Remission of relapsed/refractory classical Hodgkin lymphoma induced by brentuximab vedotin and pembrolizumab combination after allogeneic hematopoietic stem cell transplantation: a case report.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with highly chemorefractory Hodgkin lymphoma (HL). The CD30-targeting antibody-drug conjugate Brentuximab-Vedotin (BV) and programmed cell death protein-1 (PD-1) blocking agents have demonstrated clinical activity with durable responses in relapsed/refractory (r/r) HL. However, patients with a history of allo-HSCT were frequently excluded from clinical trials due to concerns about the risk of graft-versus-host disease (GVHD). We report the clinical history of a patient with refractory classical HL who underwent two allo-HSCTs (first from matched unrelated and second from haploidentical donor) after relapsing on BV and nivolumab and for whom durable remission was finally obtained using BV-pembrolizumab combination for relapse after haploidentical HSCT. Such treatment was associated with the onset of GVHD after only two cycles which led to treatment discontinuation. However, the side effects were rapidly controlled, and after 2 years of follow-up, the patient is still in remission. Our data support the feasibility and efficacy of combining PD-1 blockade with BV to enhance the graft-versus-lymphoma effect after allo-HSCT.

Molecular Imaging of Acute Graft-Versus-Host Disease.

Noninvasive molecular imaging of acute graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation has great potential to detect GvHD at the early stages, aid in grading of the disease, monitor treatment response, and guide therapeutic decisions. Although the specificity of currently available tracers appears insufficient for clinical GvHD diagnosis, recently, several preclinical studies have identified promising new imaging agents targeting one or more biologic processes involved in GvHD pathogenesis, ranging from T-cell activation to tissue damage. In this review, we summarize the different approaches reported to date for noninvasive detection of GvHD using molecular imaging with a specific focus on the use of PET. We discuss possible applications of molecular imaging for the detection of GvHD in the clinical setting, as well as some of the predictable challenges that are faced during clinical translation of these approaches.

Granulocyte-Macrophage Colony-Stimulating Factor in Allogenic Hematopoietic Stem Cell Transplantation: From Graft-versus-Host Disease to the Graft-versus-Tumor Effect.

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a widely used treatment for a broad range of hematologic malignancies because of its graft-versus-tumor (GVT) effect. Unfortunately, allo-HSCT is still associated with morbidity and mortality related to relapse and transplantation complications, namely graft-versus-host-disease (GVHD). In an era of therapies specifically targeting molecular pathways, transcription factors, and cytokines, a better understanding of GVHD physiopathology is essential for the development of new therapeutic approaches. In this review, we outline the current knowledge of the role of granulocyte- macrophage colony-stimulating factor (GM-CSF) in allo-HSCT. We first discuss the biology of GM-CSF and its signaling pathways, with a focus on the main producing cells, T cells. We discuss recent preclinical studies pointing to a pivotal role of GM-CSF in GVHD, in particular gastrointestinal GVHD. We then summarize the potential role of GM-CSF in the GVT effect, discussing some potential strategies for exploiting GM-CSF in the context of allo-HSCT.

Salvage Treatment of Refractory HSV Oral Lesions with Pritelivir in Allogeneic Hematopoietic Cell Transplant Recipients.

We present two allogeneic hematopoietic cell transplantation recipients (HCTr) treated with pritelivir for acyclovir-resistant/refractory (r/r) HSV infection based on the expanded access program of the pritelivir manufacturer. Outpatient treatment with pritelivir was administered, with partial response by week 1 of treatment and complete response by week 4 of treatment in both patients. No adverse events were noted. Pritelivir appears to be an effective and safe option for the management of acyclovir-r/r HSV infections in highly immunocompromised patients in an outpatient setting.

CD4+ T cells require Ikaros to inhibit their differentiation toward a pathogenic cell fate.

The production of proinflammatory cytokines, particularly granulocyte-macrophage colony-stimulating factor (GM-CSF), by pathogenic CD4+ T cells is central for mediating tissue injury in inflammatory and autoimmune diseases. However, the factors regulating the T cell pathogenic gene expression program remain unclear. Here, we investigated how the Ikaros transcription factor regulates the global gene expression and chromatin accessibility changes in murine T cells during Th17 polarization and after activation via the T cell receptor (TCR) and CD28. We found that, in both conditions, Ikaros represses the expression of genes from the pathogenic signature, particularly Csf2, which encodes GM-CSF. We show that, in TCR/CD28-activated T cells, Ikaros binds a critical enhancer downstream of Csf2 and is required to regulate chromatin accessibility at multiple regions across this locus. Genome-wide Ikaros binding is associated with more compact chromatin, notably at multiple sites containing NFκB or STAT5 target motifs, and STAT5 or NFκB inhibition prevents GM-CSF production in Ikaros-deficient cells. Importantly, Ikaros also limits GM-CSF production in TCR/CD28-activated human T cells. Our data therefore highlight a critical conserved transcriptional mechanism that antagonizes GM-CSF expression in T cells.

Thyroid surgical practices shaping thyroid cancer incidence in North-Eastern Italy.

AIM: To investigate the effects of changing surgical practices on thyroid cancer incidence in the Veneto Region (North-Eastern Italy). METHODS: Hospital discharge records of the period 2000-2010 were analyzed to detect trends in thyroid surgery rates by type of surgery and diagnosis. The association between surgery rates for benign and malignant diseases across the 21 Local Health Units (LHUs) was assessed by Poisson regression. In a second step, clinical and pathological charts of the year 2010 were retrieved from the larger regional surgical center. The proportions of total and incidental papillary thyroid micro carcinoma (PTMC) were compared with historical data. Factors influencing an incidental diagnosis of PTMC were analyzed by logistic regression. RESULTS: Among 26,000 procedures performed in the Region, there was an increase with time in the proportion of total thyroidectomies (from 67% to 78%) and surgeries with a diagnosis of thyroid cancer (from 17% to 28%). Cancer surgery rates across LHUs resulted associated to surgery rates for benign diseases (P<0.001). In the largest regional center, the proportion of PTMC increased from 35% to 56%, of whom almost 60% were incidental cases. The probability of finding an incidental PTMC was higher in total thyroidectomies than in other procedures (odds ratio=1.84, 95% confidence interval 1.08-3.14). CONCLUSION: Data from the Veneto Region suggest that the increase in PTMC is due to several factors: increased preoperative diagnosis, total gland removal, extensive histological examination. Moreover, geographical variations in cancer incidence were associated to surgery rates for benign diseases.

Features of papillary thyroid carcinoma in patients older than 75 years.

The aim of this study was to evaluate the prognosis in elderly patients affected by papillary thyroid carcinoma. A retrospective review was conducted on 1,407 patients operated on for papillary thyroid carcinoma at our Department from 1990 to 2007. We analyzed the frequency, the stage, the treatment, the recurrence and the survival in a group of patients aged 75 years or more when compared with a group of patients younger. Among 1,407 patients affected by papillary thyroid carcinoma, 117 (8.3%) were older than 75 years while 1,290 (91.7%) patients were younger. There was no statistical difference between the two groups in frequency of papillary histotype and type of surgery. In the older group, the incidence of anaplastic cancer was higher, p < 0.001. The rate of IV stage was 3.8% in younger versus 15.4% in older patients, p < 0.001. The incidence of recurrence was 6.1% versus 17.9%, p < 0.001, in young and elderly patients, respectively. At a mean follow-up of 8.7 years (range 2-19 years) the overall 10 and 15-year survival in younger patients was 91.3 and 88.7%, while in the older group was 71.8 and 63.9%, respectively. The Kaplan-Meier curve showed a statistically significant difference of survival rate in the two groups (p < 0.0001). Although papillary thyroid cancer is widely considered a lymph-tropic tumor, it seems to have a stronger attitude to distant metastases in elderly patients with a worse prognosis due to a more advanced stage.