS and is the first to identify molecular evidence of tumor outside the main mass. While development of a clinical tool is underway, these findings support the current approach of treating all peritumoral edema as malignant.