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In view of the relatively limited efficacy of immunotherapies targeting the PD-1–PD-L1 axis in triple-negative breast cancer (TNBC) and of published reports on tumor-promoting roles of TNFR2+ tumor-infiltrating lymphocytes (TNFR2+ TILs), we determined the incidence of TNFR2+ TILs in TNBC patient tumors, their association with disease outcome and relations with PD-1+ TILs. Using a cohort of treatment-naive TNBC patients with long follow-up (n = 70), we determined the presence of TNFR2+ TILs and PD-1+ TILs by immunohistochemistry. TILs (≥ 1% of cellular mass) and TNFR2+ TILs (≥ 1% of total TILs) were detected in 96% and 74% of tumors, respectively. The presence of TILs at > 5% of tumor cell mass (“Positive TILs”), as well as of positive TNFR2+ TILs (> 5%), was independently associated with good prognosis, and combination of both parameters demonstrated superior outcome relative to their lower levels. PD1+ TILs (> 5/hot spot) were detected in 63% of patients. High levels of PD-1+ TILs (> 20/hot spot) showed an unfavorable disease outcome, and in their presence, the favorable outcome of positive TNFR2+ TILs was ablated. Thus, TNFR2+ TILs are strongly connected to improved prognosis in TNBC; these findings suggest that TNFR2+ TILs have favorable effects in TNBC patients, unlike the tumor-promoting roles attributed to them in other cancer systems. Overall, our observations propose that the TNFR2+ TIL subset should not be targeted in the course of TNBC therapy; rather, its beneficial impacts may become into power when anti-PD-1 regimens—that may potentiate immune activities—are administered to TNBC patients.

SummaryDespite extensive research, internal tumor heterogeneity presents enormous challenges to achieve complete therapeutic responses. Changes in protein expression are central determinants of cancer phenotypes that reflect potential therapeutic targets. However, previous proteomic studies did not address internal heterogeneity, therefore, masked the necessary spatial resolution to achieve a comprehensive understanding of cancer complexity. Here we present the first large-scale multi-focal breast cancer proteomic study of 330 tumor regions which associated cancer cell function, pathological parameters, and spatial localization of each tumor region. We found marked internal proteomic heterogeneity even within tumors presenting homogeneous receptor expression. Additionally, analysis of the internal heterogeneity, based on coexisting receptor expression or histological patterns in single tumors, showed significant functional differences between homogeneous and heterogeneous tumors related to cancer metabolism, immunogenicity, and proliferation. We anticipate that this study will serve as a starting point towards the development of improved cancer therapy and diagnostics.

Esophageal pressure (Pes) measurement provides a practical means of quantifying respiratory effort during invasive mechanical ventilation and can be used as a clinical tool for assessing patients during the weaning trial. There is little data regarding a similar use in patients with acute hypercapnic respiratory failure (AHRF) under NIV. We aimed to investigate the potential utility of Pes measurement in guiding NIV weaning during AHRF due to severe COPD exacerbation. Methods: A prospective cohort study was undertaken in a respiratory intermediate care unit in an academic medical center between 2018 and 2019. We measured ∆Pes daily, and we registered these values together with patient characteristics, ventilatory function, and other data. The outcome was successful NIV weaning as opposed to the need for home NIV. Our objective was to identify Pes characteristics that would correlate with successful NIV weaning or the need to continue NIV at home. Results: We included 15 patients (8 males, mean age 65 years) with severe COPD exacerbation with AHRF requiring NIV. All patients were successfully managed with NIV. 10 patients could be weaned from NIV and had an average decrease in ∆Pes from admission to discharge of 6.2 cmH2O (SD 3.0, p 0.07) with a mean discharge ∆Pes of 9.3 cmH2O (SD 4.1). 5 patients needed home NIV and had a medium decrease of ∆Pes of 2.5 cmH2O (SD 2.7, p 0.2) with a mean discharge ∆Pes of 15.0 (SD 1.0). Mean difference of ∆Pes at discharge between the 2 groups was 5.7 (p 0.08). Conclusion: In patients with severe COPD exacerbation with AHRF that required NIV, a lack of drop in ∆Pes and a higher discharge ∆Pes could predict a need for home NIV.

Introduction: Improving patient-ventilator interaction during mechanical ventilation with acute hypercapnic respiratory failure (AHRF) reduces mortality. The esophageal pressure (Pes) measurement is an established way of detecting asynchronies in mechanically ventilated patients. This study aimed to evaluate the potential of Pes measurement in detecting patient-ventilator asynchronies in patients with AHRF due to severe COPD exacerbation requiring NIV. Methods: A prospective cohort study was undertaken in a respiratory intermediate care unit in an academic medical center between 2018 and 2019. Pes and ventilator pressure (Paw) curves and other data were recorded. The signal analysis comprised of artifact elimination and measurement of the phase difference between Pes and Paw curves. The objective was to assess the potential of using the phase difference value as an indicator of asynchrony. Results: 15 patients (8 males, mean age 65 years) with severe COPD exacerbation with AHRF requiring NIV were included. All patients were successfully managed with NIV. Patient-ventilator asynchrony was clinically detected in 3 patients at admission. The signal analysis identified all episodes of asynchrony with phase difference values of 10-15° during asynchrony and value of 170-180° during synchrony period for the same patient. Conclusion: Pes measurement can be used to detect patient-ventilator asynchronies in severe COPD exacerbation with AHRF that requires NIV.

Introduction: Noninvasive ventilation (NIV) is recommended in patients with obesity hypoventilation syndrome (OHS) with acute hypercapnic respiratory failure (AHRF). Left heart disease is frequently present in obese patients but its prognostic role in patients with OHS and AHRS is unknown. This study aimed to assess the impact of cardiac dysfunction on the outcome of acute NIV in this clinical setting. Methods: A prospective cohort study was undertaken in a respiratory intermediate care unit in an academic medical center between 2018 and 2019. Clinical characteristics, echocardiographic data (that defined left heart dysfunction), NT-pro BNP levels, hours of NIV during the first 72 hours (dNIV-72h) and other data were recorded. The main outcome was NIV failure. Secondary outcomes were NIV duration and length of hospital stay. Results: 33 patients (20 female, mean age 63 years) with OHS and AHRF were included. 26 patients (78%) had left heart dysfunction. NIV failure was 3.3%, mean LOS was 9 days, mean NIV duration was 5.5 days. The presence of left heart dysfunction increased both dNIV-72h (p Conclusion: NIV failure rate was not influenced by the presence of left heart dysfunction nor by the NT-pro BNP levels. Patients with left heart dysfunction required prolonged use of NIV.

The escalating demand for diagnosing pathological biopsies requires the procedures to be expedited and automated. The existing imaging systems for measuring biopsies only measure color, and even though a lot of effort is invested in deep learning analysis, there are still serious challenges regarding the performance and validity of the data for the intended medical setting. We developed a system that rapidly acquires spectral images from biopsies, followed by spectral classification algorithms. The spectral information is remarkably more informative than the color information, and leads to very high accuracy in identifying cancer cells, as tested on tens of cancer cases. This was improved even more by using artificial intelligence algorithms that required a rather small training set, indicating the high level of information that exists in the spectral images. The most important spectral differences are observed in the nucleus and they are related to aneuploidy in tumor cells. Rapid spectral imaging measurement therefore can bridge the gap in the machine-aided diagnostics of whole biopsies, thus improving patient care, and expediting the treatment procedure.

BACKGROUND Recent data suggest continuous chronic inflammation in patients after an acute diverticulitis (AD) episode. GOALS The aim of this article was to compare clinical parameters, inflammatory cytokine expression, and immune-cell infiltrates between patients after severe versus nonsevere AD, as defined by radiology examination during the acute episode. STUDY Sixteen patients, after suffering an episode of AD, were included, and, of them, 8 had severe disease. Demographic data, disease characteristics, and inflammatory markers were collected. Tissue samples from diverticular and unaffected tissue were obtained during colonoscopy. Mucosal inflammation was assessed histologically and by measuring inflammatory cytokine mRNA expression. RESULTS Clinically, continued nonspecific abdominal symptoms were significantly more prevalent among patients after severe AD compared with patients after nonsevere AD (P=0.0002). Patients after severe AD also had significantly higher C reactive protein levels (9.85±7.5 vs. 3±2.1 mg/dL; P=0.027) and tendency for higher calprotectin levels (115.7±85 vs. 35±8.7 mg/g; P=0.08). Reverse transcription polymerase chain reaction-determined cytokines levels were 5.4±4.4, 5.14±10, and 0.8±0.82 for tumor necrosis factor alpha, interleukin-6, and interleukin-1β, respectively, in affected mucosa compared with 1.06±1.57, 1.56±2.1, and 0.35±0.5, respectively, in nonaffected mucosa (P=0.01, 0.05, 0.14, respectively). Cytokine expression in patients after nonsevere AD did not differ significantly between affected and nonaffected mucosa. Histologic scores for crypt distortion, lymphoid aggregates, and lymphocyte infiltration were all significantly higher in patients after severe AD compared with patients after nonsevere AD (P

Spectral imaging is an important method that is used for a whole spectrum of applications, but measuring very large spectral images is a challenge that so far was not achieved. We present a novel system for scanning very large spectral images of microscopy samples in a rather short time. The system captures the information while the sample is continuously being scanned on the fly. It therefore breaks the size and speed limits that resulted from existing spectral imaging methods. The spectral separation is achieved through Fourier spectroscopy by using an interferometer mounted along the optical axis (no moving parts). We describe the system and its use for pathological samples.

Introduction One of the major obstacles in breast cancer treatment is its high degree of heterogeneity and ambiguous classification. The molecular subtypes and histological subtypes are routinely defined in the clinic to determine treatment modalities; however often these distinct subtypes co-exist in single tumours and therefore lead to treatment resistance. Here, we aim to delineate the proteomic landscapes of breast cancer intratumoral diversity based on clinical-pathological parameters using mass spectrometry-based microproteomics. Material and methods Using histopathological analysis of immunostained formalin fixed paraffin embedded (FFPE) tissues, we assembled a cohort of more than 200 tumour regions comprising of different histopathological and molecular subtypes that originate from 22 patients. Cancer cell subpopulations were harvested using laser-capture microdissection (LCM) and labelled by TMT 10-plex. After protein digestion, peptides were analysed using high resolution quantitative mass spectrometry followed by computational analysis with MaxQuant. Results and discussions Topological proteomic analysis revealed the proteomic portraits that are associated with each cancer cell subpopulation, with the association to its receptor expression level and histological characteristics. We found a clear proteomic distinction between moderately and poorly differentiated regions: moderately differentiated regions were primarily segregated based on their histological subtypes such as micropapillary vs. invasive ductal carcinoma-no special type, while poorly differentiated tumour regions were distinct based on the differential expression of the oestrogen, progesterone and Her2 receptors. We identified the significantly changing proteins between these subtypes, including significant differences in metabolic enzyme profiles between co-existing subtypes. For example, we found upregulated pentose-phosphate pathway in progesterone receptor positive regions and upregulated proline/arginine biosynthesis pathways in tumour regions with micropapillary features. Conclusion These findings suggest that integrated topo-proteomic landscape of inter- and intratumoral heterogeneity can serve as a platform for deciphering the mechanisms underlying tumorigenesis, distinct metabolic profiles of cancer cell subpopulations, cancer evolution, and therapy resistance.

Emerging mutations in the ESR1 gene that encodes for estrogen receptor (ER) have been recently associated with resistance to endocrine therapy in ER positive metastatic breast cancer patients. These mutations promote the active conformation of the receptor, conferring resistance to endocrine therapy, and were associated with shorter progression free survival. ESR1 mutations were found to rarely exist in primary tumors (~1%) but are relatively common in metastatic, endocrine therapy-resistant lesions, with an estimated prevalence of ~10-50%. Nevertheless, not much is known about the incidence of these mutations in local recurrence (breast and adjacent lymph nodes) and its clinical significance. The objective of this study is to determine the prevalence of ESR1 mutations in local recurrence of endocrine-treated breast cancer patients. To this end, we collected a cohort of breast cancer patients that had at least one local or loco-regional recurrence during or after adjuvant endocrine treatment for primary breast cancer. We analyzed the 5 most common ESR1 hotspot mutations (D538G, L536R, Y537S/N/C) using droplet digital PCR technology in 44 samples from 34 patients (some of the patients had more than one recurrence). ESR1 mutations were identified in 10/34 (29%) patients. Specifically, mutations were distributed between D538G (5/34), Y537S+ D538G (4/34) and L536R (1/34). ESR1 Mutations developed after or on Tamoxifen only treatment in 50% of the positive patients (5/10 patients) and after or on Tamoxifen + Aromatase Inhibitor (AI) treatment in the other 50% (5/10 patients). Notably, one patient developed ESR1 mutation while on neoadjuvant endocrine therapy. ESR1 mutations persisted in local recurrence samples of mutation positive patients that had more than one local recurrence and the chance of detecting a mutation in patients that had more than one recurrence was higher than in those with a single recurrence. This study demonstrates that ESR1 mutations are common in local recurrence of hormone receptor positive breast cancer. Further studies to establish the clinical significance of these mutations and their impact on survival are underway. Since local recurrences are amenable to curative therapy, the identified unexpected high prevalence of ESR1 mutations at this stage of the disease may have important consequences for choosing the optimal adjuvant treatment option for these patients. Citation Format: Adi Zundelevich, Maya Dadiani, Smadar Kahana-Edwin, Moran Gadot, Tal Sela, Irina Marin, Daniela Necula, Anya Pavlovsky, Iris Barshack, Bella Kaufman, Einav N. Gal-Yam. ESR1 mutations abundance in local recurrence of endocrine-treated breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 657.

We present a rare case of primary cardiac diffuse large B cell lymphoma with unusual presentation. Our female patient, 34 years old, presented with superior vena cava syndrome that was related to thrombophlebitis post breast augmentation. She was treated with anticoagulants but was admitted again, ten months later, due to an aggravation in her state. MRI imaging demonstrated a large mass in her right atrium that was surgically removed. The resected mass was 6 cm in diameter, lobulated and white. Microscopically, the tumor consisted of sheets of large atypical cells, with wide nuclei and prominent nucleoli. Numerous mitotic figures and necrosis were present. On immunostains the tumor cells showed strong diffuse positive staining for CD20, CD30 and vimentin. All other markers for epithelial and muscle tumors, as well as melanoma were negative. Ki67 was positive in 75% of the cells. ALK status was evaluated by both immunohistochemistry and FISH study. The diagnosis was concluded as primary cardiac diffuse large B cell lymphoma. Primary cardiac lymphoma is a very rare entity and its diagnosis is unanticipated by both clinicians and pathologists. We present the case, discuss the differential diagnosis and review the literature.