Clinicopathologic and prognostic features of TdT-negative pediatric B-lymphoblastic leukemia.

Little is known about B-lymphoblastic leukemia (B-ALL) that lacks expression of terminal deoxynucleotidyl transferase (TdT). To address this, we performed the largest study to date of TdT-negative B-ALL using data from St. Jude Total XV and XVI clinical trials. Compared to TdT-positive B-ALL (n = 896), TdT-negative B-ALL (n = 21) was associated with younger age (median, 1.4 versus 6.8 years, P < 0.001), higher white blood cell count (median, 52.8 versus 9.9 × 109/L, P < 0.001), absence of hyperdiploidy (0 versus 27.8%, P = 0.002), KMT2A rearrangement (100 versus 1.9%, P < 0.001), and inferior 5-year event-free survival (EFS) (76.2 versus 90.3%, P = 0.047). In the context of KMT2A-rearranged B-ALL (n = 38), TdT-negativity was significantly associated with the MLLT1 rearrangement partner (P = 0.026) but was not independently predictive of survival, suggesting that the high-risk features of TdT-negative B-ALL are secondary to underlying KMT2A rearrangements. Finally, we compared the sensitivity of TdT-negativity to neuron-glial antigen 2 (NG.2) expression for the detection of KMT2A rearrangements and found that 63% of KMT2A-rearranged B-ALL cases not identified by NG.2 were TdT-negative. The results of this study expand the spectrum of immunophenotypic features that are specific for high-risk KMT2A rearrangements in pediatric B-ALL and can be readily implemented using existing standard acute leukemia flow cytometry panels.

Interleukin-2, Ipilimumab, and Anti-PD-1: clinical management and the evolving role of immunotherapy for the treatment of patients with metastatic melanoma.

Treatment of metastatic melanoma has changed dramatically in the past 5 years with the approval of six new agents (vemurafenib, dabrafenib, trametinib, ipilimumab, pembrolizumab, and nivolumab) by the US Food and Drug Administration (FDA). This review will compare the immunotherapies recently approved by the FDA (ipilimumab, nivolumab and pembrolizumab) with the long-approved immunotherapy, interleukin-2. Additional consideration will be given to the evolving landscape, including the opportunities for combination regimens. Immunotherapies have distinct mechanisms of action and unique response kinetics that differ from conventional cytotoxic and targeted therapies, and have a range of adverse events that can be safely managed by experienced health-care providers. Data suggest immunotherapies can result in long-term survival in a proportion of patients. This dynamic and evolving field of immunotherapy for melanoma will continue to offer challenges in terms of optimal patient management for the foreseeable future.

Peripheral blood flow cytometry for the diagnosis of pediatric acute leukemia: Highly reliable with rare exceptions.

BACKGROUND: Recent data have demonstrated the high sensitivity and specificity of peripheral blood flow cytometry (PBFC) for the diagnosis of pediatric leukemia; however, diagnostically significant immunophenotypic discrepancies between PBFC and bone marrow (BM) evaluation, which result in different lineage assignment and treatment protocols, can rarely occur. Here, we sought to further characterize the performance of PBFC for pediatric leukemia and highlight the exceptions when PBFC can result in misdiagnosis. METHODS: An institutional database was searched between 2012 and 2016 for cases of acute leukemia with concurrent PBFC and BM evaluation. Immunophenotyping results from the peripheral blood and BM using four or eight color flow cytometry, as well as BM cytochemical staining and immunohistochemistry, were compared. RESULTS: Two hundred ninety PBFC samples with concurrent BM evaluation were identified. Based on the final immunophenotypic classification, the cases were distributed as follows: 108 B-lymphoblastic leukemia (B-ALL), 57 T-lymphoblastic leukemia (T-ALL), 116 acute myeloid leukemia (AML), and 9 mixed-phenotype acute leukemia (MPAL). Among all cases, five had a diagnostically significant discrepancy between PBFC and BM evaluation. In three cases, the immunophenotype by PBFC was consistent with early T-cell precursor ALL (ETP-ALL), whereas BM evaluation demonstrated MPAL. Two cases were suspicious for acute megakaryoblastic leukemia (AMKL) and MPAL, T/myeloid by PBFC but were diagnosed as B-ALL and T-ALL in the BM. CONCLUSION: Immunophenotypic classification by PBFC is accurate (>98%) in almost all cases of pediatric leukemia with the rare exceptions of suspected ETP-ALL, MPAL, and AMKL. These PBFC diagnoses should be confirmed with BM immunophenotyping.

The Comparative Sensitivity of Immunohistochemical Markers of Megakaryocytic Differentiation in Acute Megakaryoblastic Leukemia.

OBJECTIVES: Immunohistochemistry (IHC) staining of core biopsy sections often plays an essential role in the diagnosis of acute megakaryoblastic leukemia (AMKL). The goal of this study was to define the relative sensitivities of commonly used stains for markers of megakaryocytic differentiation. METHODS: The sensitivities of IHC stains for CD42b, CD61, and von Willebrand factor (vWF) were compared in 32 cases of pediatric AMKL. RESULTS: The sensitivities of CD42b, CD61, and vWF were 90.6%, 78.1% and 62.5%, respectively. When CD42b and CD61 were used together, the combined sensitivity increased to 93.6%. There were no cases in which vWF was positive when both CD42b and CD61 were negative. CONCLUSIONS: CD42b can reliably be used as a solitary first-line marker for blasts of megakaryocytic lineage, whereas CD61 may be reserved for infrequent cases that are CD42b negative. There is no role for the routine use of vWF when CD42b and CD61 are available.

Recurrent Cytogenetic Abnormalities in Intravascular Large B-Cell Lymphoma.

OBJECTIVES: Data characterizing the cytogenetic landscape of intravascular large B-cell lymphoma (ILBCL) are limited. Here, we developed a comprehensive karyotypic data set to identify recurrent cytogenetic abnormalities in ILBCL. METHODS: Cases of ILBCL with complete cytogenetic analysis were identified from an institutional database and the literature. The combined data were systematically reviewed for the presence of recurrent abnormalities. RESULTS: Four new cases were identified and combined with 25 karyotypes previously published in the literature. Karyotypes were uniformly complex with a median of 10 aberrations. In total, 72.4% had abnormalities involving chromosome 1, with 31.0% involving rearrangements of 1p13 or 1q21; 58.6% had abnormalities involving chromosome 6, which in almost all cases involved 6q; 34.5% had abnormalities involving chromosome 14, with 27.6% involving rearrangements of 14q32; and 55.2% had abnormalities of chromosome 18, with 37.9% harboring trisomy 18. CONCLUSIONS: Recurrent cytogenetic abnormalities involving chromosomes 1, 6q, and 18 are present in greater than 50% of ILBCL.

Prostatic adenocarcinoma oncocytic variant: Case report and literature review.

The oncocytic variant of prostatic adenocarcinoma is exceptionally rare with only 4 cases reported in the English literature. Little is known about the clinical behavior of this variant of prostatic adenocarcinoma, because of the exceptionally low number of reported cases. The 2016 World Health Organization Classification of Tumors of Prostate does not recognize the oncocytic variant, again likely related to the exceptional paucity of reported cases. Here, we report the fifth case of the oncocytic variant of acinar type prostatic adenocarcinoma in an asymptomatic 64-year-old Caucasian American male with elevated serum prostate specific antigen (7.33 ng/mL; normal range 0-4.00 ng/mL) during routine blood screening for diabetes mellitus. At subsequent transrectal prostate biopsy, the right side of prostate was infiltrated by adenocarcinoma with tumor cells forming variably differentiated glands, including some poorly differentiated. Tumor cell nuclear:cytoplasmic ratio was low, with small to intermediate sized vesicular nuclei and only rare discernable small nucleoli. Cellular cytoplasm was characteristically granular pink with sharply defined cell membranes. Positive AMACR (P504S) epithelial immunohistochemical staining and absence of staining for prostatic basal cells confirmed the tumor to be primary prostatic adenocarcinoma. AMACR immunohistochemical staining was also helpful with accurate grading of the tumor due to the difficulty of differentiating tumor cells from residual prostate myocytes at routine hematoxylin and eosin (HE) staining. This new case adds to the exceptionally small number of previously reported cases of the oncocytic variant of primary prostatic adenocarcinoma. It also highlights the difficulty associated with Gleason scoring of the oncocytic variant by routine HE evaluation and the usefulness of AMACR (P504S) immunostaining for accurate grading of prostatic adenocarcinoma in the oncocytic variant.

Four Synchronous Primary Malignancies of the Breast, Lung, Colon and Esophagus.

The literature contains few reports of patients with four more or more synchronous primary malignancies. We report the case of a 74-year-old woman who presented with synchronous primary malignant neoplasms of the breast (metaplastic carcinoma), lung (squamous cell carcinoma), esophagus (adenocarcinoma), and colon (adenocarcinoma). She was treated with multimodality therapy and demonstrated a favorable response at early follow-up. To our knowledge, this combination of synchronous primary malignancies has not been previously reported. The management of patients with multiple synchronous primary malignancies introduces a number of unique challenges which necessitate highly individualized treatment plans that may not strictly adhere to standard practices in the setting of a single malignancy.

Continuity of care in general surgery resident education.

BACKGROUND: Lack of continuity of care for patients managed by general surgery residents is a commonly recognized problem but objective data evaluating its incidence are limited. The goal of this pilot study was to determine the extent to which senior residents at a large American urban academic center participate in the full course of care for patients on whom they operate. METHODS: Two hundred twenty-eight total cases performed between January 1, 2012 and December 31, 2012 were reviewed and the operative senior resident was noted: laparoscopic cholecystectomy (n = 50), breast lumpectomy (n = 33), thyroidectomy (n = 50), laparoscopic appendectomy (n = 50), and open partial colectomy (n = 45). Frequency of operative resident involvement in the initial preoperative clinic visit, initial postoperative visit, or both (the entire course of care) was recorded. RESULTS: Overall rate of operative resident involvement was 9.2% for the initial preoperative consultation, 9.0% for the initial follow-up visit, and 0% for the entire course of a patient's care. Residents were on service for greater than 40 days, whereas the average total duration of care for an individual patient was 26 days. CONCLUSIONS: The results of this pilot study suggest that continuity of care among general surgery residents is lacking and cannot be entirely accounted for by rotation-specific time constraints. Further research is needed to identify and validate effective curricular strategies for improving opportunities to participate in this essential experience.

The prognostic significance of stable disease following high-dose interleukin-2 (IL-2) treatment in patients with metastatic melanoma and renal cell carcinoma.

High-dose interleukin-2 (HD IL-2) is an approved immunotherapy agent for metastatic melanoma and renal cell carcinoma resulting in objective responses in 15-20 % of patients. An additional subset of patients achieves stable disease, and the natural history of these patients has not been well documented. We hypothesized that stable disease following HD IL-2 is associated with a survival advantage. To explore this hypothesis, a retrospective chart review of 305 patients diagnosed with metastatic melanoma or renal cell carcinoma treated with HD IL-2 was conducted. Patient characteristics, response based on standard RECIST criteria and overall survival were analyzed using the Kaplan-Meier method and associations with clinical response were compared using a log-rank test. Two hundred and forty-five patients had melanoma and 60 had renal cell carcinoma. Of these, 217 had complete data available for analysis. Fifty-nine percentage had progressive disease (PD), 26 % had stable disease (SD) and 15 % had an objective complete (CR) or partial response (PR). Median overall survival was 16.8 months for all patients with available survival data; patients with PD had a median survival of 7.9 months compared to 38.2 months for stable disease, while the median has not been reached for those with objective responses. This retrospective data support an association between overall survival and stable disease, suggesting that clinical benefit may be underestimated for patients treated with HD IL-2. The data further support the use of disease control rate (CR + PR + SD) as a more meaningful endpoint for future clinical studies of tumor immunotherapy, including future studies of HD IL-2.

Laparoscopy has a superior diagnostic yield than percutaneous image-guided biopsy for suspected intra-abdominal lymphoma.

INTRODUCTION: To date, no study has compared laparoscopy (LB) to percutaneous (PB) biopsy for the diagnosis of abdominal lymphoma. The objective of this study is to compare the success rate and safety profile of laparoscopic lymph node biopsy to the percutaneous approach in patients with intra-abdominal lymphadenopathy concerning for lymphoma. MATERIALS AND METHODS: We performed a multi-institution, retrospective review of patients undergoing lymph node biopsy for suspected intra-abdominal lymphoma between 2005 and 2013. Our primary outcome was adequate tissue yield between the two techniques, both for histologic diagnosis and for ancillary studies such as flow cytometry. Secondary outcomes included 30-day morbidity, 30-day readmission rates, the need for additional lymph node biopsy procedures, and length of stay. RESULTS: All 34 of the LB patients had adequate specimen for histologic diagnosis compared to 92.3% of patients with a PB (p = 0.18). Significantly more patients in the LB group had sufficient tissue for ancillary studies when needed than in the PB group, 95.5 and 68.2%, respectively (p = 0.04). A second biopsy was pursued in 23.1% of failed PB patients, 0% with success on second attempt. DISCUSSION: When index of suspicion is high or when biopsy is performed for patient previously diagnosed with lymphoma and recurrence/transformation is suspected, LB safely and consistently provides adequate tissue for initial diagnosis and for ancillary studies. In contrast, image-guided PB may be more appropriate for patients for whom ancillary studies are unlikely to add to planned treatments or when there is a high risk of complications from either general anesthesia or patient comorbidities.

Annual case volume has no impact on patient outcomes in laparoscopic partial colectomy.

OBJECTIVES: Surgeon case volume has been utilized in the credentialing process as a surrogate for surgeon skill. The purpose of this study was to compare objective outcome measures of laparoscopic partial colectomies performed by laparoscopically skilled surgeons with varying annual case census. METHODS: We performed a retrospective cohort review of all patients (n = 255) undergoing elective laparoscopic partial colectomy. Patients were grouped according to surgeon's annual case volume as low annual case volume (LV; n = 48) and high annual case volume (HV; n = 207). HV is defined as performing >20 total cases and >25 cases per year. All demographic and clinical variables were evaluated with univariate logistic regression followed by a multivariate logistic regression model for variables approaching significance. RESULTS: Demographic variables were found to be similar between groups. Only median estimated blood loss (100 vs. 150 mL for HV; p = 0.040) was found to be significantly different between groups. However, this was clinically insignificant, as it did not lead to an increased rate of blood transfusions (0.0 vs. 3.9 % for HV surgeons; p = 0.184). All other variables were similar in both univariate and multivariate logistic regression models. CONCLUSIONS: Among surgeons with advanced laparoscopic training, the data suggest that LV surgeons are able to achieve similar outcomes as those who perform the operation routinely. Annual case volume should not be given undue emphasis when deciding whether to award privileges for laparoscopic partial colectomy.