Margin marking before colorectal endoscopic mucosal resection and its impact on neoplasia recurrence (with video).

BACKGROUND AND AIMS: Ablation of resection margins after EMR of large nonpedunculated colorectal polyps decreases recurrence. Margin marking before EMR (EMR-MM) may represent an alternative method to achieve a healthy resection margin. We aimed to determine the efficacy of EMR-MM in reducing neoplasia recurrence. METHODS: We conducted a single-center historical control study of EMR cases (EMR-MM vs conventional EMR) for nonpedunculated polyps ≥20 mm between 2016 and 2021. For EMR-MM, cautery marks were placed along the lateral margins of the polyp with the snare tip. EMR was then performed to include resection of the healthy mucosa containing the marks. We compared recurrence at surveillance colonoscopy after EMR-MM versus historical control subjects. Multivariable logistic regression was performed to identify factors associated with recurrence. RESULTS: Two hundred ten patients with 210 polyps (median size, 30 mm; interquartile range: 25-40) underwent EMR-MM (n = 74) or conventional EMR (n = 136). Patient and lesion characteristics were similar between the groups. At a median follow-up of 6 months, the recurrence rate was lower with EMR-MM (6/74; 8%) compared with historical control subjects (39/136; 29%) (P < .001). EMR-MM was not associated with an increased rate of adverse events. On multivariable analysis, EMR-MM remained the strongest predictor of recurrence (odds ratio, .20; 95% confidence interval, .13-.64; P = .003) aside from polyp size (odds ratio, 2.81; 95% confidence interval, 1.35-6.01; P = .008). CONCLUSIONS: In this single-center historical control study, EMR-MM of large nonpedunculated colorectal polyps reduced the recurrence risk by 80% when compared with conventional EMR. This simple technique may provide an alternative to margin ablation.

Advances in targeted therapy for acute myeloid leukemia.

Acute myeloid leukemia (AML) is a clonal malignancy characterized by genetic heterogeneity due to recurrent gene mutations. Treatment with cytotoxic chemotherapy has been the standard of care for more than half of a century. Although much progress has been made toward improving treatment related mortality rate in the past few decades, long term overall survival has stagnated. Exciting developments of gene mutation-targeted therapeutic agents are now changing the landscape in AML treatment. New agents offer more clinical options for patients and also confer a more promising outcome. Since Midostaurin, a FLT3 inhibitor, was first approved by US FDA in 2017 as the first gene mutation-targeted therapeutic agent, an array of new gene mutation-targeted agents are now available for AML treatment. In this review, we will summarize the recent advances in gene mutation-targeted therapies for patients with AML.

Effect of referral pattern and histopathology grade on surgery for nonmalignant colorectal polyps.

BACKGROUND AND AIMS: The incidence of surgery for nonmalignant colorectal polyps is rising. The aims of this study were to evaluate referral patterns to surgery for nonmalignant polyps, to compare outcomes between surgery and endoscopic resection (ER), and to identify factors associated with surgery in a university-based, tertiary care center. METHODS: Patients referred to colorectal surgery (CRS) for nonmalignant colorectal polyps between 2014 and 2019 were selected from the institution's integrated data repository. Clinical characteristics were obtained through chart review. Multivariate analysis was performed to identify factors associated with surgery for nonmalignant polyps. RESULTS: Six hundred sixty-four patients with colorectal lesions were referred to CRS, of which 315 were for nonmalignant polyps. Most referrals (69%) came from gastroenterologists. Of the 315 cases, 136 underwent surgery and 117 were referred for attempt at ER. Complete ER was achieved in 87.2% (n = 102), with polyp recurrence in 27.2% at a median of 14 months (range, 0-72). When compared with surgery, ER was associated with a lower hospitalization rate (22.2% vs 95.6%; P < .0001), shorter hospital stay (mean, .5 ± .9 vs 2.23 ± 1 days; P < .0001), and fewer adverse events (5.9% vs 22.8%; P = .0002). Intramucosal adenocarcinoma on baseline pathology (odds ratio, 5.7; 95% confidence interval, 1.2-28.2) and referrals by academic gastroenterologists (odds ratio, 2.5; 95% confidence interval, 1.11-5.72) were associated with a higher likelihood of surgery on multivariate analysis. CONCLUSIONS: Gastroenterologists commonly refer nonmalignant colorectal polyps to surgery, even though ER is effective and associated with lower morbidity. Both referrals from academic gastroenterologists and baseline pathology of intramucosal adenocarcinoma were factors associated with surgery. All colorectal polyps should be evaluated in a multidisciplinary approach to identify lesions suitable for ER before embarking in surgery.

Merkel Cell Carcinoma Clinically Mimicking a Traumatic Suture Scar in the Nasal Vestibule: Earlier Diagnosis for Better Prognosis.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive form of skin cancer that is often found in sun-exposed regions of the skin in older or immunocompromised individuals. To date there have only been four cases reported of MCC found in the nasal vestibule. CASE REPORT: We document an unusual case of MCC in the nasal vestibule of a 66-year-old female which was clinically believed to be an inflammatory reaction to a previous suture scar. The patient also had a history of dermatitis treated with UV light. The lesion was less than 5 mm in the greatest dimension and biopsied. There was small blue cell infiltrate in the dermis and the tumor cells were positive for synaptophysin, chromogranin and cytokeratin 20. They were negative for S100 proteins, melan A, human melanoma black 45 (HMB45) and lymphocyte common antigen CD45. For Ki-67, staining was positive in 90% of the tumor cells and tumor protein 53 immunoreactivity showed a wild type staining pattern. The pathological diagnosis was MCC and the patient underwent Mohs surgery with no tumor recurrence or metastasis identified at 2.5 years of follow-up. CONCLUSION: To the best of our knowledge, cases of MCC arising in the nasal vestibule with clinical features mimicking a suture scar have not been reported. The importance of early diagnosis and treatment of MCC to improve patient prognosis are discussed.

Gastric Perivascular Epithelioid Cell Tumor (PEComa).

OBJECTIVES: To review the clinicopathologic, immunophenotypic, and molecular features of gastric perivascular epithelioid cell tumor (PEComa). METHODS: We identified two new cases of gastric PEComa and summarized the clinical and pathologic characteristics of this rare neoplasm. RESULTS: The first case was a 48-year-old woman who was treated with an endoscopic submucosal dissection (ESD), and the second case was a 64-year-old man who received a distal gastrectomy. Microscopic examination showed one tumor was composed of purely epithelioid cells, while the other was composed of epithelioid and spindle cells. Both tumors were immunoreactive for melanocytic markers (HMB45 and Melan-A), smooth muscle actin, and vimentin. No TFE3 gene rearrangement was identified by fluorescence in situ hybridization in either case. CONCLUSIONS: Gastric PEComa is an exceedingly rare neoplasm, with only seven other reported cases to date. We are the first to report the results of molecular assays for the TFE3 gene rearrangement associated with gastric PEComa.

Phase Ib with expansion study of olaparib plus weekly (Metronomic) carboplatin and paclitaxel in relapsed ovarian cancer patients.

OBJECTIVE: Our goals were to: establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer; evaluate dose-limiting toxicities; and evaluate efficacy at the maximum tolerated dose. METHODS: In this open-label, single-arm, investigator-initiated trial (ClinicalTrials.gov NCT01650376), patients with high-grade serous ovarian cancer who failed primary platinum and taxane therapy received oral olaparib tablets twice daily days 1-3 each week combined with fixed-dose metronomic carboplatin AUC2 and paclitaxel 60 mg/m2 weekly for 3 out of 4 weeks. A 3 × 3 design was used to determine the olaparib maximum tolerated dose. Combination therapy continued until disease progression, but patients with partial or complete response were transitioned to olaparib maintenance therapy. All patients were included in the analysis. RESULTS: The maximum tolerated dose of olaparib tablets was 150 mg twice daily with metronomic carboplatin and paclitaxel. 54 women were enrolled, 14 in phase Ib and 40 in the expansion phase. The median number of prior therapeutic regimens was 3. Response included 13 complete remission (24%) and 16 partial remission (30%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for an overall response rate of 54% (95% CI 40% to 67%). Of 47 patients who underwent BRCA testing, 23 were BRCA mutation (BRCAm) and 24 B RCA wild type (BRCAwt). Progression-free survival for BRCAm was 12.1 months versus 4.8 for BRCAwt (p=0.0001). Median overall survival for BRCAm was 24.1 months versus 10.4 months for BRCAwt (p=0.02). 42 patients (78%) experienced grade 3-4 toxicities with combination therapy; the most common were hematologic. There were no treatment related deaths. Among 14 patients who received maintenance therapy, 7 experienced grade 1-2 non-hematologic toxicities. CONCLUSIONS: Olaparib 150 mg tablet twice daily can be safely administered in combination with metronomic carboplatin and paclitaxel in pre-treated relapsed ovarian cancer with 24% complete remission. BRCAm patients had statistically significant longer progression-free survival and overall survival than BRCAwt. TRIAL REGISTRATION NUMBER: NCT01650376.

Synchronous Laryngeal Squamous Cell Carcinoma and Intrahepatic Cholangiocarcinoma Present in an Obese Male with Poor Prognosis.

Concurrent laryngeal squamous cell carcinoma and intrahepatic cholangiocarcinoma is rare and no prior report has been found through a PubMed search. Here we report such a case of a 51-year old obese male presenting with hoarseness and trouble swallowing for 2 to 3 months. Imaging findings of computer tomography (CT) and magnetic resonance imaging (MRI) with and without contrast were suspicious for a T3N2 supraglottic laryngeal cancer. Laryngeal biopsy showed a well differentiated squamous cell carcinoma (SCC). As part of the evaluation of the laryngeal SCC, MRI abdomen showed an enhancing mass (4.6 cm in the greatest dimension) with diffusion restriction and capsular retraction in the right lobe of the liver. Ultrasound-guided percutaneous biopsy of the liver revealed a moderately differentiated adenocarcinoma, that was strongly and diffusely positive for CK7 and CK19, weakly positive for CDX2, and negative for HepPar 1, glypican 3, CK20, PSA and TTF1. The immunohistochemistry profile was consistent with cholangiocarcinoma. This is a unique case of laryngeal squamous cell carcinoma with concurrent cholangiocarcinoma. The prognosis was poor and the patient was placed in hospice care in two months after the diagnoses. To the best of our knowledge, this is the first documented case of synchronous laryngeal squamous cell carcinoma and intrahepatic cholangiocarcinoma. The pathogenesis, diagnosis and treatment of the diseases are discussed.

The KDM2B- let-7b -EZH2 axis in myelodysplastic syndromes as a target for combined epigenetic therapy.

Both DNA and histone methylation are dysregulated in the myelodysplastic syndromes (MDS). Based on preliminary data we hypothesized that dysregulated interactions of KDM2B, let-7b and EZH2 signals lead to an aberrant epigenetic landscape. Gene expression in CD34+ cells from MDS marrows was analyzed by NanoString miR array and validated by real-time polymerase chain reaction (PCR). The functions of KDM2B, let-7b and EZH2 were characterized in myeloid cell lines and in primary MDS cells. Let-7b levels were significantly higher, and KDM2B and EZH2 expression was lower in primary CD34+ MDS marrow cells (n = 44) than in healthy controls (n = 21; p<0.013, and p<0.0001, respectively). Overexpression of let-7b reduced EZH2 and KDM2B protein levels, and decreased cells in S-phase while increasing G0/G1 cells (p = 0.0005), accompanied by decreased H3K27me3 and cyclin D1. Silencing of KDM2B increased let-7b expression. Treatment with the cyclopentanyl analog of 3-deazaadenosine, DZNep, combined with the DNA hypomethylating agent 5-azacitidine, decreased levels of EZH2, suppressed methylation of di- and tri-methylated H3K27, and increased p16 expression, associated with cell proliferation. Thus, KDM2B, via let-7b/EZH2, promotes transcriptional repression. DZNep bypassed the inhibitory KDM2B/let-7b/EZH2 axis by preventing H3K27 methylation and reducing cell proliferation. DZNep might be able to enhance the therapeutic effects of DNA hypomethylating agents such as 5-azacitidine, currently considered standard therapy for patients with MDS.

Long-term dynamics of bone mineral density during intermittent androgen deprivation for men with nonmetastatic, hormone-sensitive prostate cancer.

PURPOSE: To investigate changes in bone mineral density (BMD) and fracture risk in men who received intermittent androgen deprivation (IAD) for nonmetastatic, hormone-sensitive prostate cancer. PATIENTS AND METHODS: Men with prostate cancer who lacked radiographically detectable metastases were treated in a prospective trial of IAD. After 9 months of treatment with leuprolide and flutamide, androgen deprivation therapy (ADT) was stopped until prostate-specific antigen reached a threshold (1 ng/mL for radical prostatectomy; 4 ng/mL for radiation or primary ADT) for a new cycle. Dual-energy x-ray absorptiometry (DXA) scans were performed before starting ADT and subsequently with each change in therapy. At least two consecutive DXA scans were required for this analysis. Computed tomography, bone scintigraphy, and lumbar spine x-rays were performed at the beginning and end of each treatment period. RESULTS: Fifty-six of 100 patients met criteria for this analysis. The median age at study entry was 64.5 years (range, 49.8 to 80.9 years). The average percentage change in BMD during the first on-treatment period was -3.4% (P < .001) for the spine and -1.2% (P = .001) for the left hip. During the first off-treatment period (median, 37.4 weeks; range, 13.4 weeks to 8.7+ years), BMD recovery at the spine was significant, with an average percentage change of +1.4% (P = .002). Subsequent periods had heterogeneous changes of BMD without significant average changes. After a median of 5.5 years (range, 1.1 to 13.8+) years on trial, one patient (1.8%) had a compression fracture associated with trauma. CONCLUSION: Patients experienced the greatest average change in BMD during early treatment periods of IAD with a smaller average change thereafter. Fractures were rare.

Randomized phase 2b study of pralatrexate versus erlotinib in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) after failure of prior platinum-based therapy.

INTRODUCTION: Pralatrexate, a folate analogue targeting dihydrofolate reductase, has antitumor activity in non-small-cell lung cancer (NSCLC). This randomized phase 2b trial was designed to further evaluate pralatrexate activity in NSCLC by estimating overall survival (OS) relative to erlotinib in patients with relapsed/refractory disease. METHODS: In 43 centers across 6 countries, patients were randomized 1:1 to receive intravenous pralatrexate 190 mg/m on days 1 and 15 of a 28-day cycle, or oral erlotinib 150 mg/day. The primary objective was to estimate OS in all patients and prespecified subgroups using relative comparisons of hazard ratios (HRs). Secondary endpoints included progression-free survival, response rate, and safety. Key eligibility criteria included: (1) ≥1 prior platinum-based therapy, (2) Eastern Cooperative Oncology Group performance status of 0 to 1, and 3) a smoking history of 100 cigarettes or more. RESULTS: A total of 201 patients were randomized. A trend toward improvement in OS favoring pralatrexate was observed with an HR of 0.84 (95% confidence interval: 0.61-1.14) in the intent-to-treat population. This favorable survival result was seen in most prespecified subgroups for pralatrexate. The largest reduction in the risk of death was observed in patients with nonsquamous cell carcinoma (n = 107; HR = 0.65; 95% confidence interval: 0.42-1.0). The most common grade 3 to 4 adverse event in the pralatrexate arm was mucositis (23%). Discontinuation of pralatrexate for any grade of mucositis was 21%. CONCLUSIONS: Pralatrexate demonstrated a trend toward improved survival relative to erlotinib in patients with advanced NSCLC. Future studies should include a mucositis management plan to improve tolerability and maximize treatment benefit.

Duration of first off-treatment interval is prognostic for time to castration resistance and death in men with biochemical relapse of prostate cancer treated on a prospective trial of intermittent androgen deprivation.

PURPOSE: This was an exploratory analysis of a trial of intermittent androgen deprivation (IAD) in men with biochemical relapse (BR) to establish first cycle characteristics prognostic for progression to castration-resistant prostate cancer (CRPC) and death. PATIENTS AND METHODS: Men with BR of prostate cancer after radical prostatectomy (RP) or radiation (RT) were treated with androgen deprivation therapy (ADT) comprised of leuprolide and flutamide. After 9 months on treatment, ADT was stopped, and monthly prostate-specific antigen (PSA) levels were observed during the off-treatment interval. When the PSA reached a threshold value (1 ng/mL for RP, 4 ng/mL for RT), ADT was resumed in a new cycle. Patients were treated intermittently in this manner until CRPC, which was defined as > or = two consecutive increasing PSA values while on ADT with castrate testosterone levels. RESULTS: Seventy-two of 100 patients enrolled onto the study met criteria for this analysis. The duration of the first off-treatment interval (< or = v > 40 weeks) was associated with shorter time to CRPC (hazard ratio = 2.9; 95% CI, 1.1 to 7.7; P = .03) and death (hazard ratio = 3.8; 95% CI, 1.1 to 13.6; P = .04) after adjusting for age, stage, grade, and PSA at diagnosis. CONCLUSION: In patients who completed the first cycle of IAD, a duration of the first off-treatment interval of < or = 40 weeks defines a subset of patients at higher risk of CRPC and death. Conversely, patients with an off-treatment interval of more than 40 weeks have a significantly better long-term prognosis.

Early versus delayed feeding after placement of a percutaneous endoscopic gastrostomy: a meta-analysis.

BACKGROUND: Traditionally, tube feedings have been delayed after percutaneous endoscopic gastrostomy (PEG) placement to the next day and up to 24 h postprocedure. However, results from various randomized controlled trials (RCTs) indicate earlier feeding may be an option. We conducted a meta-analysis to analyze the effect of early feedings (< or = 4 h) after PEG placement. METHODS: Multiple databases were searched (November 2007). Only RCTs on adult subjects that compared early (< or = 4 h) versus delayed or next-day feedings after PEG placement were included. Meta-analyses for the effect of early and delayed feedings were analyzed by calculating pooled estimates of complications, death < or = 72 h, and significant increases in postprocedural gastric residual volume during day 1. RESULTS: Six studies (N = 467) met the inclusion criteria. No statistically significant differences were noted between early (< or = 4 h) and delayed or next-day feedings for patient complications (OR 0.86, 95% CI 0.47-1.58, P = 0.63) or death in < or = 72 h (OR 0.56, 95% CI 0.18-1.74, P = 0.31). A statistically significant increase in gastric residual volumes during day 1 was noted (OR 1.80, 95% CI 1.02-3.19, P = 0.04). CONCLUSIONS: Early feeding < or = 4 h after PEG placement may represent a safe alternative to delayed or next-day feedings. Although an increase in significant gastric residual volumes at day 1 was noted, overall complications were not affected.

Retrospective review of cancer patients > or =80 years old treated with chemotherapy at a comprehensive cancer center.

CONTEXT: The percentage of cancer patients > or =80 years old is expected to increase in the next few years. However data on the use of chemotherapy in these patients are limited. OBJECTIVE: We conducted a retrospective review to define the profile of patients > or =80 years old who received chemotherapy at our center and assess their survival. DESIGN, SETTING AND PARTICIPANTS: Patients > or =80 years treated with chemotherapy between 1 January 2000 and 31 December 2004 were included in this analysis. RESULTS: Of the 4689 patients treated with chemotherapy over the 5-year period, 133 patients (3%) were > or =80 years old. The median age was 83 years. 61% were females and 39% were males. 16% had hematologic tumors and 84% had solid tumors. Gynecological (32%) and aerodigestive cancers (27%) were the most common sites and lung cancer (22%) was the most common cancer. During the first regimen, 512 cycles of chemotherapy were delivered with a median of 3 cycles (range: 1-24 cycles). 49% received single and 51% multidrug regimens. Carboplatin was the most common single agent and carboplatin and paclitaxel was the most common combination among solid tumor patients. 19% of solid tumor patients received radiation with chemotherapy. The 1-year survival among hematologic cancer and solid tumor patients was 65% and 48%, respectively. Stage of disease was the only statistically significant factor predicting survival. CONCLUSIONS: In cancer patients > or =80 years old selected for chemotherapy, both single and multi-agent therapy appeared to be feasible.

Hematologic responses of patients with MDS to antithymocyte globulin plus etanercept correlate with improved flow scores of marrow cells.

Myelodysplastic syndrome (MDS) comprises a spectrum of heterogeneous diseases. Most patients present with ineffective hematopoiesis. The pathophysiology involves immune-mediated effects, cytokine dysregulation, and apoptosis, among others. We treated 14 transfusion-requiring patients with MDS, 10 with refractory anemia (RA) and four with RA with excess blasts (RAEB) with a 4-day course of antithymocyte globulin (ATG) followed by intermittent etanercept for 4 months. Among 13 evaluable patients, five are red blood cell and platelet transfusion independent for intervals extending beyond 2 years, and two have normalized their peripheral blood parameters. One additional patient showed a transient rise of platelet and neutrophil counts, for an overall response rate of 46%. Responding patients showed striking improvements in marrow cell abnormalities as characterized by flow cytometry. These data show that a combination of ATG plus etanercept offers effective palliative therapy for unselected patients with MDS. Further trials incorporating these two agents are warranted.