Associations with other cancer-related biomarkers might contribute to poor outcomes in RAS-altered, younger patients with colorectal cancer.

Colorectal cancer (CRC) is a common cancer in younger adults. In patients undergoing liver resection with RAS-altered CRCs, there is evidence suggesting younger patients have worse outcomes than older patients. To explain this pattern, differences in associations between RAS status and other cancer-related biomarkers in tumors from younger versus older patients with CRC were evaluated in a cohort of 925 patients with CRC, 277 (30.0%) of whom were ≤50 years old, and 454 (49.1%) who had RAS-altered tumors. For 3 biomarkers, RNF43, APC, and microsatellite instability (MSI), the association with RAS status was significantly modified by age after adjustment for multiple testing. Specifically, younger patients with RAS-altered tumors were more likely to be MSI-high, RNF43 mutated, and APC wild type. These differences might contribute to the observed pattern of diminished survival in younger versus older patients with CRC with RAS-mutated tumors undergoing liver metastasis resection.

Phase 1 study of the safety, pharmacokinetics, and preliminary efficacy of CA102N as monotherapy and in combination with trifluridine-tipiracil in patients with locally advanced or metastatic solid tumors.

CA102N is a covalently bound conjugate of modified nimesulide (Nim) and NaHA, the sodium salt of hyaluronic acid (HA). HA is a natural ligand of cluster of differentiation 44 (CD44), which is over-expressed in colorectal cancer (CRC). CA102N is designed to deliver nimesulide directly to the tumor via the interaction of HA and CD44. A Phase 1, 2-part (dose escalation, dose expansion), non-randomized, open-label, first-in-human study of CA102N, as monotherapy and in combination with trifluridine-tipiracil, was conducted in patients with locally advanced or metastatic solid tumors. The CA102N doses evaluated were 0.36 mg/kg, 0.54 mg/kg, and 0.72 mg/kg Nim equivalent. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 as well as serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) throughout the study; secondary endpoints were pharmacodynamics parameters, objective tumor response, and urinary pharmacodynamics markers of target inhibition. Between April 2019 and October 2021, 37 patients were enrolled in 3 US centers. No DLTs were observed in Part 1, and 0.72 mg/kg Nim equivalent was the dose selected for Part 2. In total, 52 TEAEs in 18 patients were CA102N-related; 4 (in 3 patients) were ≥ Grade 3. Exploratory analysis in the dose expansion cohort revealed a median progression-free survival of 3.7 (1.0, 6.77) months. Based on this study, CA102N as monotherapy or in combination with trifluridine-tipiracil, was safe and well-tolerated at the recommended Phase 2 dose of 0.72 mg/kg Nim equivalent in patients with locally advanced or metastatic solid tumors. Preliminary evidence of antitumor activity in CRC warrants further clinical development. (ClinicalTrials.gov registration number: NCT03616574. Registration date: August 6, 2018).

Anti-angiogenesis Revisited: Combination with Immunotherapy in Solid Tumors.

PURPOSE OF REVIEW: Both anti-angiogenesis and immunotherapy are well-established therapeutic options in solid tumors. Here, we review the rationale as well as clinical evidence of combining these two approaches. RECENT FINDINGS: There is strong rationale and substantial preclinical and clinical evidence that anti-angiogenesis plays a pivotal role in overcoming immunotherapy resistance. The combination of an anti-angiogenic agent and a checkpoint inhibitor offers a more robust treatment option in many clinical trials in a wide variety of solid tumor types. Combination of anti-angiogenesis and immunotherapy has emerged as a standard of care in some tumor types and the indication is expected to expand to more tumor types in the years to come.

Liquid nitrogen spray cryotherapy for dysphagia palliation in patients with inoperable esophageal cancer.

BACKGROUND AND AIMS: Dysphagia is a debilitating symptom in patients with inoperable esophageal cancer that contributes to poor quality of life and worsening nutritional status. The 2 most commonly used palliative modalities for dysphagia are radiation therapy and esophageal stent placement. However, radiation therapy is limited by adverse events (AEs) and total dose, and stent placement has a high rate of AEs, including reflux, migration, and chest pain. A relatively new modality of liquid nitrogen endoscopic spray cryotherapy has been described as salvage when other options have been exhausted and when patients are no longer receiving systemic therapy. We evaluated the safety and efficacy of cryotherapy as the primary modality for relieving dysphagia in inoperable esophageal cancer including patients receiving systemic cancer therapy. METHODS: This is a retrospective, multicenter, consecutive case series of 49 inoperable esophageal cancer patients undergoing palliative endoscopic cryotherapy at 4 specialized cancer centers from May 2014 to May 2016. The primary outcomes were change in dysphagia scores between pre- and postcryotherapy and AEs. Dysphagia was measured using a 5-point Likert scale: 0, no dysphagia; 1, dysphagia to solids; 2, dysphagia to semisolids; 3, dysphagia to liquids; 4, dysphagia to saliva. RESULTS: Thirty-nine men and 10 women with a mean age of 58 years underwent a total of 120 cryotherapy treatments. The mean dysphagia score improved significantly from 2.4 precryotherapy to 1.7 postcryotherapy (improvement of .7 points; P < .001). Minor AEs were seen in 6 of 120 (5.0%) cryotherapy treatments (1 intraprocedural and 5 postprocedural). In addition, 1 patient developed a severe intraprocedural AE of dilation-related perforation, whereas another patient developed a benign stricture requiring dilation. CONCLUSIONS: This preliminary retrospective study suggests that liquid nitrogen spray cryotherapy may be safe and effective for dysphagia palliation in inoperable esophageal cancer. Large prospective studies are needed to confirm these findings and identify patient and procedure characteristics associated with the greatest benefit.

Comprehensive Genomic Profiling of Esthesioneuroblastoma Reveals Additional Treatment Options.

BACKGROUND: Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant neoplasm of the olfactory mucosa. Despite surgical resection combined with radiotherapy and adjuvant chemotherapy, ENB often relapses with rapid progression. Current multimodality, nontargeted therapy for relapsed ENB is of limited clinical benefit. MATERIALS AND METHODS: We queried whether comprehensive genomic profiling (CGP) of relapsed or refractory ENB can uncover genomic alterations (GA) that could identify potential targeted therapies for these patients. CGP was performed on formalin-fixed, paraffin-embedded sections from 41 consecutive clinical cases of ENBs using a hybrid-capture, adaptor ligation based next-generation sequencing assay to a mean coverage depth of 593X. The results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes (amplifications and homozygous deletions). RESULTS: Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in clinical trials. A total of 28 ENBs harbored GA, with a mean of 1.5 GA per sample. Approximately half of the ENBs (21, 51%) featured at least one CRGA, with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), with GA in PIK3CA, NF1, CDKN2A, and CDKN2C occurring in 7% of samples. CONCLUSION: We report comprehensive genomic profiles for 41 ENB tumors. CGP revealed potential new therapeutic targets, including targetable GA in the mTOR, CDK and growth factor signaling pathways, highlighting the clinical value of genomic profiling in ENB. IMPLICATIONS FOR PRACTICE: Comprehensive genomic profiling of 41 relapsed or refractory ENBs reveals recurrent alterations or classes of mutation, including amplification of tyrosine kinases encoded on chromosome 5q and mutations affecting genes in the mTOR/PI3K pathway. Approximately half of the ENBs (21, 51%) featured at least one clinically relevant genomic alteration (CRGA), with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), and alterations in PIK3CA, NF1, CDKN2A, or CDKN2C were identified in 7% of samples. Responses to treatment with the kinase inhibitors sunitinib, everolimus, and pazopanib are presented in conjunction with tumor genomics.

Novel Diagnostic and Predictive Biomarkers in Pancreatic Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for a multitude of reasons including very late diagnosis. This in part is due to the lack of understanding of the biological behavior of PDAC and the ineffective screening for this disease. Significant efforts have been dedicated to finding the appropriate serum and imaging biomarkers to help early detection and predict response to treatment of PDAC. Carbohydrate antigen 19-9 (CA 19-9) has been the most validated serum marker and has the highest positive predictive value as a stand-alone marker. When combined with carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA 125), CA 19-9 can help predict the outcome of patients to surgery and chemotherapy. A slew of novel serum markers including multimarker panels as well as genetic and epigenetic materials have potential for early detection of pancreatic cancer, although these remain to be validated in larger trials. Imaging studies may not correlate with elevated serum markers. Critical features for determining PDAC include the presence of a mass, dilated pancreatic duct, and a duct cut-off sign. Features that are indicative of early metastasis includes neurovascular bundle involvement, duodenal invasion, and greater post contrast enhancement. 18-F-fluorodeoxyglucose (18-FDG) radiotracer uptake and changes following treatment may predict patient overall survival following treatment. Similarly, pretreatment apparent diffusion coefficient (ADC) values may predict prognosis with lower ADC lesions having worse outcome. Although these markers have provided significant improvement in the care of pancreatic cancer patients, further advancements can be made with perhaps better combination of markers or discovery of unique marker(s) to pancreatic cancer.

Promising new therapies in advanced pancreatic adenocarcinomas.

Pancreatic ductal adenocarcinoma is a lethal disease due to late diagnosis, early metastasis and the lack of effective therapies. In patients with metastatic disease, 1-year survival ranges from 17 to 23% and 5-year survival is less than 5%. This necessitates an urgent need for developing more effective therapies. Targeting the neoplastic cells has been largely ineffective due to the dense stroma, which is a physical barrier for effective drug delivery and also a source for different factors that promote tumor progression and immunosuppression. In this review, we focus on understanding the complex biology of this tumor as it relates to the evaluation of previously failed molecularly targeted trials and review potential new therapies that are emerging in the treatment of metastatic pancreatic ductal adenocarcinoma.

A surprising cause of masses in the chest.

An 82-year-old male presented to the emergency department with an acute onset of chest pain and mild shortness of breath at rest. The pain in his left lower chest was pleuritic with intensity 9- on a 10-point scale. He had driven 2 h in his car that day, but had no other prolonged immobility. About 15 years previously, he was found to have increased hemoglobin (18.1 g/dL) and diagnosed with secondary erythrocytosis due to active smoking, chronic obstructive pulmonary disease (COPD), and residence in Payson, Arizona (altitude 4,999 ft). Polycythemia vera was entertained, but not pursued due to multiple secondary risks. He had been treated with daily aspirin and monthly phlebotomies to maintain a hematocrit below 45%. He also had a history of superficial thrombophlebitis, nephrolithiasis, hypertension and superficial transitional cell carcinoma of the bladder resected and in remission. There was also a deep venous thrombosis (DVT) and pulmonary embolism (PE) 13 years previously, believed to be provoked by prolonged immobility after a radical prostatectomy for prostate cancer now in remission. His medications were aspirin and lisinopril; he had no known drug allergies. He quit smoking 2 years prior after a 70 pack-year history. There was no other family history of thrombosis or bleeding disorder, autoimmune disorders, pulmonary disease or malignancy.

Methods for improving colorectal cancer annotation efficiency for artificial intelligence-observer training.

BACKGROUND: Missing occult cancer lesions accounts for the most diagnostic errors in retrospective radiology reviews as early cancer can be small or subtle, making the lesions difficult to detect. Second-observer is the most effective technique for reducing these events and can be economically implemented with the advent of artificial intelligence (AI). AIM: To achieve appropriate AI model training, a large annotated dataset is necessary to train the AI models. Our goal in this research is to compare two methods for decreasing the annotation time to establish ground truth: Skip-slice annotation and AI-initiated annotation. METHODS: We developed a 2D U-Net as an AI second observer for detecting colorectal cancer (CRC) and an ensemble of 5 differently initiated 2D U-Net for ensemble technique. Each model was trained with 51 cases of annotated CRC computed tomography of the abdomen and pelvis, tested with 7 cases, and validated with 20 cases from The Cancer Imaging Archive cases. The sensitivity, false positives per case, and estimated Dice coefficient were obtained for each method of training. We compared the two methods of annotations and the time reduction associated with the technique. The time differences were tested using Friedman's two-way analysis of variance. RESULTS: Sparse annotation significantly reduces the time for annotation particularly skipping 2 slices at a time (P < 0.001). Reduction of up to 2/3 of the annotation does not reduce AI model sensitivity or false positives per case. Although initializing human annotation with AI reduces the annotation time, the reduction is minimal, even when using an ensemble AI to decrease false positives. CONCLUSION: Our data support the sparse annotation technique as an efficient technique for reducing the time needed to establish the ground truth.

American Radium Society (ARS) Appropriate Use Criteria (AUC) for Locoregional Gastric Adenocarcinoma: Systematic Review and Guidelines.

OBJECTIVE: The objective of this study was to systematically evaluate the data regarding the use of neoadjuvant, perioperative, surgical, and adjuvant treatment options in localized gastric cancer patients and to develop Appropriate Use Criteria recommended by a panel of experts convened by the American Radium Society. METHODS: Preferred reporting items for systematic reviews and meta-analyses methodology was used to develop an extensive analysis of peer-reviewed phase 2/2R/3 trials, as well as meta-analyses found within the Ovid Medline database between 2010 and 2020. The expert panel then rated the appropriateness of various treatments in 5 representative clinical scenarios through a well-established consensus methodology (modified Delphi). RESULTS: For patients with medically operable locally advanced gastric cancer, the strongest recommendation was for perioperative chemotherapy based on high-quality data. Acceptable alternatives included surgery followed by either chemotherapy or concurrent chemoradiotherapy (CRT). For patients with upfront resection of stages I to III gastric cancer (no neoadjuvant therapy), the group strongly recommended adjuvant therapy with either chemotherapy alone or CRT, based on high-quality data. For patients with locally advanced disease who received preoperative chemotherapy without tumor regression, the group strongly recommended postoperative chemotherapy or postoperative CRT. Finally, for medically inoperable gastric cancer patients, there was moderate consensus recommending definitive concurrent CRT. CONCLUSIONS: The addition of chemotherapy and/or radiation, either in the neoadjuvant, adjuvant, or perioperative setting, results in improved survival rates for patients compared with surgery alone. For inoperable patients, definitive CRT is a reasonable treatment option, though largely palliative.

Temporal evolution of patient characteristics enrolled on phase I trials.

PURPOSE: Phase I trials serve a crucial role in anticancer drug development. Given the explosion in the number of both approved anticancer therapies and agents in development, we hypothesized that the characteristics of patients enrolling on phase I clinical trials is evolving. PATIENTS AND METHODS: We reviewed 476 published phase I trials over the past decade encompassing 15,100 patients and determined the following characteristics for patients enrolled: age; percentage with ECOG PS of 0, 1, or 2; sex; race; and number of prior chemotherapeutic therapies received: 0, 1, 2 or ≥ 3. We also identified the major tumor types enrolled: colorectal, lung, renal, breast, head/neck or "other". The change of patient characteristics over time as well as between the first half of studied period (period 1 = 1998-2001) and the second half period (period 2 = 2002-2006) was analyzed. RESULTS: Colorectal and lung cancer patients together comprise ~35% of all patients enrolled on phase I trials and this has not changed over the past decade. The contribution of "other" malignancies has however significantly increased over time. The proportion of patients with PS2 has declined while that of PS1 has increased. The proportion of patients with ≥3 prior therapies prior to study enrollment has also significantly increased. CONCLUSION: The shifting of patient characteristics especially as related to tumor types enrolled and number of prior therapies has important implications for future design of studies and inadequate attention to these issues may slow the accrual process.

An unusual presentation of hemolytic anemia in a patient with prosthetic mitral valve.

Although rare, periprosthetic valvular regurgitation can cause hemolytic anemia. We present the case of a 63-year-old man who had an unusual presentation of hemolytic anemia due to periprosthetic mitral valve regurgitation (PMVR) in the presence of cold agglutinins. Due to high surgical risk, PMVR was percutaneously closed with three Amplatzer devices under the guidance of three-dimensional transesophageal echocardiography.

Infection Masquerading as Recurrence of Pancreatic Ductal Adenocarcinoma: A Cautionary Tale.

We present a case of a 59-year-old male undergoing adjuvant chemotherapy for his pancreatic adenocarcinoma post-surgical resection. He had an acute rise in carbohydrate antigen (CA) 19-9 level, which raised suspicion of metastatic disease. Instead, the patient was diagnosed to have a liver abscess, the treatment of which brought the CA 19-9 level back to normal. Unfortunately, although CA 19-9 is Food and Drug Administration (FDA)-approved tumor marker for pancreatic cancer, it is also elevated in several benign conditions, causing fear of cancer and unnecessary diagnostic workup. Hence, caution is necessary for interpreting the significance of its elevation.

Skeletal metastases in advanced pancreatic ductal adenocarcinoma: a retrospective analysis.

BACKGROUND: Skeletal metastases (SM) in advanced pancreatic ductal adenocarcinoma (PDAC) is an infrequent occurrence that has been previously reported in literature to occur in less than 2.5% of the cases. Complications such as pathological fractures can result in intractable pain, immobilization and a significant deterioration in quality of life. The purpose of this study is to improve the understanding of the increasing incidence of SM and the importance of surveillance and adequate management of SM in these patients. METHODS: A retrospective analysis was conducted using a clinical database at a single tertiary care institution for cancer patients; this included 207 patients with advanced PDAC diagnosed between December 2004 and March 2017 receiving palliative chemotherapy. SM were identified by computerized tomography (CT)/fluorodeoxyglucose positron emission tomography (FDG-PET)/magnetic resonance imaging (MRI). Information regarding demographics, clinical course and date of last follow-up/death were collected. After a median follow-up of 11 months, an analysis was conducted, including a Kaplan-Meier survival analysis. RESULTS: The study included 207 patients; 19 out of 207 patients (9.2%) developed SM; the primary tumor was located in the pancreatic body/tail in 12 out of 19 patients (63.2%). The thoracic and lumbar vertebrae were the most common sites of SM. Other common synchronous sites of metastases included the liver and lung. A majority of the lesions were osteolytic (63.2%). The median time of diagnosis from the initial diagnosis was 2 months (range, 0-60 months). Bone pain was observed as the initial symptom in 7 out of 19 patients (36.8%), 2 out of 19 patients (10.5%) had a pathological fracture and 1 out of 19 patients (5.3%) developed a para-spinal mass causing inferior vena cava compression. The median survival period for patients with SM was 11 months (range, 0-62 months) and for those without SM was 12 months (range, 0-147 months) [hazard ratio (HR) 1.24, 95% confidence interval (CI): 0.66-2.30, P=0.51]. CONCLUSIONS: There has been a challenge with regards to management of the increasing number of patients with SM. Thoracic and lumbar vertebrae are the most common sites and pathological fractures in these sites can be catastrophic. Careful evaluation of skeletal signs and symptoms, early detection and intervention are essential to prevent morbidity and mortality from complications in patients with PDAC and SM.

When the Tumor Lyses: A Case Report on Spontaneous Tumor Lysis Syndrome.

Tumor lysis syndrome (TLS) is an oncological emergency characterized by severe electrolyte disturbance that typically occurs when hematologic cancer patients have been started on systemic chemotherapy. We present an uncommon case of spontaneous TLS (STLS) occurring in a patient with cholangiocarcinoma. The patient was a 59-year-old male with newly diagnosed differentiated carcinoma of unknown origin who presented with weakness, fatigue, and lightheadedness. Initial imaging revealed cholangiocarcinoma with innumerable pulmonary and hepatic metastases. The laboratory values showed leukocytosis, hypercalcemia, and lactic acidosis. He was diagnosed and treated for sepsis of pulmonary origin. Over the next 3 days, the patient's clinical condition steadily worsened despite aggressive treatment, with new-onset hypoxic respiratory failure, acute kidney injury, and septic shock. Chemotherapy was administered, with new laboratory values showing hyperuricemia and hyperkalemia, consistent with STLS. The patient was transferred to the ICU and emergently started on dialysis but expired a day later from multi-organ failure. To our knowledge, this is the second case of STLS in cholangiocarcinoma. Our patient was unique in that he presented with hypercalcemia and normal phosphorus levels, instead of the typical hyperphosphatemia and secondary consumptive hypocalcemia. While the exact pathophysiology of STLS is still elusive, we believe that the patient's initial sepsis-induced hypotension, aggressively enlarging tumor, and extent of metastasis all contributed to his rapid decline. Given the high mortality rate with TLS and its vague presentation, particularly in a chemotherapy-naïve solid tumor, a high level of clinical suspicion is needed to improve patients' outcome.

Chemotherapy re-challenge response rate in metastatic colorectal cancer.

BACKGROUND: There are few treatment options in metastatic colorectal cancer (mCRC) after progression on standard chemotherapy. Third and fourth line therapies typically consist of regorafenib or trifluridine-tipiracil, however, clinical benefit of these medications is limited, as progression free survival is approximately 1.9 months for regorafenib (Grothey et al. 2013) and 2.0 months for trifluridine-tipiracil (Mayer et al. 2015). Another choice in this setting may include the re-initiation of previously used chemotherapy, therefore in this study we assessed the efficacy and tolerability of chemotherapy re-challenge. METHODS: This was a retrospective, cohort study assessing patients with mCRC who were 18-89 years of age and treated with re-challenge chemotherapy. Re-challenge chemotherapy was defined as re-initiation of oxaliplatin or irinotecan-based regimens at least nine months from the end of initial exposure. A minimum of four chemotherapy cycles was required to qualify as initial exposure. The key endpoints of this study were clinical benefit rate (CBR), defined as the proportion of patients with partial response or stable disease, and time to progression (TTP). RESULTS: A total of 67 chemotherapy re-challenges were accounted for in 51 patients. The overall CBR was 70.7%. Partial responses occurred in 50.7% cases. The TTP was 6.0 months. For the 51 cases of first re-challenge, the CBR was 75.5% and TTP was 6.5 months. Fourteen patients had a second re-challenge, and in these patients, the CBR was 61.5% and TTP was 4.1 months. CONCLUSIONS: Oxaliplatin or irinotecan-based re-challenge should be considered as a third or fourth line treatment option in select patients with mCRC. CBR and especially TTP compare favorably to approved third line therapies such as regorafenib or trifluridine-tipiracil.

Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration-approved targeted therapy in advanced melanoma.

Approximately 50% of melanomas harbor an activating BRAF mutation. Combined BRAF and MEK inhibitors such as dabrafenib and trametinib, vemurafenib and cobimetinib, and encorafenib and binimetinib are US Food and Drug Administration (FDA)-approved to treat patients with BRAF V600-mutated advanced melanoma. Both genetic and epigenetic alterations play a major role in resistance to BRAF inhibitors by reactivation of the MAPK and/or the PI3K-Akt pathways. The role of BRAF inhibitors in modulating the immunomicroenvironment and perhaps enhancing the efficacy of checkpoint inhibitors is gaining interest. This article provides a comprehensive review of mechanisms of resistance to BRAF and MEK inhibitors in melanoma and summarizes landmark trials that led to the FDA approval of BRAF and MEK inhibitors in metastatic melanoma.

Complete remission of metastatic carcinoma of the prostate with bicalutamide withdrawal.

An 83-year-old man was diagnosed with stage 4 prostate cancer with a Gleason score of 7 (3+4). His initial prostate-specific antigen (PSA) level was 965 ng/dL, and he demonstrated extensive metastatic disease of the thoracic spine. After an initial response to monthly leuprolide injections, his PSA level began to increase and bicalutamide was added. An initial decrease in his PSA level was observed; however, the level gradually rose to 212 ng/dL and bicalutamide was discontinued. Three months later, his PSA level was <0.05 ng/dL and has remained <1 ng/dL for the past 27 months. Bicalutamide withdrawal usually leads to transient remission, with PSA level dropping to approximately 50% of the initial level. The duration of the remission is usually limited to approximately 6 months. However, the sustained response that was observed in our patient suggests that a trial of androgen withdrawal, even in the setting of rising PSA levels, might be reasonable before initiating more toxic therapies.

Recurrent bronchial epithelial-myoepithelial carcinoma after local therapy.

We present a rare case of recurrent multiple lesions of bronchial epithelial-myoepithelial carcinoma in a 74-year-old man treated with local resection. Two cellular types were found: epithelial cells and myoepithelial cells. The patient remains asymptomatic at 4-years of follow-up, supporting the fact that epithelial-myoepithelial carcinoma is a tumor of low-grade malignancy.