Immune checkpoint blockade (ICB) therapy is effective against many cancers, although resistance remains a major issue and new strategies are needed to improve clinical outcomes1-5. Here we studied ICB response in a cohort of patients with ovarian clear cell carcinoma-a cancer type that poses considerable clinical challenges and lacks effective therapies6-8. We observed significantly prolonged overall survival and progression-free survival in patients with tumours with PPP2R1A mutations. Importantly, our findings were validated in additional ICB-treated patient cohorts across multiple cancer types. Translational analyses from tumour biopsies demonstrated enhanced IFNγ signalling, and the presence of tertiary lymphoid structures at the baseline, as well as enhanced immune infiltration and expansion of CD45RO+CD8+ T cells in the tumour neighbourhood after ICB treatment in PPP2R1A-mutated tumours. Parallel preclinical investigations showed that targeting PPP2R1A (by pharmacological inhibition or genetic modifications) in in vitro and in vivo models was associated with improved survival in the setting of treatment with several forms of immunotherapy, including chimeric antigen receptor (CAR)-T cell therapy and ICB. The results from these studies suggest that therapeutic targeting of PPP2R1A may represent an effective strategy to improve patient outcomes after ICB or other forms of immunotherapy, although additional mechanistic and therapeutic insights are needed.

Context.— The Nottingham Grading System (NGS) developed by Elston and Ellis is used to grade invasive breast cancer (IBC). Glandular (acinar)/tubule formation is a component of NGS. Objective.— To investigate the ability of pathologists to identify individual structures that should be classified as glandular (acinar)/tubule formation. Design.— A total of 58 hematoxylin-eosin photographic images of IBC with 1 structure circled were classified as tubules (41 cases) or nontubules (17 cases) by Professor Ellis. Images were sent as a PowerPoint (Microsoft) file to breast pathologists, who were provided with the World Health Organization definition of a tubule and asked to determine if a circled structure represented a tubule. Results.— Among 35 pathologists, the κ statistic for assessing agreement in evaluating the 58 images was 0.324 (95% CI, 0.314–0.335). The median concordance rate between a participating pathologist and Professor Ellis was 94.1% for evaluating 17 nontubule cases and 53.7% for 41 tubule cases. A total of 41% of the tubule cases were classified correctly by less than 50% of pathologists. Structures classified as tubules by Professor Ellis but often not recognized as tubules by pathologists included glands with complex architecture, mucinous carcinoma, and the “inverted tubule” pattern of micropapillary carcinoma. A total of 80% of participants reported that they did not have clarity on what represented a tubule. Conclusions.— We identified structures that should be included as tubules but that were not readily identified by pathologists. Greater concordance for identification of tubules might be obtained by providing more detailed images and descriptions of the types of structures included as tubules.

OBJECTIVES:Afirma has recently introduced its Xpression Atlas (XA) as an adjunct to its Genomic Sequencing Classifier (GSC) for risk stratification of cytologically indeterminate thyroid nodules. We evaluated the performance of Afirma XA and associated pathologic findings for Afirma GSC suspicious nodules.METHODS:Intradepartmental records of thyroid fine-needle aspirations (FNAs) from January 2021 to December 2022 were identified and reviewed for patient and nodule characteristics, FNA findings, molecular test results, and final surgical pathology, if available.RESULTS:Material for Afirma GSC testing was collected in 624 thyroid FNAs, and 148 (24%) were classified as cytologically indeterminate. Afirma GSC testing was successful in 132 (89%) of those cases, of which 35 (27%) were Afirma GSC suspicious. Afirma XA testing was positive in 11 cases (11/35 [31%]). Eight (73%) patients underwent surgery that revealed 7 patients with papillary thyroid carcinoma and 1 patient with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) (risk of malignancy: 100% [8/8]). Among the 24 patients with negative Afirma XA results, 19 (79%) underwent surgery, revealing 5 patients with malignancy and 3 patients with NIFTP (risk of malignancy: 42% [8/19]). Overall, the risk of malignancy for Afirma GSC suspicious nodules was 59% (16/27).CONCLUSIONS:Afirma XA improved risk stratification of thyroid disease with a high risk of malignancy in Afirma GSC suspicious nodules. A negative Afirma XA result, however, should not be used as a rule-out test.

BACKGROUND:Single-agent immune checkpoint inhibitors (ICIs) have demonstrated limited responses in recurrent ovarian cancer; however, 30%-40% of patients achieve stable disease. The primary objective was to estimate progression-free survival (PFS) after sequential versus combination cytotoxic T-lymphocyte antigen 4 and programmed death ligand 1 ICIs in patients with platinum-resistant high-grade serous ovarian cancer (HGSOC). METHODS:Patients were randomized to a sequential arm (tremelimumab followed by durvalumab on progression) or a combination arm (tremelimumab plus durvalumab, followed by durvalumab) via a Bayesian adaptive design that made it more likely for patients to be randomized to the more effective arm. The primary end point was immune-related PFS (irPFS). RESULTS:Sixty-one subjects were randomized to sequential (n = 38) or combination therapy (n = 23). Thirteen patients (34.2%) in the sequential arm received durvalumab. There was no difference in PFS in the sequential arm (1.84 months; 95% CI, 1.77-2.17 months) compared with the combination arm (1.87 months; 95% CI, 1.77-2.43 months) (p = .402). In the sequential arm, no responses were observed, although 12 patients (31.6%) demonstrated stable disease. In the combination arm, two patients (8.7%) had partial response, whereas one patient (4.4%) had stable disease. Adverse events were consistent with those previously reported for ICIs. Patient-reported outcomes were similar in both arms. CONCLUSIONS:There was no difference in irPFS for combination tremelimumab plus durvalumab compared to tremelimumab alone (administered as part of a sequential treatment strategy) in a heavily pretreated population of patients with platinum-resistant HGSOC. Response rates were comparable to prior reports, although the combination regimen did not add significant benefit, as has been previously described.

BACKGROUND:Per the College of American Pathologist's National Breast Fine Needle Aspiration Biopsy (FNAB) Practice Survey, ∼40% of laboratories use liquid-based cytology (LBC) for breast FNAB. The reproducibility of the International Academy of Cytology Yokohama System (YS) for reporting breast FNAB on LBC was explored. DESIGN:Breast FNAB specimens submitted as LBC only (all ThinPrep) between January 2017 and January 2021 were retrieved. Cases without histopathologic follow-up were excluded. Clinical and radiologic information was collected. One cytologist and six cytopathologists rendered diagnoses per YS. All reviewers were blinded to the original diagnosis and histopathologic follow-up. The risk of malignancy was calculated. Concordance rates were calculated by a weighted Cohen Kappa score (κ). RESULTS:Review of 110 cases demonstrated substantial to near-perfect agreement between each reviewer (κ = 0.73-0.91) and follow-up histopathology (κ = 0.66-0.85). The agreement was lowest in the inadequate (κ = 0.05) and atypical (κ = 0.04) categories. The lack of concordance in the atypical category was common in cases with low cellularity or incomplete structural features. The risk of malignancy for inadequate, benign, atypical, suspicious for malignancy, and malignant categories were 12.5% (2/16), 3% (2/65), 67%, (8/12) 100% (1/1), and 100% (16/16). CONCLUSION:Interobserver agreement is excellent using the five YS categories in LBC. Lack of cellularity and incomplete architectural features were barriers to perfect agreement. Established pitfalls in the interpretation of LBC were cause for atypical diagnoses. Continuous training and education are recommended to avoid misdiagnosis because of the nonconventional cytomorphologic features of LBC and to improve inadequate and atypical rates within YS.

Supplementary Table 1: Table provides information on the siRNA sequences and/or chemical structures of the non-FDA approved inhibitors for bromodomain proteins, transcription factors and kinases described in the current study. Supplementary Table 2: Sequences of primers used for qRT-PCR analysis of various targets described in the study. Supplementary Table 3: Sequences of primers used for ChIP analysis of various targets described in the study. Supplementary Table 4: Analysis of HOXB13 target gene expression in the GSE92721 data set. Supplementary Table 5: Analysis of HOTBIN10 gene expression in the GSE92721data set. Supplementary Table 6: Analysis of HOTBIN10 gene expression in the Moffitt TCC data set. Supplementary Table 7: Clinical parameters of the primary cancers in the Moffitt TCC data set. Supplementary Table 8: Clinical parameters of the metastatic cancers in the Moffitt TCC data set. Supplementary Table 9: Analysis of HOTBIN10 genes in MSKCC gene expression data set (GSE21034). Supplementary Table 10: Analysis of HOTBIN10 gene expression in the GSE67980 CTC data set.

PURPOSE:More oncologists desire to treat their patients with immune checkpoint inhibitors (ICIs) in the inpatient setting as their use has become more widespread for numerous oncologic indications. This is cost-prohibitive to patients and institutions because of high drug cost and lack of reimbursement in the inpatient setting. We sought to examine current practice of inpatient ICI administration to determine if and in which clinical scenarios it may provide significant clinical benefit and therefore be warranted regardless of cost.METHODS:We conducted a retrospective chart review of adult patients who received at least one dose of an ICI for treatment of an active solid tumor malignancy during hospitalization at a single academic medical center between January 2017 and June 2018. Patient, disease, and admission characteristics including mortality data were examined, and cost analysis was performed.RESULTS:Sixty-five doses of ICIs were administered to 58 patients during the study period. Nearly 40% and 80% of patients died within 30 days and 180 days of ICI administration, respectively. There was a trend toward longer overall survival in patients with good prognostic factors including positive programmed death-ligand 1 (PD-L1) expression or microsatellite instability-high (MSI-H) status. Slightly over 70% of patients were discharged within 7 days of ICI administration. The total cost of inpatient ICI administration over the 18-month study period was $615,016 US dollars.CONCLUSION:Inpatient ICI administration is associated with high costs and poor outcomes in acutely ill hospitalized patients with advanced solid tumor malignancies and therefore should largely be avoided. Careful discharge planning to expedite outpatient treatment after discharge will be paramount in ensuring patients with good prognostic features who will benefit most from ICI therapy can be promptly treated in the outpatient setting as treating very close to discharge in the inpatient setting appears to be unnecessary, regardless of tumor features.

Chronic myelogenous leukemia (CML) is a hematologic malignancy with unique significance to the field of hematology and oncology, specifically due to the development of tyrosine kinase inhibitors (TKIs). CML often presents with nonspecific symptoms, and the quality of life in patients with CML has drastically improved as a result of TKIs. However, complications of CML including the risk of transforming into life-threatening blast crises continue to exist. Further, as most patients are asymptomatic in the chronic phase, patients often present with serious complications associated with noncompliance to TKIs. For example, central nervous system (CNS) manifestations of CML have been reported, both as the initial presentation of undiagnosed CML and as known complication of uncontrolled CML. Hyperleukocytosis is a manifestation of uncontrolled CML and leukostasis is a complication, occurring in cases of acute myeloid leukemia (AML). Here we present a rare case of leukostasis in a patient with known CML presenting on computed tomography (CT) as intracranial masses in the chronic phase. Our goal is to discuss this rare case of leukostasis in adult CML and describe its management.

Supplementary Fig. 1. Epigenetic landscape and the transcription cofactor recruitment at the HOXB13 enhancer region under various treatments; Supplementary Figure 2. BRD4 is a target of the dual BET-kinase inhibitors in CRPCs; Supplementary Figure 3. Sensitivity of normal and AR negative cell lines to the novel BET-kinase inhibitors; Supplementary Figure 4. HOXB13 but not FOXA1 is under the epigenetic control of BRD4 in prostate cancer cells; Supplementary Figure S5. Haploinsufficiency of HOXB13 sensitizes CRPCs to the novel BET-kinase inhibitors; Supplementary Figure S6. AURKB expression correlates with HOXB13 in human CTCs from mCRPC patients following Abiraterone therapy; Supplementary Fig. S7. AURKB is a therapeutic vulnerability of HOXB13 positive prostate cancers

Introduction: Pulmonary embolism (PE) remains a significant cause of morbidity and mortality, often due to right ventricular (RV) failure. Pulmonary vasodilators, such as inhaled nitric oxide (iNO) or epoprostenol (iEPO) may be used to decrease RV afterload and prevent RV failure in patients with submassive PE. Studies characterizing the use of iEPO in PE, including dose, duration, and weaning, are lacking. The purpose of this study was to evaluate the use of iEPO in patients with PE at our institution. Methods: This cohort study was a retrospective chart review of adult patients diagnosed with acute PE who received at least one dose of iEPO from 7/2019 - 7/2021. Patients with a documented history of pulmonary hypertension or RV dysfunction were excluded. The primary objective of this study was to characterize the use of iEPO in patients with acute PE, including dose, duration, and weaning strategies. Safety objectives included the incidence of hypotension or initiation of vasopressors after iEPO administration. Results: Among the 111 patients evaluated, median age was 59 years (45-68). Of these, 48 (43%) and 51 (46%) had a massive and submassive PE, respectively. A total of 96 (86%) patients had RV dysfunction per TTE at the time of PE. The maximum dose of iEpo used was 50 ng/kg/min. The median duration of treatment was 39 hours (17.9-80.2), in which 57 (51%) were weaned to discontinuation. Weaning strategies most often included a 50% decrease in dose in 40 (70%) or a 10 ng/kg/min decrease in 6 (11%) during each rate change. The median duration of wean was 19.2 hours (5.3-20.2). A total of 15 (14%) patients experienced hypotension after administration, 6 (5%) required vasopressors. One or more inotropic agents were used concomitantly in 81 (73%) patients, with 73 (90%) having received epinephrine. Conclusions: The majority of patients receiving iEPO for PE had confirmed RV dysfunction. iEPO use generally followed our institutional guidelines with maximum dose and weaning strategies; however, it was weaned in only about half of patients. Systemic hypotension requiring vasopressors was experienced, which may warrant closer monitoring of therapy. Further research to evaluate efficacy, appropriate duration of treatment, and a standardized weaning process is needed to optimize the role of iEPO in PE.

Introduction EFFORT, a randomized noncomparative phase II study of adavosertib (WEE1 inhibitor) +/- olaparib [poly (ADP-ribose) polymerase inhibitor (PARPi)] in patients with PARPi-resistant ovarian cancer (OC), demonstrated efficacy and moderate toxicity. We report updated progression-free survival (PFS) and clinical/molecular features associated with clinical benefit from adavosertib (A) +/- olaparib (O). Methods Eligible patients had recurrent OC after progression on PARPi, measurable disease, and adequate end-organ function. Primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included PFS and clinical benefit (ORR/stable disease > 4 months) based on BRCA status, homologous recombination deficiency (HRD), platinum sensitivity, and intervening alternate therapy after prior PARPi before trial enrollment. Replication stress and HRD are being assessed using novel pRPA32 and Rad51 foci. Results There were 35 evaluable patients on each arm. Patients received a median of 4 prior therapies (range 1–11), including olaparib (41%). Median PFS was 5.5 months (95% CI, 3.9–6.9) from A and 6.8 months (95% CI, 4.3–8.3) from A/O. Table 1 demonstrates clinical benefit based on clinical/molecular features. Clinical benefit was observed on both arms regardless of BRCA status, platinum sensitivity, or use of intervening therapy after PARPi. Figure 1 demonstrates clinical benefit based on platinum sensitivity, with intriguing activity in platinum-resistant disease. Conclusion/Implications Efficacy of adavosertib +/- olaparib was retained across multiple clinical cohorts of PARPi-resistant OC, including BRCAwt and platinum-resistant disease. Ongoing analysis using a novel functional HRD assay consisting of concordant measurement of Rad51, gH2AX and geminin foci will elucidate the role of HRD in clinical benefit.

The category of papillary breast tumors includes a limited number of entities. Nonetheless, this relatively uncommon group of tumors seems to instigate a disproportionate degree of diagnostic disquiet. As a group, papillary breast tumors suffer from a relatively high rate of discordant interpretation. The latter is due to the inherent complexity of the lesions compounded by conflicting criteria as well as simmering controversies. For instance, "encapsulated" papillary carcinoma remains contentious with regards to whether these are noninvasive or not, and the assessment of the extent of the invasive versus noninvasive components in many solid papillary carcinomas can be problematic. The latest classification system of breast tumors enunciated by the World Health Organization (WHO), that is, Breast Tumors, which appeared in 2019, mainly sought to incorporate advances in basic and clinical sciences into diagnostic criteria for the entire spectrum of breast neoplasms-including papillary ones. The latter category of tumors is discussed at some length in Breast Tumors; however, it still appears to suffer from some lack of clarity in its subclassification. It is our intent in this communication to provide an overview of the controversies around papillary breast tumors, and offer comments on its coverage in Breast Tumors-so that any tangible or perceived ambiguities therein could be addressed in its next edition.

Introduction: A young male with past medical history (PMH) of severely uncontrolled non-insulin dependent diabetes mellitus (NIDDM) with recurrent admissions for diabetic ketoacidosis (DKA) and hypertriglyceridemia-induced pancreatitis, both secondary to medication non-adherence, presented via emergency medical services (EMS) after being found unresponsive at home and subsequently developed acute esophageal necrosis (AEN) during a prolonged stay in the intensive care unit (ICU) for acute respiratory failure. He was successfully treated with extended duration of proton pump inhibitor (PPI) therapy and control of underlying risk factors despite being continued on anticoagulation. Case Description/Methods: A 39-year-old male with PMH of uncontrolled NIDDM presented was admitted for acute respiratory failure secondary to DKA and pneumonia. He was intubated and admitted to ICU, while continued on DKA protocol including antibiotics. GI was consulted for hematemesis and melena 2 weeks into hospitalization. EGD revealed circumferential black esophageal mucosa in the distal esophagus abruptly ending at the gastroesophageal junction (GEJ) and hiatal hernia. Recommendations included Intravenous (IV) proton pump inhibitor (PPI) and strict avoidance of naso/orgastric (NG/OG) tube. Follow up EGD few months after discharge showed remarkable improvement of mucosa as noted in Figures A and B, despite continuation of DOAC as per patient wishes for DVT developed during the stay. Discussion: AEN is a rare syndrome disproportionately reported in men which is characterized by circumferential black esophageal mucosa in the distal 2 thirds of the esophagus, abruptly ceasing at the GEJ. Ischemia is postulated to be an inciting event. Conditions associated with AEN are antibiotics, sepsis, gastric volvulus, hernia, DKA, malignancy, and prolonged vomiting. Symptoms of upper gastrointestinal bleeding (UGIB) and shock are common presentations. Although biopsy establishes diagnosis and rules out other causes, EGD finding is generally sufficient. Initial management consists of IV fluids and treatment of the underlying cause. IV PPI and nil per os (NPO) is recommended. NG/OG tubes are avoided unless vomiting or obstruction is present. Mortality is largely due to underlying disease rather than directly from AEN, hence supportive care results in resolution in most cases, as seen in our patient. Our case demonstrates the importance of addressing underlying causes, as well as PPI therapy, which can overcome continued anticoagulation.Figure 1.: A. Acute esophageal necrosis discovered on endoscopy while undergoing EGD for acute GI bleeding during ICU admission for DKA and acute respiratory failure requiring mechanical ventilation B. Resolution of acute esophageal necrosis with grossly normal mucosa on follow up endoscopy conducted after extended duration PPI therapy and relatively controlled diabetes.