Clinical implementation of artificial-intelligence-assisted detection of breast cancer metastases in sentinel lymph nodes: the CONFIDENT-B single-center, non-randomized clinical trial.

Pathologists' assessment of sentinel lymph nodes (SNs) for breast cancer (BC) metastases is a treatment-guiding yet labor-intensive and costly task because of the performance of immunohistochemistry (IHC) in morphologically negative cases. This non-randomized, single-center clinical trial (International Standard Randomized Controlled Trial Number:14323711) assessed the efficacy of an artificial intelligence (AI)-assisted workflow for detecting BC metastases in SNs while maintaining diagnostic safety standards. From September 2022 to May 2023, 190 SN specimens were consecutively enrolled and allocated biweekly to the intervention arm (n = 100) or control arm (n = 90). In both arms, digital whole-slide images of hematoxylin-eosin sections of SN specimens were assessed by an expert pathologist, who was assisted by the 'Metastasis Detection' app (Visiopharm) in the intervention arm. Our primary endpoint showed a significantly reduced adjusted relative risk of IHC use (0.680, 95% confidence interval: 0.347-0.878) for AI-assisted pathologists, with subsequent cost savings of ~3,000 €. Secondary endpoints showed significant time reductions and up to 30% improved sensitivity for AI-assisted pathologists. This trial demonstrates the safety and potential for cost and time savings of AI assistance.

Clinical and Histological Response to Talimogene Laherparepvec Therapy in Advanced Melanoma: Impact on Overall Survival.

BACKGROUND: Talimogene laherparepvec (T-VEC) is an FDA-approved oncolytic herpesvirus therapy used for unresectable stage IIIB through IV metastatic melanoma. However, the correlation between clinical complete response (cCR) and pathologic complete response (pCR) in patients treated with T-VEC is understudied. STUDY DESIGN: We conducted a retrospective study from a prospectively maintained IRB-approved melanoma single-center database in patients treated with T-VEC from October 2015 to April 2022. Patients were categorized into 3 groups: cCR with pCR, cCR without pCR, and less than cCR. The primary endpoint was overall survival. We used descriptive statistics, chi-square tests, and Wilcoxon rank-sum tests to compare key covariates among exposure groups. We used survival analysis to compare survival curves and reported hazard ratio of death (95% CI) across exposure groups. RESULTS: We included 116 patients with a median overall survival (interquartile range) of 22.7 (14.8-39.3) months. The majority were men (69%) and White (97.4%), with a median age of 74.5 years. More than half of patients (n = 60, 51.6%) achieved cCR. Distribution among the groups was as follows: cCR with pCR (35.3%), cCR without pCR (16.3%), and less than cCR (48.4%). Median overall survival time (interquartile range) was 26.5 (18.6-36.0) months for cCR with pCR, 22.7 (14.4-35.5) months for cCR without pCR, and 17.8 (9.2-47.0) months for less than cCR (log-rank p value = 0.0033). CONCLUSIONS: Patients achieving cCR with pCR after T-VEC therapy have the most favorable overall survival outcomes, whereas those achieving cCR without pCR have inferior survival and those achieving less than cCR have the poorest overall survival outcomes. These findings emphasize the importance of histological confirmation and provide insights for optimizing T-VEC therapy in patients with advanced melanoma.

Foot-and-Mouth Disease Virus Serotype O/CATHAY Genome Sequences from Five Outbreaks in Vietnam, 2017 to 2019.

We report the genomes of five foot-and-mouth disease viruses (FMDVs) from distinct provinces in Vietnam. All five viruses were grouped within the O/CATHAY topotype. Sequences contain the full polyprotein coding sequence and partial untranslated regions. These genomes provide critical data on the spread and evolution of FMDVs in the region.

First Genome Sequence of Foot-and-Mouth Disease Virus Serotype O Sublineage Ind2001e from Southern Vietnam.

We report the polyprotein coding sequence of the newly defined Ind2001e sublineage of foot-and-mouth disease virus (FMDV) serotype O, isolated from a bovine epithelial tissue sample collected in 2017 in Kon Tum Province, Vietnam. This discovery updates FMDV diversity in Vietnam, has implications for FMDV epidemiology, and influences future vaccine selections.

Mid-term outcomes of routine proximal row carpectomy compared with proximal row carpectomy with dorsal capsular interposition arthroplasty for the treatment of late-stage arthropathy of the wrist.

AIMS: The aims of this study were to compare the mid-term outcomes of patients with late-stage arthritis of the wrist treated with proximal row carpectomy (PRC) and dorsal capsular interposition (DCI) arthroplasty with a matched cohort treated with routine PRC alone. PATIENTS AND METHODS: A total of 25 arthritic wrists (24 patients) with pre-existing degenerative changes of the proximal capitate and/or the lunate fossa of the radius were treated with PRC + DCI over a ten-year period. This group of patients were matched 1:2 with a group of 50 wrists (48 patients) without degenerative changes in the capitate or lunate fossa that were treated with a routine PRC alone during the same period. The mean age of the patients at the time of surgery was 56.8 years (25 to 81), and the demographics and baseline range of movement of the wrist, grip strength, Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score, and Patient-Rated Wrist Evaluation (PRWE) score were similar in both groups. RESULTS: At a mean follow-up of 5.9 years (1.8 to 11.8), significant improvements in mean grip strength, the flexion-extension arc of movement of the wrist, QuickDASH, and PRWE scores were seen in both groups. There was no diifference between the groups for any of the outcomes. One patient in the PRC + DCI group required additional surgery for a deep infection, while two in the PRC group had complications (one wound dehiscence requiring revision closure, one transient radial sensory neuritis). One patient in each group required total arthrodesis of the wrist for progressive degenerative radiocarpal changes. A total of 70 patients (93%) were satisfied with the outcomes. CONCLUSION: PRC with DCI is an effective form of treatment for late-stage arthritis of the wrist involving the capitolunate joint, with mid-term outcomes that are similar to those in patients without degenerative changes affecting the capitate or lunate fossa who are treated with a routine PRC alone. Cite this article: Bone Joint J 2018;100-B:197-204.

Early introduction of palliative care and advanced care planning for children with complex chronic medical conditions: a pilot study.

BACKGROUND: Children with complex chronic medical conditions benefit from early introduction of palliative care services and advanced care planning for symptom management and to support quality of life and medical decision-making. This study evaluated whether introducing palliative care during primary care appointments (1) was feasible; (2) increased access and improved knowledge of palliative care; and (3) facilitated advanced care planning. METHODS: Pilot study of a multi-modal intervention including targeted education for primary care providers (PCPs), an informational packet for families and presence of a palliative care team member in the outpatient clinic. PCPs completed pre- and post-surveys assessing experience, knowledge and comfort with palliative care. Enrolled families received an information packet; a subset also met a palliative care team member. All families were encouraged to make an appointment with the palliative care team, during which the team assessed palliative care needs and goals of care. Upon study completion, the investigators assessed family and PCP satisfaction and collected feedback on project feasibility. RESULTS: Twenty families were enrolled and received the information packet; 15 met a palliative care team member. Of the 17 participating families who were reached and completed a post-study survey, 11 families had never heard of palliative care and 13 were unaware that the palliative care team existed. Most families perceived palliative care information as 'very helpful' and 'very important'. All would recommend palliative care team services to others. Nine families followed up with the palliative care team, but none was prepared to complete an advanced care plan. PCPs reported lack of training in communicating bad news and conducting goals of care discussions. However, they felt increasingly comfortable introducing palliative care to families and supported program continuation. CONCLUSIONS: Initiating palliative care services in the outpatient primary care setting is logistically challenging but increases access to palliative care for children with complex chronic medical conditions and improves palliative care knowledge and comfort for PCPs.

Temporary protection of rainbow trout gill epithelial cells from infection with viral haemorrhagic septicaemia virus IVb.

The branchial epithelium is not only a primary route of entry for viral pathogens, but is also a site of viral replication and subsequent shedding may also occur from the gill epithelium. This study investigated the potential of agents known to stimulate innate immunity to protect rainbow trout epithelial cells (RTgill-W1) from infection with VHSV IVb. RTgill-W1 cells were pretreated with poly I:C, FuGENE(®) HD + poly I:C, lipopolysaccharide (LPS), LPS + poly I:C or heat-killed VHSV IVb and then infected with VHSV IVb 4 days later. Cytopathic effect (CPE) was determined at 2, 3, 4, 7 and 11 days post-infection. Virus in cells and supernatant was detected using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). All of the treatments delayed the onset of CPE (per cent of monolayer destruction), compared with untreated controls; however, killed VHSV or poly I:C combined with LPS was the most effective. Similarly, the detection of viral RNA in the supernatant was delayed, and the quantity was significantly (P < 0.05) reduced by all treatments with the exception of LPS alone (4 days). Unlike many of the other treatments, pretreatment of RTgill-W1 with heat-killed VHSV did not upregulate interferon 1, 2 or MX 1 gene expression.

Use of cell lines and primary cultures to explore the capacity of rainbow trout to be a host for frog virus 3 (FV3).

The capacity of rainbow trout, Oncorhynchus mykiss, to be a host for frog virus 3 (FV3) was evaluated at the cellular level. Cell cultures from this species were tested for their ability to express FV3 major capsid protein (MCP) gene, to develop cytopathic effect (CPE), and to produce FV3. After FV3 addition, MCP transcripts were detected in six of six cell lines and in primary macrophage cultures. CPE developed in all cell culture systems, except primary lymphocytes. For the macrophage cell line, RTS11, and primary macrophages, cell death was by apoptosis because DNA laddering and Annexin staining were detected. By contrast, markers of apoptosis did not accompany CPE in three epithelial cell lines from the gill (RTgill-W1), intestine (RTgut-GC), and liver (RTL-W1) and in two fibroblast cell lines from gonads (RTG-2) and skin (RTHDF). Therefore, FV3 was able to enter and begin replicating in several cell types. Yet, FV3 was produced in only two cell lines, RTG-2 and RTL-W1, and only modestly. Overall, these results suggest that if tissue accessibility were possible, FV3 would have the capacity to induce injury, but the ability to replicate would be limited, likely making rainbow trout a poor host for FV3.

Evidence for the role of EPHX2 gene variants in anorexia nervosa.

Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric conditions with likely rare and common genetic and environmental determinants. To identify genetic variants associated with AN, we pursued a series of sequencing and genotyping studies focusing on the coding regions and upstream sequence of 152 candidate genes in a total of 1205 AN cases and 1948 controls. We identified individual variant associations in the Estrogen Receptor-ß (ESR2) gene, as well as a set of rare and common variants in the Epoxide Hydrolase 2 (EPHX2) gene, in an initial sequencing study of 261 early-onset severe AN cases and 73 controls (P=0.0004). The association of EPHX2 variants was further delineated in: (1) a pooling-based replication study involving an additional 500 AN patients and 500 controls (replication set P=0.00000016); (2) single-locus studies in a cohort of 386 previously genotyped broadly defined AN cases and 295 female population controls from the Bogalusa Heart Study (BHS) and a cohort of 58 individuals with self-reported eating disturbances and 851 controls (combined smallest single locus P<0.01). As EPHX2 is known to influence cholesterol metabolism, and AN is often associated with elevated cholesterol levels, we also investigated the association of EPHX2 variants and longitudinal body mass index (BMI) and cholesterol in BHS female and male subjects (N=229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (P<0.01). These findings suggest a novel association of gene variants within EPHX2 to susceptibility to AN and provide a foundation for future study of this important yet poorly understood condition.

Combination antifungal therapy for cryptococcal meningitis.

BACKGROUND: Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days. METHODS: We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks. RESULTS: A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P=0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P=0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P=0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P=0.13). Amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (-0.42 log10 colony-forming units [CFU] per milliliter per day vs. -0.31 and -0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy. CONCLUSIONS: Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.).

Differential effects of viral hemorrhagic septicaemia virus (VHSV) genotypes IVa and IVb on gill epithelial and spleen macrophage cell lines from rainbow trout (Oncorhynchus mykiss).

The two most prominent genotypes of viral hemorrhagic septicemia virus (VHSV) are -I in the Northeastern Atlantic region and -IV in North America, but much more is known about the cellular pathogenesis of genotype -I than -IV. VHSV genotype -IV is divided into -IVa from the Northeast Pacific Ocean and -IVb from the Great Lakes and both of which are less virulent to rainbow trout than genotype -I. In this work, infections of VHSV-IVa and -IVb have been studied in two rainbow trout cell lines, RTgill-W1 from the gill epithelium, and RTS11 from spleen macrophages. RTgill-W1 produced infectious progeny of both VHSV-IVa and -IVb. However, VHSV-IVa was more infectious than -IVb toward RTgill-W1: -IVa caused cytopathic effect (CPE) at a lower viral titre, elicited CPE earlier, and yielded higher titres. By contrast, no CPE and no increase in viral titre were observed in RTS11 cultures infected with either genotype. Yet in RTS11 all six VHSV genes were expressed and antiviral genes, Mx2 and Mx3, were up regulated by VHSV-IVb and -IVa. However, replication appeared to terminate at the translational stage as viral N protein, presumably the most abundant of the VSHV proteins, was not detected in either infected RTS11 cultures. In RTgill-W1, Mx2 and Mx3 were up regulated to similar levels by both viral genotypes, while VHSV-IVa induced higher levels of IFN1, IFN2 and LGP2A than VHSV-IVb.

Ischemic preconditioning induces autophagy and limits necrosis in human recipients of fatty liver grafts, decreasing the incidence of rejection episodes.

Whether ischemic preconditioning (IP) reduces ischemia/reperfusion (I/R) injury in human normal and fatty livers remains controversial. We compared two independent groups of liver donor transplants with versus without steatosis to evaluate IP consequences. Liver donors with (n=22) or without (n=28) steatosis either did or did not undergo IP before graft retrieval. Clinical data from the recipients, as well as histological and immunohistological characteristics of post-reperfusion biopsies were analyzed. Incidence of post-reperfusion necrosis was increased (10/10 versus 9/14, respectively; P<0.05) and the clinical outcome of recipients was worse for non-IP steatotic liver grafts compared with non-IP non-steatotic grafts. IP significantly lowered the transaminase values only in patients receiving a non-steatotic liver. An increased expression of beclin-1 and LC3, two pro-autophagic proteins, tended to decrease the incidence of necrosis (P=0.067) in IP steatotic livers compared with non-IP steatotic group. IP decreased the incidence of acute and chronic rejection episodes in steatotic livers (2/12 versus 6/10; P=0.07 and 2/12 versus 7/10; P<0.05, respectively), but not in non-steatotic livers. Thus, IP may induce autophagy in human steatotic liver grafts and reduce rejection in their recipients.

Pain prevalence in patients with chronic kidney disease.

BACKGROUND: The prevalence of pain in patients with chronic kidney diseases (CKD) is not known. In the current study, we aim to determine the prevalence of pain in CKD patients and its associations with various medical and psychosocial factors. METHODS: Consecutive CKD patients who were presented to the renal clinic at Olive View-UCLA Medical Center, a Los Angeles County tertiary referral center, over a 3-month period were interviewed on their medical and psychosocial histories and a history of pain including duration, severity and source. Chi2-testing for independence and binary logistic regression performed for the presence of pain and CKD stages as well as other medical and psychosocial factors were determined. A separate survey for pain was also done for 100 consecutive non-CKD patients who were presented to our ambulatory medicine clinic for routine care. RESULTS: 54.6% of 130 patients with known CKD interviewed were women. Any type of pain of at least a 2 week duration was reported in 72.9%. The most common source of pain was musculoskeletal. The presence of pain of less than a 2 week duration was associated with worse CKD stages (3 - 5 versus 1 - 2) and non-exercisers. Higher body mass index was associated with having pain lasting longer than a 2 week duration. Among patients who had pain, 33.8% used acetaminophen, 15.4% nonsteroidal anti-inflammatory drugs and 7.8% combination analgesics. In contrast to CKD patients, only 9% of non-CKD patients reported to have any type or duration of pain. CONCLUSIONS: Pain was much more prevalent among our CKD compared with non-CKD patients.

Death from metastatic donor-derived ovarian cancer in a male kidney transplant recipient.

Posttransplant malignancy developing in an allograft is an uncommon complication of organ transplantation. The tumor may represent malignant transformation of donor or recipient cells that were previously normal, metastatic malignancy of recipient origin or malignancy transmitted from organ donor to recipient. Establishing the origin of the malignancy is critical to treatment algorithms. It is generally believed allograft removal and immunosuppression withdrawal will lead to resolution of transmitted malignancies in cases where the renal allograft is the origin. We report a male patient who developed metastatic ovarian malignancy secondary to donor transmission.

Clinical pathways in general surgery. Development, implementation, and evaluation.

OBJECTIVES: To emphasize the importance of the view of business process management for development and implementation of clinical pathways, and to evaluate their effectiveness in reducing cost and effort as well as enhancing patient satisfaction. METHODS: We describe the development and implementation of pathways with methods of process management and the design and realization of an evaluation study in the setting of a surgical department. For this study 67 patients treated without clinical pathways were compared with 62 patients treated using pathways. RESULTS: The approach explicitly enhances the development and implementation of clinical pathways. The introduction of pathways reduces length of hospital stay, number of laboratory tests, number of consultations, and number of imaging procedures. Patient satisfaction is improved. CONCLUSIONS: Depending on design and setting, the introduction of clinical pathways may be a very promising method to improve the inpatient service at a hospital and so to react to the challenges of increasing competition in medical care.

[Molecular biology and hepatocellular carcinoma: current status and future prospects]. / Biologie moléculaire et carcinome hépatocellulaire: données actuelles et développements futurs. Prix international de la SFBC 2003.

Hepatocellular carcinoma (HCC) is among the fifth most common cancers worldwide. Its incidence is still rising in part because of the high level of hepatitis C virus infection. Tumor markers currently used such as serum alpha-foetoprotein are not sufficient for diagnosis of the tumor and satisfying follow-up of the patients. Mechanisms of hepatocarcinogenesis ar not completely understood although several altered genes have been described in HCC. The genetic changes involved can be divided in at least 4 different pathways, each pathway contributing to a limited number of tumors. These are: 1) the p53 pathway involved in response to DNA damage, 2) the retinoblastoma pathway involved in the control of the cell cycle, 3) the transforming growth factor-beta (TGF-beta) pathway involved in growth inhibition, and 4) the Wnt pathway involved in cell-cell adhesion and signal transduction. Alterations of the epigenetic regulation of gene expression have also been described. Evolution of molecular biology methods tends to the development of more global genomic approaches; microsatellite instability analysis, chromosomal instability analysis or gene expression profile analysis have been used to investigate HCC. Finally, attempts to develop molecular biomarkers based on peripheral blood analysis more easily accessible in clinical routine patients have also been developed.

Sodium and water disturbances in patients with Sheehan's syndrome.

Sheehan's syndrome has been attributed to ischemic damage of the pituitary gland or hypothalamic-pituitary stalk during the peripartum period. Well-described clinical features of Sheehan's syndrome include hypothyroidism, adrenal insufficiency, hypogonadism, growth hormone deficiency, hypoprolactinemia, and different sodium and water disturbances. The occurrence of sodium and water disturbances associated with Sheehan's syndrome depends on the degree of pituitary damage, time of onset since the initial pituitary insult, and concurrent medical conditions that also may play a role in sodium and water balance. We present a patient with Sheehan's syndrome with severe chronic hyponatremia; discuss a potential problem in the patient's management; and review the literature for various sodium and water disturbances, including acute and chronic hyponatremia as well as overt and subclinical central diabetes insipidus. Although Sheehan's syndrome is more prevalent in developing countries, the increasingly large immigrant population within the United States warrants better awareness of this syndrome and its potential complicating sodium and water disturbances. Prompt diagnosis and an understanding of the pathogenic mechanisms of sodium and water disturbances associated with Sheehan's syndrome may avoid potential treatment-related complications.

Detection of gammopathy by serum protein electrophoresis for predicting and managing therapy of lymphoproliferative disorder in 911 recipients of liver transplants.

Monitoring of posttransplantation lymphoproliferative disorder (LPD) is usually based on imaging, which lacks sensitivity. A prospective study in 911 consecutive recipients of liver transplants was conducted to assess the value of gammopathy monitoring by serum protein electrophoresis (SPE) and to compare it with conventional follow-up methods. Patients systematically underwent SPE testing just before transplantation, at least twice during the first year after transplantation, and once a year thereafter. Patients with LPD underwent SPE testing every month. Immunofixation was done if abnormalities were detected by SPE. Gammopathy was observed in 114 patients, 18 of whom had onset of LPD. In 3 other patients, LPD developed, but no gammopathy was detected before onset of LPD or while LPD was present. Multivariate analyses showed gammopathy (relative risk [RR], 65.3), more than one transplantation (RR, 7.5), and viral cirrhosis (RR, 2.8) to be independent prognostic factors associated with occurrence of LPD. LPD was treated by reducing immunosuppression, with or without chemotherapy, administration of anti-CD20 monoclonal antibody, or surgery. The mortality rate was 24% (5 of 21 patients). Remission, which occurred in 13 patients, was associated with disappearance of gammopathy in 10 patients. In 5 patients, normalization of SPE results preceded the diagnosis of remission based on imaging, by a mean of 4 months. For diagnosis of LPD remission, the positive and negative predictive values of disappearance of gammopathy were 91% and 100%, respectively; and gammopathy monitoring was more sensitive than imaging (100% and 38%, respectively). Gammopathy monitoring is an inexpensive, noninvasive, sensitive way to detect LPD and assess the efficacy of treatment. It could be used routinely in follow-up of recipients of transplants.