Healthy tissue metabolism assessed by [18F]FDG PET/CT as a marker of prognosis and adverse events in advanced Hodgkin lymphoma patients.

The aim of the study was to assess healthy tissue metabolism (HTM) using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) during chemotherapy in Hodgkin lymphoma (HL) and the association of HTM with baseline metabolic tumour volume (MTV), haematological parameters, adverse events (AEs), early response and progression-free survival (PFS). We retrospectively identified 200 patients with advanced HL from the RATHL trial with [18F]FDG-PET/CT before (PET0) and following 2 cycles of chemotherapy (PET2). [18F]FDG-uptake was measured in bone marrow (BM), spleen, liver and mediastinal blood pool (MBP). Deauville score (DS) 1-3 was used to classify responders and DS 4-5, non-responders. [18F]FDG-uptake decreased significantly in BM and spleen and increased in liver and MBP at PET2 (all p < 0.0001), but was not associated with MTV. Higher BM uptake at PET0 was associated with lower baseline haemoglobin and higher absolute neutrophil counts, platelets, and white blood cells. High BM, spleen, and liver uptake at PET0 was associated with neutropenia after cycles 1-2. BM uptake at PET0 was associated with treatment failure at PET2 and non-responders with higher BM uptake at PET2 had significantly inferior PFS (p = 0.023; hazard ratio = 2.31). Based on these results, we concluded that the change in HTM during chemotherapy was most likely a direct impact of chemotherapy rather than a change in MTV. BM uptake has prognostic value in HL.

A first-in-class inhibitor of HSP110 to potentiate XPO1-targeted therapy in primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma.

BACKGROUND: Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) are distinct hematological malignancies of B-cell origin that share many biological, molecular, and clinical characteristics. In particular, the JAK/STAT signaling pathway is a driver of tumor development due to multiple recurrent mutations, particularly in STAT6. Furthermore, the XPO1 gene that encodes exportin 1 (XPO1) shows a frequent point mutation (E571K) resulting in an altered export of hundreds of cargo proteins, which may impact the success of future therapies in PMBL and cHL. Therefore, targeted therapies have been envisioned for these signaling pathways and mutations. METHODS: To identify novel molecular targets that could overcome the treatment resistance that occurs in PMBL and cHL patients, we have explored the efficacy of a first-in-class HSP110 inhibitor (iHSP110-33) alone and in combination with selinexor, a XPO1 specific inhibitor, both in vitro and in vivo. RESULTS: We show that iHSP110-33 decreased the survival of several PMBL and cHL cell lines and the size of tumor xenografts. We demonstrate that HSP110 is a cargo of XPO1wt as well as of XPO1E571K. Using immunoprecipitation, proximity ligation, thermophoresis and kinase assays, we showed that HSP110 directly interacts with STAT6 and favors its phosphorylation. The combination of iHSP110-33 and selinexor induces a synergistic reduction of STAT6 phosphorylation and of lymphoma cell growth in vitro and in vivo. In biopsies from PMBL patients, we show a correlation between HSP110 and STAT6 phosphorylation levels. CONCLUSIONS: These findings suggest that HSP110 could be proposed as a novel target in PMBL and cHL therapy.

Antibody-Drug Conjugate Made of Zoledronic Acid and the Anti-CD30 Brentuximab-Vedotin Exert Anti-Lymphoma and Immunostimulating Effects.

Relevant advances have been made in the management of relapsed/refractory (r/r) Hodgkin Lymphomas (HL) with the use of the anti-CD30 antibody-drug conjugate (ADC) brentuximab-vedotin (Bre-Ved). Unfortunately, most patients eventually progress despite the excellent response rates and tolerability. In this report, we describe an ADC composed of the aminobisphosphonate zoledronic acid (ZA) conjugated to Bre-Ved by binding the free amino groups of this antibody with the phosphoric group of ZA. Liquid chromatography-mass spectrometry, inductively coupled plasma-mass spectrometry, and matrix-assisted laser desorption ionization-mass spectrometry analyses confirmed the covalent linkage between the antibody and ZA. The novel ADC has been tested for its reactivity with the HL/CD30+ lymphoblastoid cell lines (KMH2, L428, L540, HS445, and RPMI6666), showing a better titration than native Bre-Ved. Once the HL-cells are entered, the ADC co-localizes with the lysosomal LAMP1 in the intracellular vesicles. Also, this ADC exerted a stronger anti-proliferative and pro-apoptotic (about one log fold) effect on HL-cell proliferation compared to the native antibody Bre-Ved. Eventually, Bre-Ved-ZA ADC, in contrast with the native antibody, can trigger the proliferation and activation of cytolytic activity of effector-memory Vδ2 T-lymphocytes against HL-cell lines. These findings may support the potential use of this ADC in the management of r/r HL.

Protein kinase CK2α is overexpressed in classical hodgkin lymphoma, regulates key signaling pathways, PD-L1 and may represent a new target for therapy.

Introduction: In classical Hodgkin lymphoma (cHL), the survival of neoplastic cells is mediated by the activation of NF-κB, JAK/STAT and PI3K/Akt signaling pathways. CK2 is a highly conserved serine/threonine kinase, consisting of two catalytic (α) and two regulatory (ß) subunits, which is involved in several cellular processes and both subunits were found overexpressed in solid tumors and hematologic malignancies. Methods and results: Biochemical analyses and in vitro assays showed an impaired expression of CK2 subunits in cHL, with CK2α being overexpressed and a decreased expression of CK2ß compared to normal B lymphocytes. Mechanistically, CK2ß was found to be ubiquitinated in all HL cell lines and consequently degraded by the proteasome pathway. Furthermore, at basal condition STAT3, NF-kB and AKT are phosphorylated in CK2-related targets, resulting in constitutive pathways activation. The inhibition of CK2 with CX-4945/silmitasertib triggered the de-phosphorylation of NF-κB-S529, STAT3-S727, AKT-S129 and -S473, leading to cHL cell lines apoptosis. Moreover, CX-4945/silmitasertib was able to decrease the expression of the immuno-checkpoint CD274/PD-L1 but not of CD30, and to synergize with monomethyl auristatin E (MMAE), the microtubule inhibitor of brentuximab vedotin. Conclusions: Our data point out a pivotal role of CK2 in the survival and the activation of key signaling pathways in cHL. The skewed expression between CK2α and CK2ß has never been reported in other lymphomas and might be specific for cHL. The effects of CK2 inhibition on PD-L1 expression and the synergistic combination of CX-4945/silmitasertib with MMAE pinpoints CK2 as a high-impact target for the development of new therapies for cHL.

Spatial phenotyping of nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma with sparse tumor B-cells and a favorable prognosis. Variant growth patterns of NLPHL, however, often show advanced stage, progression to T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) and a worse prognosis. We studied the tumor microenvironment (TME) of NLPHL and THRLBCL using highplex imaging and spatial profiling at the single cell level. Our findings show distinct differences in TME composition and spatial configuration that differ among typical and variant NLPHL and THRLBCL. Typical NLPHL show abundant helper T-cell subsets, while THRLBCL show abundant cytotoxic T-cells and macrophages. Tumor B-cell size and content is lowest in typical NLPHL, followed by variant NLPHL, and highest in THRLBCL, whereas an opposite trend characterized TME B-cells. CD4/CD8 double-positive T-cells are seen in all NLPHL but not in the majority of THRLBCL and are spatially distant from LP-cells and TFH-rosettes. The differences in macrophage/monocyte content in distinguishing NLPHL pattern E from THRLBCL is further corroborated in independent cohorts of cases. Our results validate the current approach to classification and in addition provide novel insights that could be leveraged to refine clinical management for patients with this spectrum of lymphomas.

Two Cases of Synchronous Hodgkin Lymphoma and Papillary Thyroid Carcinoma in 18 F-FDG PET/CT.

ABSTRACT: The concurrence of Hodgkin lymphoma and papillary thyroid carcinoma is a rare clinical event. Two women presented with a painless mass in the neck that was suspected malignancy by ultrasonography. Both cases shown in the 18 F-FDG PET/CT images demonstrated multiple foci of increased FDG uptake in the neck, mimicking thyroid carcinoma with contralateral cervical lymph node metastases. Unexpectedly, the postoperative pathologies confirmed the thyroid lesion of papillary carcinoma and contralateral cervical lymph nodes of classical Hodgkin lymphoma.

Real-life study on the use of response adapted therapy in patients with Hodgkin Lymphoma: Results from a multicenter experience.

Few data are known regarding the use of interim positron emission tomography (iPET) after the first two cycles (iPET2) of chemotherapy in treatment-naïve classical Hodgkin lymphoma (cHL) in routine clinical practice, and about the real-life adoption of intensification strategies for iPET positive patients. We conducted a multicenter retrospective study on cHL to investigate the use of iPET in the real-life setting, its prognostic role and outcomes of patients early shifted to intensification. Six hundreds and forty-one patients were enrolled (62% had advanced stage). iPET2 was positive in 89 patients (14%) including 8.7% and 17% early and advanced stage patients, respectively (p = 0.003). Among iPET 2 positive cases treatment was immediately modified in 19 cases; in 14 cases treatment was modified after an additional positive iPET4. Overall 56 iPET2 positive patients never received intensified therapies. Most frequently used intensified therapy was autologous stem cell transplantation followed by BEACOPP. After a median follow-up of 72 months, the 5-year progression-free survival (PFS) was 82% with iPET2 positive patients showing a worse PFS compared with iPET2 negative cases: 31% versus 85%. Focusing on advanced stage patients with a positive iPET2, the 5-year PFS was 59% for patients shifted to intensified therapy at any time point versus 61% for patients who never received intensified therapy. Our study confirmed the higher curability of naïve cHL patients in a real-world setting, and the prognostic role of iPET2 in this setting. A poor adherence to response-adapted strategy which however did not translate into a difference in patient outcomes.

Evidence for external beam radiotherapy in mediastinal Hodgkin and non-Hodgkin lymphoma - systematic review.

INTRODUCTION AND OBJECTIVE: Proton beam therapy (PBT) provides the opportunity for a more localized delivery of high energy protons and may reduce the damage to healthy tissues and vital organs. The aim of this review was to assess the effects of proton therapy for patients diagnosed with Hodgkin or non-Hodgkin lymphoma treated with mediastinal irradiation. REVIEW METHODS: A systematic search of EMBASE, MEDLINE via OVID and Cochrane Library was conducted in May 2022 according to PRISMA guidelines to identify relevant data on the efficacy and toxicity of proton beam therapy for patients diagnosed with Hodgkin or non-Hodgkin lymphoma. BRIEF DESCRIPTION OF THE STATE OF KNOWLEDGE: Of 566 screened abstracts (430 after de-duplication) 11 studies with a total of 529 patients were included. All studies were case series published between 2011-2021. Median range of follow-up time was 15-63.6 months. The overall survival (OS) for 2 years varied from 91% - 98% for 5 of the included studies. Three of the included studies had favourable outcomes with 2-year progression-free survival (PFS) ranging from 73% - 94%. Skin reaction, oesophagitis and fatigue were found to be the most common grade 1 and grade 2 toxicities. No acute or late grade 4 and higher toxicities/adverse events were observed. SUMMARY: There are data indicating that PBT may to be an effective treatment against mediastinal Hodgkin and non-Hodgkin lymphoma. Because all the studies were case series, the authors of this review have little confidence in the evidence. There remains a need for well-designed randomized controlled trials to inform about the optimal approach to proton irradiation in HL and NHL.

[Radiation-induced parotid leiomyosarcoma]. / Léiomyosarcome parotidien en territoire irradié.

INTRODUCTION: First case of radiation-induced parotid leiomyosarcoma. ANATOMO-CLINICAL OBSERVATION: A 50-year-old woman with a history of cervical irradiation for Hodgkin's lymphoma presented with a right parotid tumefaction. Examination noted a deep adherent pretragal mass with peripheral facial palsy. A total parotidectomy with intra-operative examination and cervical curage was performed. Histopathological analysis concluded to a grade 3 parotid leiomyosarcoma according to the National Federation of Cancer Centers. Adjuvant radiotherapy was performed. After 24 months of follow-up, the patient presented bone and liver metastases without local recurrence. DISCUSSION: This is the first case of radiation-induced leiomyosarcoma and the 12th case of parotid leiomyosarcoma described in the literature. The management associates surgery with adjuvant radiotherapy. Follow-up is by clinical examination, parotid MRI, and annual thoracoabdominal CT scan to search for metastases. Recurrences occur during the first year in 40 to 64% of cases, and distant metastases in 40 to 60% of cases. The 5-year survival rate is between 10 and 30%.

The relationship and clinical significance of serum cytokine expression level and skin pruritus in patients with Hodgkin lymphoma and angioimmunoblastic T-cell lymphoma.

Pruritus of lymphoma is commonly associated with both Hodgkin lymphoma (HL) and angioimmunoblastic T cell lymphoma (AITL) and critically affects the life quality of patient. Recent evidence suggests that the pruritogenic cytokines seem to play a significant role in the genesis of chronic. This study aims to investigate the cytokines associated with itching in lymphoma patients and provide the basis for potential therapeutic targets. Serum samples were collected from 60 lymphoma patients, including 47 with Hodgkin lymphoma (HL) and 13 with angioimmunoblastic T-cell lymphoma (AITL), serving as the observation group (lymphoma group, LP group, n = 60). Additionally, serum samples from 8 healthy donors (HD group, n = 8) were collected for comparison. Within the lymphoma group, patients were stratified into those with pruritus (LWP group, n = 30) and those without pruritus (LWOP group, n = 30) based on the presence of skin pruritus symptoms. Elevated levels of multiple cytokines were significantly observed in the LP group in comparison to the HD group (p < 0.01). Patients in LWP group exhibited higher serum levels of IL-31 (p < 0.001), IL-1ß (P = 0.039), and IL-1α (P = 0.037) compared to LWOP group. Notably, serum IL-31 levels were higher in advanced AITL patients (stage IV) than in early AITL patients (stage I-Ⅲ, P < 0.05). In subgroup analysis, patients with pruritus in the AITL group exhibited higher serum levels of MIG and CTACK compared to HL group, whereas PDGF-BB levels were significantly lower (p < 0.05). Elevated serum levels of IL-31, IL-1ß, and IL-1α are linked to lymphoma-associated pruritus. Differences in serum cytokine profiles between HL and AITL subgroups are also highlighted. These findings offer valuable insights for clinical intervention in managing lymphoma-related pruritus.

Epstein-Barr virus latency patterns in polymorphic lymphoproliferative disorders and lymphomas in immunodeficiency settings: Diagnostic implications.

Epstein-Barr virus (EBV) is responsible for many B cell lymphoproliferative disorders (LPD) spanning subclinical infection to immunodeficiency-related neoplasms. EBV establishes a latent infection in the host B cell as defined histologically by the expression of EBV latent membrane proteins and nuclear antigens. Herein, we characterize the latency patterns of immunodeficiency-related neoplasms including post-transplant lymphoproliferative disorders (PTLD) and therapy-related LPD (formerly iatrogenic) with latent membrane protein-1 (LMP-1) and EBV nuclear antigen-2 (EBNA-2) immunohistochemistry. The latency pattern was correlated with immunodeficiency and dysregulation (IDD) status and time from transplant procedure. 38 cases of EBV+ PTLD in comparison to 27 cases of classic Hodgkin lymphoma (CHL) and diffuse large B cell lymphoma (DLBCL) arising in either the therapy-related immunodeficiency setting (n = 12) or without an identified immunodeficiency (n = 15) were evaluated for EBV-encoded small RNAs by in situ hybridization (EBER-ISH) and for LMP-1 and EBNA-2 by immunohistochemistry. A full spectrum of EBV latency patterns was observed across PTLD in contrast to CHL and DLBCL arising in the therapy-related immunodeficiency setting. Polymorphic-PTLD (12 of 16 cases, 75 %) and DLBCL-PTLD (9 of 11 cases, 82 %) showed the greatest proportion of cases with latency III pattern. Whereas, EBV+ CHL in an immunocompetent patient showed exclusively latency II pattern (13 of 13 cases, 100 %). The majority of EBV+ PTLD occurred by three years of transplant procedure date and were enriched for latency III pattern (21 of 22 cases, 95 %). Immunohistochemical identification of EBV latency by LMP-1 and EBNA-2 can help classify PTLD in comparison to other EBV+ B cell LPD and lymphomas arising in therapy-related immunodeficiency and non-immunodeficiency settings.

Pathogenic Variants Associated with Epigenetic Control and the NOTCH Pathway Are Frequent in Classic Hodgkin Lymphoma.

Classic Hodgkin lymphoma (cHL) constitutes a B-cell neoplasm derived from germinal center lymphocytes. Despite high cure rates (80-90%) obtained with the current multiagent protocols, a significant proportion of cHL patients experience recurrences, characterized by a lower sensitivity to second-line treatments. The genomic background of chemorefractory cHL is still poorly understood, limiting personalized treatment strategies based on molecular features. In this study, using a targeted next-generation sequencing (NGS) panel specifically designed for cHL research, we compared chemosensitive and chemorefractory diagnostic tissue samples of cHL patients. Furthermore, we longitudinally examined paired diagnosis-relapsesamples of chemorefractory cHL in order to define patterns of dynamic evolution and clonal selection. Pathogenic variants in NOTCH1 and NOTCH2 genes frequently arise in cHL. Mutations in genes associated with epigenetic regulation (CREBBP and EP300) are particularly frequent in relapsed/refractory cHL. The appearance of novel clones characterized by mutations previously not identified at diagnosis is a common feature in cHL cases showing chemoresistance to frontline treatments. Our results expand current molecular and pathogenic knowledge of cHL and support the performance of molecular studies in cHL prior to the initiation of first-line therapies.

Camrelizumab plus gemcitabine and oxaliplatin for relapsed or refractory classical Hodgkin lymphoma: a phase II trial.

BACKGROUND: Classical Hodgkin lymphoma (cHL) is a highly curable disease, while novel therapy is needed for refractory or relapsed (R/R) patients. This phase II trial aimed to evaluate the role of camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in R/R cHL patients. METHODS: Transplant-eligible patients with R/R cHL were enrolled and received two 14-day cycles of camrelizumab 200 mg intravenously (IV) and two 28-day cycles of camrelizumab 200 mg IV, gemcitabine 1000 mg/m2 IV, and oxaliplatin 100 mg/m2 IV on days 1 and 15. Patients with partial response (PR) or stable disease received an additional cycle of combination therapy. Those who achieved complete response (CR) or PR proceeded to autologous stem cell transplantation (ASCT). The primary endpoint was the CR rate at the end of protocol therapy before ASCT. RESULTS: Forty-two patients were enrolled. At the end of protocol therapy, the objective response rate and CR rate were 94.9% (37/39) and 69.2% (27/39) in the evaluable set, and 88.1% (37/42) and 64.3% (27/42) in the full analysis set, respectively. Twenty-nine patients (69.0%) proceeded to ASCT, and 4 of 5 patients with PR achieved CR after ASCT. After a median follow-up of 20.7 months, the 12-month progression-free survival rate was 96.6% and the 12-month overall survival rate was 100%. Grade 3 or higher treatment emergent adverse events occurred in 28.6% of patients (12/42), mainly hematological toxicity. CONCLUSIONS: Camrelizumab combined with GEMOX constitutes an effective salvage therapy for R/R cHL, proving to be relatively well-tolerated and facilitating ASCT in most patients, thus promoting sustained remission. TRIAL REGISTRATION: ClinicalTrials.gov NCT04239170. Registered on January 1, 2020.

Patient preferences in the treatment of stage III/IV classic Hodgkin lymphoma: Results from the CONNECT cross-sectional survey.

We explored patient front-line treatment preferences in newly diagnosed stage III/IV classic Hodgkin lymphoma (cHL). The CONNECT patient survey, administered online from 30 December 2020 to 1 March 2021, examined preferences overall and by age at diagnosis in 182 adult patients diagnosed with stage III/IV cHL within the past 10 years in the United States. At diagnosis, patients' median age was 36 years; 66% of patients were younger (aged 16-41 years) and 34% older (aged 42-85 years). When asked about initial treatment goals, 74% of patients ranked cure as their first or second goal (86% younger vs. 52% older patients; p < 0.001). At diagnosis, 72% of patients preferred aggressive treatment, and 85% were willing to accept more short-term risks in exchange for a better-working therapy long term. For long-term risks, younger versus older patients were significantly more concerned about second cancers (p < 0.001) and fertility issues (p = 0.007), whereas older patients were more concerned about lung damage (p = 0.028) and infections (p < 0.001). Most patients (94%) reported having a caregiver at some point, but 99% of these patients retained some control of treatment decisions. Collectively, these survey results highlight patient treatment preferences and differences in treatment goals and long-term side effect concerns based on patient age.

Loss of or decrease in CD30 expression in four patients with anaplastic large cell lymphoma after brentuximab vedotin-containing therapy.

Brentuximab vedotin (BV), CD30 specific antibody drug conjugate, has been used to treat anaplastic large cell lymphoma (ALCL) and classic Hodgkin lymphoma (CHL); it is also used in the treatment of other CD30-positive peripheral T-cell lymphomas. We aimed to investigate the incidence and clinicopathological characteristics of patients with ALCL or CHL with loss of or decrease in CD30 expression after BV-containing therapy. Twelve and nine patients with refractory/relapsed CHL and ALCL, respectively, were analyzed after receiving BV-containing therapy. In four ALCL patients (44%), CD30 expression was lost/decreased in re-biopsy materials, including one with complete loss and three with a reduction of less than 20%. All 12 CHL patients showed consistent CD30 expression levels after BV treatment. Compared with five ALCL patients with consistent CD30 expression, four ALCL patients with a loss of/decrease in CD30 expression received a higher cumulative dose of BV (P = 0.014) and revealed a lower intensity of CD30 expression in initial biopsy materials (P = 0.017). The subtypes of ALCL (ALK positive, ALK negative, and primary cutaneous) were not related to the loss of/decrease in CD30 expression. In conclusion, 44% of ALCL patients, regardless of histological subtypes, showed a loss of/decrease in CD30 expression after receiving BV-containing therapy, but this phenomenon was not observed in CHL patients. A higher cumulative dose of BV and a lower amount of CD30 antigen in tumor cells in the initial biopsy materials might be predictors of a loss of/decrease in CD30 expression in ALCL patients.

Bone marrow biopsy in geriatric patients above the age of 85 years: invaluable or unnecessary? A retrospective analysis.

Bone marrow biopsy (BMB) is a well-established diagnostic tool for various hematological, oncological, and other medical conditions. However, treatment options for geriatric patients (pts) facing these diseases are often constrained. In this single-center, retrospective analysis we assessed the diagnostic value of BMB in geriatric pts aged ≥ 85 years and examined its impact on therapeutic decisions. We examined 156 BMB procedures in 129 pts, extracting data from the electronic patient records and applying descriptive statistical methods. Nearly half of the primary diagnostic procedures (26; 44.1%) resulted in a modification of the initially suspected diagnosis. Notably, 15 (25.4%) of these procedures, led to changes in both the diagnosis and planned interventional treatment. Among the 15 follow-up procedures (36.6%), disease progression was initially suspected based on symptoms, but BMB results excluded such progression. In lymphoma staging biopsies, only 2 (3.6%) prompted a change in therapeutic intervention. Importantly, no BMB-related complications, such as bleeding, infection or nerve damage, were reported. Median survival after BMB was 16.1 months across all pts, yet it varied based on the diagnosis and comorbidity score. The survival of pts with a change in therapy based on BMB results did not significantly differ from those who did not undergo a therapy change. In conclusion, BMB proved to be generally safe and beneficial in this geriatric cancer patient cohort beyond the age of 85 years. However, the advantages of lymphoma staging in this patient population warrant further consideration.

Interfollicular Hodgkin's lymphoma: A diagnostic challenge for pathologists.

Interfollicular Hodgkin's lymphoma (IFHL) is a rare pattern of classical Hodgkin's lymphoma (CHL) showing reactive follicular hyperplasia with involvement of the interfollicular area by HL. Two cases are reported in this study having primary IFHL out of total of 500 cases of CHL reported at our center. Diagnosis of IFHL was made on the basis of morphological and immunohistochemical features. As they represent an early stage of the disease, their identification and awareness s very important to get proper treatment at its earliest. This variant is very unusual and is diagnostically challenging for pathologists.