Multi-Institutional Study of Referral Patterns for Gynecologic Oncology Consultation.

PURPOSE: Evaluation by a gynecologic oncologist (GO) is associated with improved clinical outcomes for patients with gynecologic cancers, yet little is known about health care factors that influence patients' referrals to GO. METHODS: Medical records of 50 consecutive new patients seen in GO clinics at each of six referral centers across the United States were reviewed. Patient and disease characteristics were collected along with referral indication, evaluation and referral dates, diagnostic procedures, provider specialties, and zone improvement plan (ZIP) code of up to three referring providers per patient. The primary outcome was interval between first evaluation and referral. Univariate associations were evaluated with Chi-square and Wilcoxon rank-sum tests and multivariable associations with negative binomial regression models. Secondary outcome was prolonged time to GO referral, defined as greater than the 75th percentile. Logistic regression was used for multivariable modeling. RESULTS: Three hundred patient records were analyzed. The median time from first health care encounter to referral was 15 days (IQR, 5-43). The mean distance from residence to GO was 39.8 miles (standard deviation, 53.8). Seventy-one percent of GO referrals were initiated by obstetrician-gynecologists, 9% by family physicians, and 6% internists. Presentation-to-referral interval was 76% shorter for patients evaluated by an emergency medicine clinician (exp(Beta), 0.24; 95% CI, 0.11 to 0.53; P < .001). Public insurance was associated with 1.47 times longer time to referral compared with private insurance (exp(Beta), 1.47; 95% CI, 1.05 to 2.04; P = .001). Residents of nonmetropolitan ZIP codes were less likely to have prolonged time to referral (odds ratio [OR], 0.288; P = .017). Distance from residence to GO (per 10 miles) increased the likelihood of prolonged time to referral (OR, 1.10; P = .010). CONCLUSION: Interventions are needed to improve recognition and referral of patients for gynecologic oncology evaluation. Community outreach and engagement with obstetrician-gynecologists should be prioritized to improve times to referral.

Novel Definitive Hypofractionated Accelerated Radiation Dose-painting (HARD) for Unresected Soft Tissue Sarcomas.

Purpose: Soft tissue sarcomas (STS) are historically radioresistant, with surgery being an integral component of their treatment. With their low α/ß, STS may be more responsive to hypofractionated radiation therapy (RT), which is often limited by long-term toxicity risk to surrounding normal tissue. An isotoxic approach using a hypofractionated accelerated radiation dose-painting (HARD) regimen allows for dosing based on clinical risk while sparing adjacent organs at risk. Methods and Materials: We retrospectively identified patients from 2019 to 2022 with unresected STS who received HARD with dose-painting to high, intermediate, and low-risk regions of 3.0 Gy, 2.5 Gy, and 2.0 to 2.3 Gy, respectively, in 20 to 22 fractions. Clinical endpoints included local control, locoregional control, progression free survival, overall survival, and toxicity outcomes. Results: Twenty-seven consecutive patients were identified and had a median age of 68 years and tumor size of 7.0 cm (range, 1.2-21.0 cm). Tumors were most often high-grade (70%), stage IV (70%), located in the extremities (59%), and locally recurrent (52%). With a median follow-up of 33.4 months, there was a 3-year locoregional control rate of 100%. The 3-year overall and progression-free survival were 44.9% and 23.3%, respectively. There were 5 (19%) acute and 2 (7%) late grade 3 toxicities, and there were no grade 4 or 5 toxicities at any point. Conclusions: The HARD regimen is a safe method of dose-escalating STS, with durable 3-year locoregional control. This approach is a promising alternative for unresected STS, though further follow-up is required to determine long-term control and toxicity.

Habitat escalated adaptive therapy (HEAT): a phase 2 trial utilizing radiomic habitat-directed and genomic-adjusted radiation dose (GARD) optimization for high-grade soft tissue sarcoma.

BACKGROUND: Soft tissue sarcomas (STS), have significant inter- and intra-tumoral heterogeneity, with poor response to standard neoadjuvant radiotherapy (RT). Achieving a favorable pathologic response (FPR ≥ 95%) from RT is associated with improved patient outcome. Genomic adjusted radiation dose (GARD), a radiation-specific metric that quantifies the expected RT treatment effect as a function of tumor dose and genomics, proposed that STS is significantly underdosed. STS have significant radiomic heterogeneity, where radiomic habitats can delineate regions of intra-tumoral hypoxia and radioresistance. We designed a novel clinical trial, Habitat Escalated Adaptive Therapy (HEAT), utilizing radiomic habitats to identify areas of radioresistance within the tumor and targeting them with GARD-optimized doses, to improve FPR in high-grade STS. METHODS: Phase 2 non-randomized single-arm clinical trial includes non-metastatic, resectable high-grade STS patients. Pre-treatment multiparametric MRIs (mpMRI) delineate three distinct intra-tumoral habitats based on apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) sequences. GARD estimates that simultaneous integrated boost (SIB) doses of 70 and 60 Gy in 25 fractions to the highest and intermediate radioresistant habitats, while the remaining volume receives standard 50 Gy, would lead to a > 3 fold FPR increase to 24%. Pre-treatment CT guided biopsies of each habitat along with clip placement will be performed for pathologic evaluation, future genomic studies, and response assessment. An mpMRI taken between weeks two and three of treatment will be used for biological plan adaptation to account for tumor response, in addition to an mpMRI after the completion of radiotherapy in addition to pathologic response, toxicity, radiomic response, disease control, and survival will be evaluated as secondary endpoints. Furthermore, liquid biopsy will be performed with mpMRI for future ancillary studies. DISCUSSION: This is the first clinical trial to test a novel genomic-based RT dose optimization (GARD) and to utilize radiomic habitats to identify and target radioresistance regions, as a strategy to improve the outcome of RT-treated STS patients. Its success could usher in a new phase in radiation oncology, integrating genomic and radiomic insights into clinical practice and trial designs, and may reveal new radiomic and genomic biomarkers, refining personalized treatment strategies for STS. TRIAL REGISTRATION: NCT05301283. TRIAL STATUS: The trial started recruitment on March 17, 2022.

Ki-67 Testing in Breast Cancer: Assessing Variability With Scoring Methods and Specimen Types and the Potential Subsequent Impact on Therapy Eligibility.

Abemaciclib was originally FDA approved for patients with ER-positive/HER2-negative breast cancer with Ki-67 expression ≥20%. However, there were no guidelines provided on which specimen to test or which scoring method to use. We performed a comprehensive study evaluating the variation in Ki-67 expression in breast specimens from 50 consecutive patients who could have been eligible for abemaciclib therapy. Three pathologists with breast expertise each performed a blinded review with 3 different manual scoring methods [estimated (EST), unweighted (UNW), and weighted (WT) (WT recommended by the International Ki-67 in Breast Cancer Working Group)]. Quantitative image analysis (QIA) using the HALO platform was also performed. Three different specimen types [core needle biopsy (CNB) (n=63), resection (RES) (n=52), and axillary lymph node metastasis (ALN) (n=50)] were evaluated for each patient. The average Ki-67 for all specimens was 14.68% for EST, 14.46% for UNW, 14.15% for WT, and 11.15% for QIA. For the manual methods, the range between the lowest and highest Ki-67 for each specimen between the 3 pathologists was 8.44 for EST, 5.94 for WT, and 5.93 for UNW. The WT method limited interobserver variability with ICC1=0.959 (EST ICC1=0.922 and UNW=0.949). Using the aforementioned cutoff of Ki-67 ≥20% versus <20% to determine treatment eligibility, the averaged EST method yields 20 of 50 patients (40%) who would have been treatment-eligible, versus 15 (30%) for the UNW, 17 (34%) for the WT, and 12 (24%) for the QIA. There was no statistically significant difference in Ki-67 among the 3 specimen types. The average Ki-67 difference was 4.36 for CNB vs RES, 6.95 for CNB versus ALN, and RES versus ALN (P=0.93, 0.99, and 0.94, respectively). Our study concludes that further refinement in Ki-67 scoring is advisable to reduce clinically significant variation.

Effect of aromatic substituents on thermoresponsive functional polycaprolactone micellar carriers for doxorubicin delivery.

Amphiphilic functional polycaprolactone (PCL) diblock copolymers are excellent candidates for micellar drug delivery. The functional groups on the backbone significantly affect the properties of PCL. A systematic investigation of the effect of aromatic substituents on the self-assembly of γ-functionalized PCLs and the delivery of doxorubicin (DOX) is presented in this work. Three thermoresponsive amphiphilic diblock copolymers with poly(γ-benzyloxy-ε-caprolactone) (PBnCL), poly(γ-phenyl- ε-caprolactone) (PPhCL), poly(γ-(4-ethoxyphenyl)-ε-caprolactone) (PEtOPhCL), respectively, as hydrophobic block and γ-tri(ethylene glycol) functionalized PCL (PME3CL) as hydrophilic block were prepared through ring-opening polymerization (ROP). The thermoresponsivity, thermodynamic stability, micelle size, morphology, DOX-loading, and release profile were determined. The LCST values of amphiphilic diblock copolymers PME3CL-b-PBnCL, PME3CL-b-PPhCL, and PME3CL-b-PEtOPhCL are 74.2°C, 43.3°C, and 37.3°C, respectively. All three copolymers formed spherical micelles in phosphate-buffered saline (PBS, 1×, pH = 7.4) at low concentrations ranging from 8.7 × 10-4 g/L to 8.9 × 10-4 g/L. PME3CL-b-PBnCL micelles showed the highest DOX loading capacity of 3.01 ± 0.18 (wt%) and the lowest drug release, while PME3CL-b-PEtOPhCL micelles exhibited the lowest DOX loading capacity of 1.95 ± 0.05 (wt%) and the highest drug release. Cytotoxicity and cellular uptake of all three micelles were assessed in vitro using MDA-MB-231 breast cancer cells. All three empty micelles did not show significant toxicity to the cells at concentrations high up to 0.5 mg/mL. All three DOX-loaded micelles were uptaken into the cells, and DOX was internalized into the nucleus of the cells.

Novel Postoperative Hypofractionated Accelerated Radiation Dose-Painting Approach for Soft Tissue Sarcoma.

Purpose: Hypofractionated radiation therapy (RT) offers benefits in the treatment of soft tissue sarcomas (STS), including exploitation of the lower α/ß, patient convenience, and cost. This study evaluates the acute toxicity of a hypofractionated accelerated RT dose-painting (HARD) approach for postoperative treatment of STS. Methods and Materials: This is a retrospective review of 53 consecutive patients with STS who underwent resection followed by postoperative RT. Standard postoperative RT dosing for R0/R1/gross disease with sequential boost (50 Gy + 14/16/20 Gy in 32-35 fractions) were replaced with dose-painting, which adapts dose based on risk of disease burden, to 50.4 and 63, 64.4, 70 Gy in 28 fractions, respectively. The first 10 patients were replanned with a sequential boost RT approach and dosimetric indices were compared. Time-to-event outcomes, including local control, regional control, distant control, and overall survival, were estimated with Kaplan-Meier analysis. Results: Median follow-up was 25.2 months. Most patients had high-grade (59%) STS of the extremity (63%) who underwent resection with either R1 (40%) or close (36%) margins. Four patients experienced grade 3 acute dermatitis which resolved by the 3-month follow-up visit. The 2-year local control, regional control, distant control, and overall survival were 100%, 92%, 68%, and 86%, respectively. Compared with the sequential boost plan, HARD had a significantly lower field size (total V50 Gy; P = .002), bone V50 (P = .031), and maximum skin dose (P = .008). Overall treatment time was decreased by 4 to 7 fractions, which translated to a decrease in estimated average treatment cost of $3056 (range, $2651-$4335; P < .001). Conclusions: In addition to benefits in cost, convenience, and improved biologic effect in STS, HARD regimen offers a safe treatment approach with dosimetric advantages compared with conventional sequential boost, which may translate to improved long-term toxicity.

Regioselective Direct C-H Bond Heteroarylation of Thiazoles Enabled by an Iminopyridine-Based α-Diimine Nickel(II) Complex Evaluated by DFT Studies.

Direct C-H bond arylation is a highly effective method for synthesizing arylated heteroaromatics. This method reduces the number of synthetic steps and minimizes the formation of impurities. We report an air- and moisture-stable iminopyridine-based α-diimine nickel(II) complex for direct C5-H bond arylation of thiazole derivatives. Under a low catalyst loading and performing the reactions at lower temperatures (80 °C) under aerobic conditions, we produced mono- and diarylated thiazole units. Competition experiments and density functional theory calculations revealed that the mechanism of C-H activation in 4-methylthiazole involves an electrophilic aromatic substitution.

Design of Beta-2 Microglobulin Adsorbent Protein Nanoparticles.

Beta-2 microglobulin (B2M) is an immune system protein that is found on the surface of all nucleated human cells. B2M is naturally shed from cell surfaces into the plasma, followed by renal excretion. In patients with impaired renal function, B2M will accumulate in organs and tissues leading to significantly reduced life expectancy and quality of life. While current hemodialysis methods have been successful in managing electrolyte as well as small and large molecule disturbances arising in chronic renal failure, they have shown only modest success in managing plasma levels of B2M and similar sized proteins, while sparing important proteins such as albumin. We describe a systematic protein design effort aimed at adding the ability to selectively remove specific, undesired waste proteins such as B2M from the plasma of chronic renal failure patients. A novel nanoparticle built using a tetrahedral protein assembly as a scaffold that presents 12 copies of a B2M-binding nanobody is described. The designed nanoparticle binds specifically to B2M through protein-protein interactions with nanomolar binding affinity (~4.2 nM). Notably, binding to the nanoparticle increases the effective size of B2M by over 50-fold, offering a potential selective avenue for separation based on size. We present data to support the potential utility of such a nanoparticle for removing B2M from plasma by either size-based filtration or by polyvalent binding to a stationary matrix under blood flow conditions. Such applications could address current shortcomings in the management of problematic mid-sized proteins in chronic renal failure patients.

Risk Factors for Revision Surgery Following Revision Total Knee Arthroplasty Using a Hinged Knee Prosthesis for Septic and Aseptic Indications.

INTRODUCTION: The use of hinged knee replacements (HKRs) for limb salvage is a popular option for revision total knee arthroplasty (RTKA). Although recent literature focuses on the outcomes of HKR for septic and aseptic RTKAs, little is reported on the risk factors of returning to the operating room. The purpose of this study was to evaluate risk factors of revision surgery and revision after receiving HKR for septic versus aseptic etiology. METHODS: A multicenter, retrospective review was conducted on consecutive patients who received HKR from January 2010 to February 2020 with a minimum follow-up of 2 years. Patients were separated into two groups: septic and aseptic RTKAs. Demographic, comorbidity, perioperative, postoperative, and survivorship data were collected and compared between groups. Cox hazard regression was used to identify risk factors associated with revision surgery and revision. RESULTS: One-hundred fifty patients were included. Eighty-five patients received HKR because of prior infection, and 65 received HKR for aseptic revision. A larger proportion of septic RTKA returned to the OR versus aseptic RTKA (46% vs 25%, P = 0.01). Survival curves revealed superior revision surgery-free survival favoring the aseptic group ( P = 0.002). Regression analysis revealed that HKR with concomitant flap reconstruction was associated with a three-fold increased risk of revision surgery ( P < 0.0001). DISCUSSION: HKR implantation for aseptic revision is more reliable with a lower revision surgery rate. Concomitant flap reconstruction increased the risk of revision surgery, regardless of indication for RTKA using HKR. Although surgeons must educate patients about these risk factors, HKR remains a successful treatment option for RTKA when indicated. LEVEL OF EVIDENCE: prognostic, level III evidence.

Synthetic cartilage implant hemiarthroplasty versus cheilectomy for the treatment of hallux rigidus.

Degenerative arthritis of the first metatarsophalangeal joint, hallux rigidus, is the most common type of arthritis of the foot, affecting nearly 2.5% of the population over the age of 50. Hallux rigidus can be treated surgically with either Cheilectomy or Synthetic cartilage implant (SCI) hemiarthroplasty. The purpose of this study is to compare outcomes from a single institution on the treatment of hallux rigidus using cheilectomy and SCI hemiarthroplasty. Between 2012 and 2020, 49 patients underwent either a SCI (Polyvinyl alcohol hydrogels) hemiarthroplasty or Cheilectomy for the treatment of hallux rigidus. Functional scores were assessed pre and postoperatively using the American Orthopedic Foot and Ankle scoring System (AOFAS) and the Foot and Ankle Outcome Score survey (FAOS). Plantar and Dorsal range of motion was also assessed pre and postoperatively. Outcomes, complications, and any reoperations were recorded for all patients. Mean pre-op AOFAS for Cheilectomy and SCI were 49.6 and 54.8, respectively, compared to 85.3 and 89.7, respectively, after surgery (p value < 0.05). Mean pre-op Dorsal range of motion (ROM) for Cheilectomy and SCI were 24.0 and 26.0 degrees, respectively, compared to 38.0 and 42.6 degrees, respectively, after surgery (p value < 0.05). SCI hemiarthroplasty patients had higher AOFAS and dorsal ROM at the latest follow up (p value < 0.05). Synthetic cartilage implant (SCI) hemiarthroplasty and cheilectomy both offer promising results and remain viable treatment options to decrease pain, improve function, and maintain motion for hallux rigidus. SCI hemiarthroplasty may offer superior range of motion and functional outcomes than cheilectomy for hallux rigidus. LEVEL OF CLINICAL EVIDENCE: 3.

Mini-Open Achilles Tendon Repair: Improving Outcomes While Decreasing Complications.

An acute rupture of the Achilles tendon is a traumatic injury that can cause considerable morbidity and reduced function. Nonoperative intervention may put patients at higher risk of rerupture, whereas surgical intervention carries risk of infection, wound complications, and iatrogenic nerve injury. The mini-open Achilles tendon repair technique has been popularized in helping decrease complications. The goal of this study was to examine and compare the functional outcomes and rate of complications in patients treated with a mini-open repair technique versus a traditional open repair for acute Achilles tendon ruptures. A retrospective review was performed of all patients with a complete Achilles tendon rupture that were treated by a single foot and ankle fellowship-trained surgeon. Functional outcome scores were assessed using the American Orthopaedic Foot and Ankle scoring system (AOFAS) and the Achilles Tendon Rupture Score (ATRS). Eighty-one patients with a complete Achilles tendon rupture underwent mini-open repair and 22 patients underwent traditional open repair surgery between 2013 and 2020. The mean follow-up was 38.40 months (range, 12-71). Mean preoperative AOFAS and ATRS improved in the mini-open group from 45.60 and 47.18 respectively, to 90.29 and 87.97 after surgery (p < .05). Mean preoperative AOFAS and ATRS scores for the traditional open repair (n = 22) cohort were 44.02 and 42.27, respectively. Postoperatively, the AOFAS and ATRS scores improved to 85.27 and 86.64 (P value < .05), respectively. There was no statistically significant difference in postoperative ATRS scores. However, the mini-open repair group showed a statistically higher postoperative AOFAS score (90.30) than the traditional open-repair group (85.27) (P value < .05). The overall complication rate for our study was 2.9% (2 mini-open repair and 1 traditional open repair). The complication rate in the mini-open repair group and traditional open repair cohort were 2.4% and 4.5%, respectively (P value > .05). One patient in the mini-open repair cohort (1.2%) reruptured his Achilles tendon 4 months postoperatively. A second patient in the mini-open repair group (1.2%) developed a superficial skin infection and suture irritation. One patient (4.5%) in the traditional open repair group developed a superficial skin infection. There were no sural nerve injuries in our series. The mini-open approach to repair a ruptured Achilles tendon is a viable treatment option to decrease the incidence rate of postoperative complications and rerupture rates while also producing a superior cosmetic result.Level of Evidence: 3 (retrospective cohort study N ≥ 30).

Designing Protease-Triggered Protein Cages.

Proteins that self-assemble into enclosed polyhedral cages, both naturally and by design, are garnering attention for their prospective utility in the fields of medicine and biotechnology. Notably, their potential for encapsulation and surface display are attractive for experiments that require protection and targeted delivery of cargo. The ability to control their opening or disassembly would greatly advance the development of protein nanocages into widespread molecular tools. Toward the development of protein cages that disassemble in a systematic manner and in response to biologically relevant stimuli, here we demonstrate a modular protein cage system that is opened by highly sequence-specific proteases, based on sequence insertions at strategically chosen loop positions in the protein cage subunits. We probed the generality of the approach in the context of protein cages built using the two prevailing methods of construction: genetic fusion between oligomeric components and (non-covalent) computational interface design between oligomeric components. Our results suggest that the former type of cage may be more amenable than the latter for endowing proteolytically controlled disassembly. We show that a successfully designed cage system, based on oligomeric fusion, is modular with regard to its triggering protease. One version of the cage is targeted by an asparagine protease implicated in cancer and Alzheimer's disease, whereas the second version is responsive to the blood-clotting protease, thrombin. The approach demonstrated here should guide future efforts to develop therapeutic vectors to treat disease states where protease induction or mis-regulation occurs.

Acute Pancreatitis Secondary to Newly Diagnosed Intraductal Papillary Mucinous Neoplasm.

Acute pancreatitis (AP) is a common gastrointestinal cause of hospital admissions and is prevalent in the United States. AP etiologies include alcohol use, cholelithiasis, hypertriglyceridemia, hypercalcemia, autoimmune phenomena, medications, or idiopathic. Rarely, intraductal papillary mucinous neoplasms can cause AP, as we present in this case report.

Proof of principle study of sequential combination atezolizumab and Vigil in relapsed ovarian cancer.

Vigil® is a personalized vaccine that enhances tumor neoantigen expression. We investigated for the first time safety and efficacy of Vigil in combination with atezolizumab in relapsed ovarian cancer (OC) patients. This is a randomized, Phase 1 study of Vigil, an autologous tumor tissue transfected vaccine encoding for GMCSF and bi-shRNA-furin thereby creating enhanced immune activation and TGFß expression control. Part 1 is a safety assessment of Vigil (1 × 10e7 cells/mL/21 days) plus atezolizumab (1200 mg/21 days). Part 2 is a randomized study of Vigil first (Vigil-1st) or atezolizumab first (Atezo-1st) for two cycles followed by the combination of both agents. The primary endpoint of the study was the determination of safety. Twenty-four patients were enrolled in the study; three patients to Part 1 and 21 to Part 2. Patients in Part 1 completed combination therapy without dose-limiting toxicity justifying expansion to Part 2. Twenty-one patients were randomized (1:1) to Part 2 to Vigil-1st (n = 11) or Atezo-1st (n = 10). Grade 3/4 treatment-related adverse events of Atezo-1st vs. Vigil-1st were 17.2% vs. 5.1%. Median overall survival (OS) was not reached (NR) (Vigil-1st) vs. 10.8 months (Atezo-1st) (hazard ratio [HR] 0.33). The exploratory subset analysis of BRCAwt suggested improved OS benefit [NR in Vigil-1st vs. 5.2 months in Atezo-1st, HR 0.16, p 0.027]. The Vigil-1st combination therapy with atezolizumab was safe and results in support continued investigation in BRCAwt patients.

Engineered Sphingomonas sp. KT-1 PahZ1 monomers efficiently degrade poly(aspartic acid).

In recent years, there has been an effort toward creating and utilizing novel biodegradable polymeric materials. As products become available, it is necessary to concurrently search for novel biodegradation catalysts and further investigate the properties of known biodegradation enzymes. Regarding the latter, we recently reported the crystal structure of a dimeric enzyme, Sphingomonas sp. KT-1 PahZ1, capable of degrading poly(aspartic acid), a green alternative to non-biodegradable polycarboxylates. However, the role of the dimeric state in catalytic function remained unclear. Here we report PahZ1KT-1 constructs with either single or multiple mutation(s) at the dimer interface yield active monomers. Our data indicates PahZ1KT-1 monomers and dimers catalyze PAA degradation at equivalent rates. Unfolding experiments reveal differences where the activation energy for monomers is ~ 46 kJ mol-1 lower than for dimers despite similar thermodynamic properties. Characterization of this biodegradation enzyme and others is critical for future protein engineering efforts toward polymer remediation.

From Bench to Bedside: How the Tumor Microenvironment Is Impacting the Future of Immunotherapy for Renal Cell Carcinoma.

Immunotherapy has revolutionized the treatment landscape for many cancer types. The treatment for renal cell carcinoma (RCC) has especially evolved in recent years, from cytokine-based immunotherapies to immune checkpoint inhibitors. Although clinical benefit from immunotherapy is limited to a subset of patients, many combination-based approaches have led to improved outcomes. The success of such approaches is a direct result of the tumor immunology knowledge accrued regarding the RCC microenvironment, which, while highly immunogenic, demonstrates many unique characteristics. Ongoing translational work has elucidated some of the mechanisms of response, as well as primary and secondary resistance, to immunotherapy. Here, we provide a comprehensive review of the RCC immunophenotype with a specific focus on how preclinical and clinical data are shaping the future of immunotherapy.

Combining Algorithms to Find Signatures That Predict Risk in Early-Stage Stomach Cancer.

This study applied two mathematical algorithms, lattice up-stream targeting (LUST) and D -basis, to the identification of prognostic signatures from cancer gene expression data. The LUST algorithm looks for metagenes, which are sets of genes that are either overexpressed or underexpressed in the same patients. Whereas LUST runs unsupervised by clinical data, the D -basis algorithm uses implications and association rules to relate gene expression to clinical outcomes. The D -basis selects a small subset of the metagene (a signature) to predict survival. The two algorithms, LUST and D-basis, were combined and applied to mRNA expression and clinical data from The Cancer Genome Atlas (TCGA) for 203 stage 1 and 2 stomach cancer patients. Two small (four-gene) signatures effectively predict survival in early-stage stomach cancer patients. These signatures could be used as a guide for treatment. The first signature (DU4) consists of genes that are underexpressed on the long-survival/low-risk group: FLRT2, KCNB1, MYOC, and TNXB. The second signature consists of genes that are overexpressed on the short-survival/high-risk group: ASB5, SFRP1, SMYD1, and TACR2. Another nine-gene signature (REC9) predicts recurrence: BNC2, CCDC8, DPYSL3, MOXD1, MXRA8, PRELP, SCARF2, TAGLN, and ZNF423. Each patient is assigned a score that is a linear combination of the expression levels for the genes in the signature. Scores below a selected threshold predict low-risk/long survival, whereas high scores indicate a high risk of short survival. The metagenes associate with TCGA cluster C1. Both our signatures and cluster C1 identify tumors that are genomically silent, and have a low mutation load or mutation count. Furthermore, our signatures identify tumors that are predominantly in the WHO classification of poorly cohesive and the Lauren class of diffuse samples, which have a poor prognosis.