Microscopic sex cord-stromal proliferations in extraovarian heterotopic sites: Report of a rare case and review of the literature.

Microscopic heterotopic extraovarian sex cord-stromal proliferations were first reported in the literature in 2015 by McCluggege. Afterwards, few similar cases have been described. Herein, we report the fourteenth case of microscopic heterotopic sex cord-stromal proliferation and the third case sited in the pelvic peritoneum. The clinical history of these rare cases suggests their benign nature. Knowledge of this histological pattern is important for differential diagnoses such as malignant pathologies and metastatic diseases.

Features of infective endocarditis in a contemporary cohort of persons who inject drugs: a matched comparison analysis of long-term prognostic factors.

The objective of the study was to assess the short- and long-term mortality of infective endocarditis (IE) among people who inject drugs (PWID). Using prospectively collected data on hospitalized patients (years 2000 through 2021) with IE, PWID were identified and included in this study. Survival analysis was performed to analyze short- and long-term mortality and study their risk factors among PWID and a matched group of non-intravenous drug users (N-IDU). In a study of 485 patients admitted for IE, 55 (11%) of them were PWID. These PWID patients were 1:1 age- and sex- matched to an N-IDU group (N = 55 per group). Both groups had similar baseline comorbid conditions, including congestive heart failure, type 2 diabetes, and neoplastic diseases. However, PWID were more likely to have HCV co-infection (62% vs 16%, respectively, p < 0.001) and advanced liver disease/cirrhosis (52% vs 7.9%, respectively, p < 0.001). IE in PWID more often affected the tricuspid valve (42% vs 22%, respectively, p = 0.024) and presented with more embolic events (66% vs 35%, respectively, p < 0.01). S. aureus was the primary cause of IE in PWID (44% vs 21%, respectively, p = 0.01). After adjusting for other variables, PWID (HR = 2.99, 95% CI [1.06, 8.43], p = 0.038) and valve bioprosthetic replacement (HR = 5.37, 95% CI [1.3, 22.1], p = 0.02) were independently associated with increased mortality risk, whereas IE caused by tricuspid valve infection was associated with reduced mortality risk (HR = 0.25, 95% CI [0.06, 0.97], p = 0.046). In this cohort, PWID had increased risk of long-term mortality after hospital discharge for IE, when compared to matched N-IDU with similar baseline characteristics. The reasons behind the significant increase in mortality warrant further investigation.

Streamlined Strategy for Scalable and Enantioselective Total Syntheses of the Eburnane Alkaloids.

A general, concise, and efficient strategy for the enantioselective synthesis of the eburnane alkaloid family of natural products is disclosed. Specifically, 13 members of the natural product family were prepared from commercially available and inexpensive starting materials. The brevity and modularity of the route are largely on account of a two-phase synthesis logic and a key catalytic enantioconvergent cross-coupling to establish the C20 stereogenic center. The strategies described here are expected to facilitate in-depth biological studies and provide access to new anticancer eburnane analogues.

IMMUNOREACT 6: weak immune surveillance characterizes early-onset rectal cancer.

BACKGROUND: Colon cancer in young patients is often associated with hereditary syndromes; however, in early-onset rectal cancer, mutations of these genes are rarely observed. The aim of this study was to analyse the features of the local immune microenvironment and the mutational pattern in early-onset rectal cancer. METHODS: Commonly mutated genes were analysed within a rectal cancer series from the University Hospital of Padova. Mutation frequency and immune gene expression in a cohort from The Cancer Genome Atlas ('TCGA') were compared and immune-cell infiltration levels in the healthy rectal mucosa adjacent to rectal cancers were evaluated in the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 ('IMMUNOREACT') series. RESULTS: In the authors' series, the mutation frequency of BRAF, KRAS, and NRAS, as well as microsatellite instability frequency, were not different between early- and late-onset rectal cancer. In The Cancer Genome Atlas series, among the genes with the most considerable difference in mutation frequency between young and older patients, seven genes are involved in the immune response and CD69, CD3, and CD8ß expression was lower in early-onset rectal cancer. In the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 series, young patients had a lower rate of CD4+ T cells, but higher T regulator infiltration in the rectal mucosa. CONCLUSION: Early-onset rectal cancer is rarely associated with common hereditary syndromes. The tumour microenvironment is characterized by a high frequency of mutations impairing the local immune surveillance mechanisms and low expression of immune editing-related genes. A constitutively low number of CD4 T cells associated with a high number of T regulators indicates an imbalance in the immune surveillance mechanisms.

Malaria as a Papal Disease.

OBJECTIVES: In this study, we aimed to investigate the effects of malaria on the lives of Roman pontiffs. MATERIALS AND METHODS: The histories of all 264 popes from Saint Peter to John Paul II were extensively studied. RESULTS: Malaria affected the lives of Roman pontiffs. Between 999 AD and 1644 AD, 21 of 99 popes were affected by malaria (21.4%). The first affected was Gregory V and the last was Urban VII, the 138th and the 235th pope, respectively. There were 15 deaths (15.2%). Six pontiffs (6.1%) were infected but survived. Many cardinals and their assistants, especially those coming from northern countries, contracted malaria during conclaves, and many died. CONCLUSIONS: By about 450 BC, malaria had arrived in Rome. By the second century BC, malaria was endemic. It affected the lives of Roman people. To prevent infection, the popes adopted the custom of ancient affluent Romans who used to spend summer months in high plains far from Rome. The first to adopt the custom was Paul I in 767, who just moved his residence to Saint Paul, out of the walls. Sixtus V started the Congregation of Waters and Streets, which was routinely reinforced by his successors until 1860, when the Kingdom of Italy was born.

Acute Kidney Injury as a Leading Cause of Papal Deaths in the Years 1277 to 2005: A Review of 21 Cases.

OBJECTIVES: This study was devised to investigate papal deaths due to acute kidney injury, a topic for which scarce data exist. MATERIALS AND METHODS: We studied all popes between John XXI, who died in 1277 of crush syndrome, and John Paul II, who died of anuria and urinary sepsis in 2005. RESULTS: Between pontification years from 1277 to 2005, 21 of 78 popes (26.9%) died of acute kidney injury. Sepsis was identified as the leading cause of acute kidney injury and death in 20 of 21 popes (95.2%). Mean ± SE age at death of the 21 popes was 69.4 ± 2.26 years. Six popes (28.6%) died of stroke. CONCLUSIONS: Sepsis-associated acute kidney injury, a syndrome with a complex pathogenesis and poor prognosis, which is far from being fully understood, contributed to a high number of papal deaths.

High Prevalence of Kidney Stone Disease of Gouty Origin in Roman Pontiffs Reigning in the Years 537-2005.

OBJECTIVES: Many Roman pontiffs are known to have had kidney stone disease. However, no specific report has explored the prevalence of the various stones in popes, which is the purpose of this study. MATERIALS AND METHODS: We extensively studied the histories of all popes (n = 264) from Saint Peter to John Paul II (34-2005). RESULTS: Among 206 popes reigning from 537 to 2005, 26 popes (12.6%) had uric acid stones. In the same period, 11 of 206 popes (5.3%) had nongouty stones (mainly calcium stones). In total, 37 of 208 (17.8%) popes complained of kidney stone disease. The ratio of calcium stone formers to other stone formers (including uric acid) was 0.42. CONCLUSIONS: The data suggest a higher prevalence of uric acid stones, which is linked to higher consumption of meat and sodium chloride. However, the last pope with kidney stone disease died in 1914. Although renal stone disease disappeared from papal palaces, population studies now indicate an increase in uric acid levels in the general population. The data can be explained based on the "Theory of Epidemiological Transition," pointing to the importance of education in eradicating poor lifestyles.

Role of Immune Microenvironment in Pancreatic Ductal Adenocarcinoma: Could It Be Considered a Predictor of Prognosis?

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly immunosuppressive tumor microenvironment (TME). The aim of this study is to determine the potential significant TME immune markers of long-term survival. METHODS: We retrospectively included patients with a diagnosis of resectable PDAC having undergone upfront surgery. Immunohistochemical (IHC) staining using tissue microarray for PD-L1, CD3, CD4, CD8, FOXP3, CD20, iNOS and CD163 was performed in order to characterize the TME. The primary endpoint was long-term survival, defined as the Overall Survival > 24 months from surgery. RESULTS: A total of 38 consecutive patients were included, and 14 (36%) of them were long-term survivors. Long-term survivors showed a higher density of CD8+ lymphocytes intra- and peri-acinar (p = 0.08), and a higher CD8/FOXP3 intra- and peri-tumoral ratio (p = 0.05). A low density of intra- and peri-tumoral FOXP3 infiltration is a good predictor of long-term survival (p = 0.04). A significant association of the low density of intra- and peri-tumoral tumor-associated macrophages (TAMs) iNOS+ with long-term survival was detected (p = 0.04). CONCLUSIONS: Despite the retrospective nature and small sample size, our study showed that the high infiltration of CD8+ lymphocytes and low infiltration of FOXP3+ and TAMs iNOS+ are predictors of good prognosis. A preoperative assessment of these potential immune markers could be useful and determinant in the staging process and in PDAC management.

The Day-To-Day Practice of MMR and MSI Assessment in Colorectal Adenocarcinoma: What We Know and What We Still Need to Explore.

BACKGROUND: The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA replication and recombination. MMR protein status is identified using immunohistochemistry. Deficit in one or more MMR proteins, configuring deficient MMR status (dMMR), leads to frameshift mutations particularly clustered in microsatellite repeats. Thus, microsatellite instability (MSI) is the epiphenomenon of dMMR. In colorectal cancer (CRC), MMR/MSI status is a biomarker with prognostic and predictive value of resistance to 5-fluorouracil and response to immune checkpoint inhibitor therapy. SUMMARY: In this Review, we describe the challenges the practicing pathologist may face in relation to the assessment of MMR/MSI status and any open issues which still need to be addressed, focusing on pre-analytic issues, pitfalls in the interpretation, and technical aspects of the different assays. KEY MESSAGES: The current methods of detecting dMMR/MSI status have been optimized for CRCs, and whether these techniques can be applied to all tumor and specimen types is still not fully understood. Following the Food and Drug Administration (FDA), tissue/site agnostic drug approval of pembrolizumab for advanced/metastatic MSI tumors, MMR/MSI status in gastrointestinal tract is a common request from the oncologist. In this setting, several issues still need to be addressed, including criteria for sample adequacy.

IMMUNOREACT 5: female patients with rectal cancer have better immune editing mechanisms than male patients - a cohort study.

BACKGROUND: Studies evaluating sex differences in colorectal cancer (CRC) tumor microenvironment are limited, and no previous study has focused on rectal cancer patients' constitutive immune surveillance mechanisms. The authors aimed to assess gender-related differences in the immune microenvironment of rectal cancer patients. METHODS: A systematic review and meta-analysis were conducted up to 31 May 2021, including studies focusing on gender-related differences in the CRC tumor microenvironment. Data on the mutational profile of rectal cancer were extracted from the Cancer Genome Atlas (TCGA). A subanalysis of the two IMMUNOREACT trials (NCT04915326 and NCT04917263) was performed, aiming to detect gender-related differences in the immune microenvironment of the healthy mucosa in patients with early (IMMUNOREACT 1 cohort) and locally advanced rectal cancer following neoadjuvant therapy (IMMUNOREACT 2 cohort). In the retrospective IMMUNOREACT 1 cohort (therapy naive), the authors enrolled 442 patients (177 female and 265 male), while in the retrospective IMMUNOREACT 2 cohort (patients who had neoadjuvant therapy), we enrolled 264 patients (80 female and 184 male). In the prospective IMMUNOREACT 1 cohort (therapy naive), the authors enrolled 72 patients (26 female and 46 male), while in the prospective IMMUNOREACT 2 cohort (patients who had neoadjuvant therapy), the authors enrolled 105 patients (42 female and 63 male). RESULTS: Seven studies reported PD-L1 expression in the CRC microenvironment, but no significant difference could be identified between the sexes. In the TGCA series, mutations of SYNE1 and RYR2 were significantly more frequent in male patients with rectal cancer. In the IMMUNOREACT 1 cohort, male patients had a higher expression of epithelial cells expressing HLA class I, while female patients had a higher number of activated CD4+Th1 cells. Female patients in the IMMUNOREACT 2 cohort showed a higher infiltration of epithelial cells expressing CD86 and activated cytotoxic T cells (P=0.01). CONCLUSIONS: Male patients have more frequent oncogene mutations associated with a lower expression of T-cell activation genes. In the healthy mucosa of female patients, more Th1 cells and cytotoxic T cells suggest a potentially better immune response to the tumor. Sex should be considered when defining the treatment strategy for rectal cancer patients or designing prognostic scores.

Prognostic Implication of Preoperative Anemia in Redo Cardiac Surgery: A Single-Center Propensity-Matched Analysis.

Preoperative anemia has been associated with increased morbidity and mortality after cardiac surgery, but little is known about its prognostic value in the setting of redo procedure. A retrospective, observational cohort study of prospectively collected data was undertaken on 409 consecutive patients referred for redo cardiac procedures between January 2011 and December 2020. The EuroSCORE II calculated an average mortality risk of 25.7 ± 15.4%. Selection bias was assessed with the propensity-adjustment method. The prevalence of preoperative anemia was 41%. In unmatched analysis, significant differences between the anemic and nonanemic groups emerged in the risk for postoperative stroke (0.6% vs. 4.4%, p = 0.023), postoperative renal dysfunction (29.7% vs. 15.6%, p = 0.001), a need for prolonged ventilation (18.1% vs. 7.2%, p = 0.002), and high-dosage inotropes (53.1% vs. 32.9%, p < 0.001) along with both length of ICU and hospital stay (8.2 ± 15.9 vs. 4.3 ± 5.4 days, p = 0.003 and 18.8 ± 17.4 vs. 14.9 ± 11.1, p = 0.012). After propensity matching (145 pairs), preoperative anemia was still significantly associated with postoperative renal dysfunction, stroke, and the need for high-dosage inotrope cardiac morbidity. Preoperative anemia is significantly associated with acute kidney injury, stroke, and the need for high-dosage inotropes in patients referred for redo procedures.

Higher accuracy of surgical over core needle biopsy for the diagnosis of lymphoproliferative disorders.

INTRODUCTION: The diagnosis of lymphoproliferative disorders (LPDs) is based on histological evaluation of representative tissue samples. Despite surgical excision biopsies (SEBs) are reference procedures for such diagnoses, lymph node core needle biopsies (LNCBs) are increasingly performed. The diagnostic yield of LNCB is, however, debated and few studies have compared the reproducibility of LNCB and SEB findings. METHODS: To address the diagnostic value of LNCB and SEB, the present study considered a retrospective series of 43 paired LNCB/SEB samples. After histological revision, concordance rates between matched LNCB/SEB samples were evaluated, assuming SEB as gold standard procedure. The actionability of LNCB and SEB-based diagnoses (i.e., relevance for planning further medical interventions) was also assessed. RESULTS: Overall, LNCB provided actionable diagnoses in 39/43 (90.7%) cases, but a consistent subset of them (7/39 [17.9%]) turned out to be wrong at SEB. The cumulative diagnostic inaccuracy of LNCB (i.e., inadequate samples plus wrong diagnoses) was 25.6% and the mean diagnostic delay in such cases was 54.2 days. CONCLUSIONS: Although limited by selection biases due to its retrospective nature, this study highlights the intrinsic limitations of LNCB for the diagnosis of LPDs. SEB remains the gold standard procedure and should be performed in all suitable cases.

Morphological and molecular characterization of colorectal sessile serrated lesions with dysplasia.

In sessile serrated lesions (SSLs) with adenomatous dysplasia, the dysplastic component and the serrated component without dysplasia should be considered as part of the same lesion, classified as SSL with dysplasia. However, some of these lesions may actually represent collisions between a serrated polyp and a conventional adenoma. Further supporting the "collision theory", conventional adenomatous dysplasia may be found in association with hyperplastic polyps (HPs). In order to determine the molecular and biological landscape of conventional type dysplasia in serrated lesions, we collected 17 cases of colorectal serrated lesions with adenomatous dysplasia, classifying them as SSL with dysplasia (n = 10) or as mixed lesions comprising a HP component and a conventional adenomatous component (n = 7). We characterized the dysplastic and the non-dysplastic component of each lesion, after microdissection, through the targeted mutational analysis of 11 commonly altered genes in colorectal cancer (AKT1, APC, BRAF, CTNNB1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, PTEN and TP53). We also characterized MMR and p53 status by immunohistochemistry. Overall, 14/17 (82.4 %) cases harbored a mutation in at least one of the two components. The most altered genes were BRAF in 10/17 (58.8 %) cases, APC in 2/17 (11.8 %) and TP53 in 4/17 (23.5 %). Among the SSL with dysplasia, the mutational profile was concordant between the two components in 7/10 (70 %) cases, while among the mixed lesions, the mutational profile was concordant in 1/7 (14.3 %). In all but two cases of SSL with dysplasia, MMR status was concordant between the two components of the serrated lesions. Our findings suggest that adenomatous dysplasia may develop in SSL as part of the serrated lesion, even if some SSL with dysplasia may actually be collision lesions. On the other hand, the polyps that are morphologically classifiable as mixed lesions composed of a HP and a conventional adenomatous component are more likely to be collision lesions.

The Dropsy of Popes (1555-1978): A Bad Prognostic Sign Foreboding of Death.

The purpose of this study is to explore the historical background of edema as a prognostic sign in popes, a special category of medical subjects whose health status was closely monitored and chronicled because of their unique important status in the events of their times. Nine out of 51 popes, who reigned in the years 1555-1978, died edematous at a mean age of 75.5 years of age. The cause of edema was: heart failure for John Paul I, liver disease, obstructive nephropathy associated with anemia for Paul IV, who also suffered from deep vein thrombosis, and malnutrition for Innocent XIII. Chronic kidney disease due to renal stones of gouty origin caused edema in Clement VIII, Clement X, Clement XI, and Benedict XIV. Obstructive nephropathy due to renal stones of non-gouty origin caused edema in Clement XIII, whereas toxic nephropathy due to the use of mercurials caused edema in Clement XIV. Innocent XI, Benedict XIV, and Clement XIV were bled before death because of impending pulmonary edema. It is not surprising that chronic kidney disease was a significant cause of edema in popes with chronic kidney disease which is associated with impaired sodium excretion. The edema was likely aggravated by the excessive dietary salt intake of the period when the importance of sodium chloride restriction was still not discovered and effective diuretic agents were not available.

Pius X (1835-1914): the last gouty pope.

Gout is a common, complex, systemic and well-studied form of chronic inflammatory arthritis in adults. It is due to the deposition of sodium monourate crystals in peripheral joints and periarticular tissues driven by hyperuricemia. Gout is the oldest recorded inflammatory arthritis to affect humankind, with roots stretching back to 2460 BC. It is known as "the rich man's disease", "the patrician malady", "a disease of plenty", "disease of kings", "disease of Western Society", and also "a life-style disease". Few studies have addressed the problem of gout among popes, affluent people who usually live longer than their contemporaries and are among the most scrutinized persons. Pius X (1835-1914) was the last pope with gout. Gout seems to have affected 26 out of 265 popes (9.81%) from Saint Peter to Benedict XVI (34-2013 AD). The first was Gregory I Magnus, who was pope in the years 590-604, the last was Pius X, who reigned from 1903 to 1914 at age 79. Their age at death was 71.7 ±9.2 years (Mean ± SD). All popes were elderly men, some had voracious appetites and/or were wine drinkers. Several were sedentary and obese, while others were sober eaters, who took long walks or went riding. Chiragra (arthritic pain in the hands), podagra (arthritic pain in the big toe) and renal stone disease were among the most frequent disturbances. The causes of death, due to CKD, strokes and infections are discussed along with the fact that gout disappeared from the Vatican Palace on August 22, 1914. However, in accordance with the Theory of Epidemiological Transition, gout seems likely to become a problem for the general population, increasingly adopting unhealthy lifestyle choices, in the absence of a correct education.

Incidental lymphomas in surgical pathology: diagnostic clues and clinical-pathological correlations.

Incidental lymphomas (ILs) are rare and challenging lesions with poorly characterized clinical-epidemiological and histological features. The present study addressed the open issues concerning these tumors, by assessing the clinical-pathological features of 28 consecutive ILs, diagnosed over a 10-year period at a tertiary center for surgical pathology. ILs were more frequently documented in elderly males (mean age at surgery 70.8 years; M/F ratio 3.3), with sharp prevalence of gastrointestinal and urinary tract involvement (22/28 [78.6%] cases). Low-grade B-cell lymphomas outnumbered all other entities, and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was the most common subtype (18/28 [64.3%] cases). Compared to other ILs, CLL/SLL occurred at older age and was the sole lymphoid neoplasm affecting the urinary tract. In conclusion, ILs are rare lesions, mostly affecting the gastrointestinal and urinary tract of elderly males. The diagnosis of IL is based on a high degree of suspicion and on careful morphological/phenotypic characterization.

Beware of Histiocytes: Whipple Adenopathy and its Mimics.

Histiocytic proliferations are heterogeneous lesions with distinct pathogenic and clinical-pathological features. While many of these conditions are nonspecific immune responses to variable causes, a minority of them is associated with specific etiological factors and unique clinical-pathological pictures. By presenting a rare case of Whipple adenopathy, we address the peculiar histological features of this condition and the differential diagnosis of nodal histiocytosis in general.