Development and external validation of a machine learning model for prediction of survival in extremity leiomyosarcoma.

PURPOSE: Machine learning (ML) models have been used to predict cancer survival in several sarcoma subtypes. However, none have investigated extremity leiomyosarcoma (LMS). ML is a powerful tool that has the potential to better prognosticate extremity LMS. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for cases of histologic extremity LMS (n = 634). Patient, tumor, and treatment characteristics were recorded, and ML models were developed to predict 1-, 3-, and 5-year survival. The best performing ML model was externally validated using an institutional cohort of extremity LMS patients (n = 46). RESULTS: All ML models performed best at the 1-year time point and worst at the 5-year time point. On internal validation within the SEER cohort, the best models had c-statistics of 0.75-0.76 at the 5-year time point. The Random Forest (RF) model was the best performing model and used for external validation. This model also performed best at 1-year and worst at 5-year on external validation with c-statistics of 0.90 and 0.87, respectively. The RF model was well calibrated on external validation. This model has been made publicly available at https://rachar.shinyapps.io/lms_app/ CONCLUSIONS: ML models had excellent performance for survival prediction of extremity LMS. Future studies incorporating a larger institutional cohort may be needed to further validate the ML model for LMS prognostication.

Specific Polo-Like Kinase 1 Expression in Nodular Lymphocyte-Predominant Hodgkin Lymphoma Suggests an Intact Immune Surveillance Program.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare and relatively indolent B-cell lymphoma. Characteristically, the [lymphocyte-predominant (LP)] tumor cells are embedded in a microenvironment enriched in lymphocytes. More aggressive variants of mature B-cell and peripheral T-cell lymphomas exhibit nuclear expression of the polo-like kinase 1 (PLK1) protein, stabilizing MYC (alias c-myc) and associated with worse clinical outcomes. This study demonstrated expression of PLK1 in the LP cells in 100% of NLPHL cases (n = 76). In contrast, <5% of classic Hodgkin lymphoma cases (n = 70) showed PLK1 expression within the tumor cells. Loss-of-function approaches demonstrated that the expression of PLK1 promoted cell proliferation and increased MYC stability in NLPHL cell lines. Correlation with clinical parameters revealed that the increased expression of PLK1 was associated with advanced-stage disease in patients with NLPHL. A multiplex immunofluorescence panel coupled with artificial intelligence algorithms was used to correlate the composition of the tumor microenvironment with the proliferative stage of LP cells. The results showed that LP cells with PLK1 (high) expression were associated with increased numbers of cytotoxic and T-regulatory T cells. Overall, the findings demonstrate that PLK1 signaling increases NLPHL proliferation and constitutes a potential vulnerability that can be targeted with PLK1 inhibitors. An active immune surveillance program in NLPHL may be a critical mechanism limiting PLK1-dependent tumor growth.

Iatrogenic Immunodeficiency Associated Lymphoproliferative Disorder in a Patient With Inflammatory Bowel Disease.

Primary colorectal lymphoma is incredibly rare and cases of iatrogenic immunodeficiency associated lymphoproliferative disorder (IILPD) isolated to colorectal area are even more uncommon. Immunodeficiency associated lymphoproliferative disorders can occur in association with primary immune disorders such as inflammatory bowel diseases (IBDs) which are often treated with various immunomodulatory drugs. Of the immunomodulatory drugs, thiopurines, in particular, are known to have a significantly increased relative risk for development of IILPDs. Here we present the case of a 43-year-old Caucasian man with a 22-year history of IBD treated with longstanding immunomodulatory therapy who presented with severe rectal pain and drainage. He underwent an examination under anesthesia with rigid proctoscopy and biopsies were taken of a hard exophytic appearing tissue along the posterior wall of the rectosigmoid junction. Pathological investigation of the samples revealed IILPD. He underwent treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) and achieved complete remission. Literature demonstrates that the use of immunomodulators such as azathioprine has been shown to significantly improve the quality of life in patients with IBD. However, while the absolute risk of lymphoma for any given patient remains quite low, the relative risk of lymphoma in patients who are actively treated with thiopurines is moderate. Therefore, the decision to proceed with thiopurine treatment, especially in the setting of long-term therapy, requires extensive discussion and patient education of the risks/benefits along with closer monitoring of new or uncharacteristic symptoms.

Radiotherapy, volume reduction, and short-term surgical outcomes in the treatment of large myxoid liposarcomas.

PURPOSE: While tumor volume reduction following radiation has been documented in myxoid liposarcomas, it is unclear whether large tumors experience similar volume reduction to smaller tumors. MATERIALS AND METHODS: MRI studies performed before and after completion of pre-operative radiation therapy (RT) were examined. Tumor sizes were noted and categorized as large versus small based on size >10 cm. Tumor volumes were calculated, and operative duration and major wound complications were recorded. RESULTS: The median largest tumor dimension was 12.4 cm before RT and 8.7 cm after RT. The median tumor volume was 298.9 cm3 before RT and 106.9 cm3 after RT. There was no significant difference in the mean percent tumor volume reduction between large tumors and small tumors (p = 0.11, 56.3% vs. 64.5%). Operative duration most strongly correlated to post-RT MRI volume (R2=0.674, p<0.001). Despite volume reduction, tumors that were large on presentation were more likely to experience major wound complications post-operatively. CONCLUSION: Radiation appears to be as effective at reducing myxoid liposarcoma tumor volume in large and small tumors. However, large tumors on presentation appear more likely to experience wound complications despite tumor volume reduction. Future studies should investigate disease-related outcomes as a factor of volume reduction in myxoid liposarcoma.

Pulmonary metastasectomy in bone and soft tissue sarcoma with metastasis to the lung.

OBJECTIVES: This study investigated the outcomes of sarcoma patients with lung metastases who underwent pulmonary metastasectomy (PM), compared to patients who underwent medical management alone. The secondary objective was to compare survival after PM between variables of interest. METHODS: This was a retrospective review of 565 sarcoma patients with confirmed, isolated pulmonary metastasis identified from the Surveillance, Epidemiology and End Results database between 2010 and 2015. 1:4 propensity score matching was used to select PM and non-PM groups. The multivariable Cox proportional hazards model was used to analyse prognostic factors of disease-free survival (DFS). RESULTS: Of the eligible 565 patients, 59 PM patients were matched to 202 non-PM patients in a final ratio of 3.4. After propensity matching, there were no significant differences in baseline characteristics between PM and non-PM patients. The median DFS after PM was 32 months (interquartile range 18-59), compared to 20 months (interquartile range 7-40) in patients without PM (P = 0.032). Using a multivariable Cox proportional hazards model, metastasectomy (hazard ratio 0.536, 95% confidence interval 0.33-0.85; P = 0.008) was associated with improved DFS. In a subset analysis of patients who underwent PM only, the median DFS was longer in males compared to females (P = 0.021), as well as in bone sarcoma compared to soft tissue sarcoma (P = 0.014). CONCLUSIONS: For sarcoma patients with metastatic lung disease, PM appears to improve the prognosis compared to medical management. Furthermore, there may be a survival association with gender and tumour origin in patients who underwent PM. These data may be used to inform the surgical indications and eligibility criteria for metastasectomy in this setting.

Follicular Dendritic Cell Sarcoma or Not? A Series of 5 Diagnostically Challenging Cases.

Imperfect or unusual presentation, morphology, or immunophenotype can make the diagnosis of follicular dendritic cell sarcoma (FDCS) very challenging. To illustrate this, we present 5 unique cases from the archives of our tertiary care academic medical center that presented a diagnostic challenge wherein FDCS was the top differential diagnostic possibility. The workup of these cases, including multiple expert consultations, highlights the importance of avoiding specific pitfalls in the diagnosis of FDCS.

Metastatic Involvement of the Prostatic Anterior Fat Pad: Implications for the Pathologist.

OBJECTIVES: There is little information regarding the utility of pathologic evaluation of the prostatic anterior fat pad (PAFP) in patients with a low preoperative probability of recurrence. Our study aimed to determine the utility of PAFP pathologic examination, especially for this group of patients. METHODS: We analyzed a tertiary care academic center's radical prostatectomy (RP) specimens from 2009 to 2017. RESULTS: Of 602 RP specimens, 420(70%) included the PAFP; four of 420 (1%) had lymph node involvement (LNI) in the PAFP. In two of four cases with LNI in the PAFP, this was the only site of LNI. Of these two cases, one occurred in a patient with low probability of recurrence and involved a nonpalpable PAFP lymph node. CONCLUSIONS: Pathologic evaluation of the PAFP may be useful even in patients with low probability of recurrence because it may change staging by detecting metastatic involvement of small PAFP lymph nodes.

A Second-Generation Proteasome Inhibitor and Doxorubicin Modulates IL-6, pSTAT-3 and NF-kB Activity in MDA-MB-231 Breast Cancer Cells.

Triple-Negative Breast Cancer (TNBC) has a poor prognosis due to lack of targeted therapy. Doxorubicin (DOX) has failed for multiple reasons, including development of multi-drug resistance, induction of inflammation (IL-6 secretion) and long-term toxicities. DOX is also known to have off target proteasomal activation, justifying the concept of combining it with a proteasomal inhibitor. Our study investigated the therapeutic potential of an irreversible proteasome inhibitor carfilzomib (CARF) alone or in combination with DOX in two TNBC cell lines (MDA-MB-231 and MDA-MB-468). CARF was as effective in inhibiting mitosis in vitro for both cell lines in comparison to DOX alone. CARF performed similar to DOX in inhibiting apoptosis but had better results in reducing proliferation. Further studies in MDA-MB-231 cells demonstrated that CARF also inhibited pro-inflammatory IL-6 secretion and NF κB transcriptional activity while DOX stimulated both IL-6 and NF kappa-B activity. The reduction of IL-6 while using CARF highlights its therapeutic potential and ability to enhance current clinical drug regimens. Furthermore, exogenous administration of IL-6 potentiated NF Kappa B transcriptional activity, pSTAT3 (Tyr705) and JAK inflammatory signaling as well as cell proliferation in CARF- or DOX-treated MDA-MB-231 cells. In vivo, CARF treatment resulted in reduced serum IL-6 compared to treatment with DOX in female SCID-NOD mice with MDA-MB-231 cell tumor. A combinational approach using DOX and CARF presents a clinical potential for better efficacy, reduced proliferation, apoptosis, anti-angiogenesis, and less cardiac dysfunction when compared to current treatments using standalone DOX.

Doxorubicin-Hyaluronan Conjugated Super-Paramagnetic Iron Oxide Nanoparticles (DOX-HA-SPION) Enhanced Cytoplasmic Uptake of Doxorubicin and Modulated Apoptosis, IL-6 Release and NF-kappaB Activity in Human MDA-MB-231 Breast Cancer Cells.

Triple negative breast cancer exhibit increased IL-6 expression compared with matched healthy breast tissue and a strong link between inflammation and cancer progression and metastasis has been reported. We investigated whether doxorubicin-hyaluronan-super-paramagnetic iron oxide nanoparticles (DOX-HA-SPION) would show greater therapeutic efficacy in human triple negative breast cancer cells (TNBC) MDA-MB-231, as was recently shown in drug-sensitive and multi-drug-resistant ovarian cancer cells. Therefore, we measured cellular DOX uptake via confocal microscopy; observed morphologic changes: mitochondrial and nuclear changes with electron microscopy, and quantitated apoptosis using FACS analysis after Annexin V and PI staining in MDA-MB-231 cells treated with either DOX alone or DOX-HA-SPION. We also measured both proinflammatory and anti-inflammatory cytokines; IL-6, IL-10 respectively and also measured nitrate levels in the conditioned medium by ELISA. Inaddition, NF-κB activity was measured by luciferase assay. Confocal microscopy demonstrated greater cytoplasmic uptake of DOX-HA-SPION than free DOX. We also demonstrated reduction of Vimentin with DOX-HA-SPION which is significantly less than both control and DOX. DOX-HA-SPION enhanced apoptosis and significantly down regulated both pro-inflammatory mediators IL-6 and NF-κB in comparison to DOX alone. The secretion levels of anti-inflammatory mediators IL-10 and nitrate was not decreased in the DOX or DOX-HA-SPION treatment groups. Our data suggest that DOX-HA-SPION nanomedicine-based drug delivery could have promising potential in treating metastasized and chemoresistant breast cancer by enhancing the drug efficacy and minimizing off-target effects.