Faculty Bibliography

Introduction: A transcatheter aortic valve replacement (TAVR) carries a 2% risk of postoperative upper gastrointestinal bleeding. It presents as extensive bleeding resulting in hemorrhagic shock or respiratory failure. In this case, an early clot with sentinel bleeding prevented the widening of a full thickness aortoesophageal fistula formed from the TAVR placement, was symptomatic enough to prompt an earlier esophagogastroduodenoscopy (EGD) and prevented a probable fatality. Case Description/Methods: An 85-year-old male with a past medical history of AAA repair, GERD, HLD, TIA, aortic dissection s/p coronary bypass graft, AS with TAVR 5 months prior presented with hematemesis after initiating colonoscopy bowel prep. He also had unintentional 30-lb weight loss over 3 months, fecal incontinence, and melena. Medications include a daily aspirin. Abdominal CT demonstrated an 8cm aortic arch aneurysm, a 5cm descending thoracic aortic aneurysm, and a 5.8 x 4 cm collection posterolateral to the aorta with proximal dilation of the esophagus. EGD demonstrated a partially obstructing protruding mass in the esophagus 20 cm from the incisors with sentinel bleeding from an adherent clot. The mass was determined to be extrinsic compression from the aortic arch aneurysm with the TAVR seen through the aortoesophageal fistula (Image 1A-1B). The stomach and duodenum were unremarkable. Patient was transferred to vascular surgery where a 1cm compressed Amplatzer Vascular Plug II embolization and reinforcement of the endoleak was done. Patient remained hemodynamically stable and discharged home with a vascular follow up.
Discussion(s): Aorto-esophageal fistula following TAVR is a rare complication with a wide etiology ranging from infections, antithrombotic use, pressure necrosis, angiodysplasia, underlying PUD, or uncontrolled comorbidities such as HTN. Our patient's risk factors were his elderly age, comorbidities, use of daily aspirin, and contribution from the pressure or ischemic necrosis of the aortic aneurysm compressing on the esophagus. Presentation involves hemoptysis, chest pain, hemorrhagic shock, respiratory failure and frank bleeding. CTA is considered the initial test of diagnosis as endoscopy, though sensitive, could rupture the clot and unleash massive bleeding. In this case, sentinel bleeding and visualization of the TAVR through the fistula was enough to diagnose and retreat to be treated appropriately with embolization and reinforcement

Introduction: Gastrointestinal follicular lymphoma (FL) is a rare, but distinct extra-nodal variant of non-Hodgkin's lymphoma. Its incidence has grown outside of known genetic inheritance, due to epigenetic mutations from increased toxic exposure to benzene and pesticides, expanded life spans, and widespread standardized screening efforts. Diagnosis is by colonoscopy-obtained tissue staining and can be missed if alternative CRC screening methods are used in lieu. Case Description/Methods: A 54-year-old Ukranian male with a past medical history of HTN and GERD came in for an asymptomatic screening colonoscopy. One 8 mm polyp in the transverse colon was positive for FL. IHC staining demonstrated atypical small B-lymphocytes, positive for CD451, CD201, PAX51, CD101, and BCL-21. Bloodwork, including LDH, beta-2-microglobulin, were normal. A staging PET scan was negative indicating an isolated disease within the colonic polyp. As the patient was asymptomatic, no further treatment was indicated and the patient was scheduled for regular follow-up.
Discussion(s): GI FL is a B-cell lymphoma with an incidence slightly higher in women and a median age of 65. Occurrence outside of the bone marrow, spleen, or liver is uncommon. Descending incidence within the GI tract is the duodenum, ileum, stomach, and rarely colon. Within the colon, it presents asymptomatically. Definitive diagnosis is by a colonoscopy-obtained tissue staining. Colonoscopy adherence is generally high after the age of 65, given the median age of colorectal cancer incidence is 67 and the availability of Medicare coverage. However, if alternatively approved screening modalities are utilized such as the gFOBT, FIT, FIT-DNA, or flexible sigmoidoscopy, then the diagnosis of a FL might be missed until either mass or metastatic effects become apparent. Diagnostic work-up includes IHC staining for CD-20, CD-36, a follicular cell pattern, increase in B cells, bcl-2, bcl-6, and a 14:18 translocation by FISH or PCR (85% of cases). Investigation into a primary NHL, leukemia, or MDS includes flow cytometry, bone marrow biopsy, and cytogenetics. Increased LDH indicates rapid progression with staging done by PET or pan CTs. Colonic FL have a 10-year survival rate of 80% and an indolent course, so treatment is only indicated if the patient is symptomatic. Treatment for stage 1 is radiation, stages 2-4 is CHO P-R chemotherapy. Adjuvant or refractory treatments include anti-CD20 monoclonal antibodies, such as rituximab or obinutuzumab.

INTRODUCTION/BACKGROUND:Accurate assessment of estrogen receptor (ER) expression is crucial to ensure that patients with early breast cancer are accurately identified for appropriate treatment with endocrine therapy. Reverse transcriptase polymerase chain reaction (RT-PCR), compared with immunohistochemistry (IHC), may provide a more precise indication of ER status. Data were pooled and analyzed from two independent, but similarly designed, studies that examined ER status by IHC and the 21-gene Recurrence Score that employs RT-PCR-based methodology. METHODS:Tumor tissue from patients with early stage breast cancer where ER status could be determined by both IHC and RT-PCR was included. ER status by IHC staining was defined as ER-negative (< 1%), ER-low+ (1-10%), or ER+ (> 10%). ER status by RT-PCR was defined as ER-negative (≤ 6.5) or ER+ (> 6.5). Recurrence Score results from the 21-gene assay were reported on a continuous scale from 0 to 100. A sub-analysis examined the association between ER expression (Allred score 2-7) and response to a 14-day pre-surgery pulse with an aromatase inhibitor. A separate sub-analysis examined the association between ER expression and human epidermal growth factor receptor 2 (HER2) expression. RESULTS:Tumor specimens from 192 patients (aged 25-92 years) were included in the pooled analysis. Correlation between IHC- and RT-PCR-measured ER was strong for IHC-defined ER-negative and ER+ samples (r = 0.646 [95% CI 0.553-0.720]). There was 100% concordance for ER+ tumors; however, 56% of the ER-low+ tumors were negative by RT-PCR. Allred score correlated better with ER status measured by RT-PCR at pre-treatment (r = 0.83) than at post-treatment (r = 0.76). The majority (77%) of ER-negative and ER-low+ tumors were HER2-negative. CONCLUSIONS:RT-PCR provided a more accurate assessment of ER expression in patients with ER-low+ tumors, and data support dual testing for patients with ER-low+ status to ensure appropriate treatment planning as it pertains to endocrine therapy. FUNDING/BACKGROUND:Genomic Health, Inc.

Metaplastic breast cancer (MPBC) is a rare subtype that accounts for <1% of all breast cancers. Although these are typically "triple negative," they are relatively chemotherapy-refractory compared to conventional triple negative invasive breast cancers with more aggressive features and an overall poor prognosis. MPBC is a heterogeneous group of tumors that are enriched for TP53 and PIK3CA mutations, and have been found to have high PD-L1 expression though the mechanisms underlying its immunogenicity remain unclear. We perform comprehensive genomic profiling in the largest MPBC dataset (n = 192) to date and assess for other potential biomarkers of immune response.

Morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer is gaining momentum as evidence strengthens the clinical relevance of this immunological biomarker. TILs in the post-neoadjuvant residual disease setting are acquiring increasing importance as a stratifying marker in clinical trials, considering the raising interest on immunotherapeutic strategies after neoadjuvant chemotherapy. TILs in ductal carcinoma in situ, with or without invasive carcinoma, represent an emerging area of clinical breast cancer research. The aim of this report is to update pathologists, clinicians and researchers on TIL assessment in both the post-neoadjuvant residual disease and the ductal carcinoma in situ settings. The International Immuno-Oncology Working Group proposes a method for assessing TILs in these settings, based on the previously published International Guidelines on TIL Assessment in Breast Cancer. In this regard, these recommendations represent a consensus guidance for pathologists, aimed to achieve the highest possible consistency among future studies.

Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.

PURPOSE: Several pathologic staging systems characterize residual tumor in patients undergoing neoadjuvant chemotherapy for breast cancer. Pathologic complete response (pCR) is now accepted by the Food and Drug Administration as an endpoint for granting accelerated drug approval. Two other systems of post-neoadjuvant pathologic tumor staging-residual cancer burden (RCB) and the American Joint Committee on Cancer post-neoadjuvant therapy staging system (yAJCC)-have been developed to characterize residual tumors when patients do not achieve pCR. The optimal system and the ways in which these systems complement each other have not been fully determined. METHODS: Using data from the I-SPY 1 TRIAL, we compared pCR, RCB, and yAJCC as predictors of early recurrence-free survival (RFS) to identify ways to improve post-neoadjuvant pathologic evaluation. RESULTS: Among 162 patients assessed, pCR identified patients at lowest risk of recurrence, while RCB and yAJCC identified patients at highest risk. Hormone-receptor (HR) and HER2 subtypes further improved risk prediction. Recursive partitioning indicated that triple-negative or HER2+ patients with yAJCC III or RCB 3 have the highest recurrence risk, with an RFS of 27%. Our analysis also highlighted discrepancies between RCB and yAJCC stratification: 31% of patients had discrepant RCB and yAJCC scores. We identified differential treatment of lymph node involvement and tumor cellularity as drivers of these discrepancies. CONCLUSIONS: These data indicate that there is benefit to reporting both RCB and yAJCC for patients in order to identify those at highest risk of relapse.

DCIS is a non-obligate precursor in which epithelial cells with features of cancer reside in and expand otherwise normal appearing mammary ducts and lobules. DCIS increases the relative risk of developing invasive breast cancer (IBC) by up to 10 fold. Treatment of DCIS includes breast conserving surgery (BCS), tumor margins permitting, followed by radiation, or mastectomy. Recently we found that pasireotide, a somatostatin analog inhibitor of IGF-I, was effective in reducing cell proliferation and increasing apoptosis in patients with atypical hyperplasia (AH) and or proliferative disease of the breast. At present there are no recognized medical treatments for DCIS. Here we raise the possibility that pasireotide might also be an effective therapy for some DCIS. To make this determination, 8 patients previously diagnosed with DCIS were treated with pasireotide, 600mug twice daily subcutaneously for a period of 20 days. Lesion size was assessed on DCE-MRIs in 3 planes before and after treatment. Of the eight, two had lesions characterized as low grade DCIS on core biopsy, 4 had intermediate or intermediate to high grade lesions, and two had high grade lesions. After treatment they all had surgical excision biopsies. We also measured proliferation and apoptosis to assess effects of pasireotide by expression of Ki67 and caspase 3. To confirm that the effect of pasireotide was mediated via the IGF-I pathway, p-AKT and p-ERK 1/2 were evaluated. Core and excision samples from 14 untreated patients where used as control. Overall, treatment with pasireotide reduced DCIS lesion size by >=30% according the RECIST criteria in 4 of 8 patients, as measured by DCE-MRI. Of those, pathology of the surgical excision confirmed that there was no remaining DCIS tissue in the two patients with low grade disease. The two additional lesions that were reduced in size one was intermediate to high grade and the other a high grade DCIS. The remaining 4 patients had tumors that were stable in size. Pasireotide reduced cell proliferation and significantly increased apoptosis in the DCIS lesions. While DCIS is less responsive to pasireotide than AH and proliferative disease, it may nevertheless provide a window of opportunity for treatment and possibly eradication of some low grade or higher grade DCIS as well. The main side effect included hyperglycemia, intestinal discomfort and rash or redness at the injection area. Our data show that hyperglycemia disappears relatively fast after ending treatment with pasireotide. In conclusion, treatment with pasireotide eliminated 2 low grade DCIS lesions, shrunk two higher grade ones and also decreased proliferation and increased apoptosis. Additional evidence in a larger number of patients will be necessary