Identifying and addressing unmet clinical needs in primary cutaneous B-cell lymphoma: A consensus-based paper from an ad-hoc international panel.

Primary cutaneous B-cell lymphomas (PCBCLs) are lymphoproliferative disorders that appear on the skin without evidence of extracutaneous manifestations at the time of diagnosis. There is a lack of evidence-based guidelines for their clinical management due to the availability of very few large scale studies and controlled clinical trials. Here we present and discuss a series of major unmet clinical needs (UCNs) in the management of PCBCLs by a panel of 16 experts involved in research and clinical practice of PCBCL. The Panel produced recommendations on the appropriateness of the clinical decisions concerning the identified clinical needs and proposed research for improving the knowledge needed to solve them. Recommendations and proposals were achieved by multiple-step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. Recommendations and proposals lay in the domain of classification uncertainties of PCBCL, optimization of diagnosis, optimization of prognosis, optimization of staging and critical issues on therapeutic strategies with particular focus on new treatments. These recommendations are intended for use not only by experts but above all by dermatologists and hematologists with limited experience in the field of PCBCLs as well as general practitioners.

BRAFV600 variant allele frequency predicts outcome in metastatic melanoma patients treated with BRAF and MEK inhibitors.

BACKGROUND: The prognostic impact of variant allele frequency (VAF) on clinical outcome in BRAFV600 mutated metastatic melanoma patients (MMPs) receiving BRAF (BRAFi) and MEK inhibitors (MEKi) is unclear. MATERIALS AND METHODS: A cohort of MMPs receiving first line BRAFi and MEKi was identified by inspecting dedicated databases of three Italian Melanoma Intergroup centres. VAF was determined by next generation sequencing in pre-treatment baseline tissue samples. Correlation between VAF and BRAF copy number variation was analysed in an ancillary study by using a training and a validation cohort of melanoma tissue samples and cell lines. RESULTS: Overall, 107 MMPs were included in the study. The VAF cut-off determined by ROC curve was 41.3%. At multivariate analysis, progression-free survival (PFS) was significantly shorter in patients with M1c/M1d [HR 2.25 (95% CI 1.41-3.6, p < 0.01)], in those with VAF >41.3% [HR 1.62 (95% CI 1.04-2.54, p < 0.05)] and in those with ECOG PS ≥1 [HR 1.82 (95% CI 1.15-2.88, p < 0.05)]. Overall survival (OS) was significantly shorter in patients with M1c/M1d [HR 2.01 (95% CI 1.25-3.25, p < 0.01)]. Furthermore, OS was shorter in patients with VAF >41.3% [HR 1.46 (95% CI 0.93-2.29, p = 0.06)] and in patients with ECOG PS ≥1 [HR 1.52 (95% CI 0.94-2.87, p = 0.14)]. BRAF gene amplification was found in 11% and 7% of samples in the training and validation cohort, respectively. CONCLUSIONS: High VAF is an independent poor prognostic factor in MMP receiving BRAFi and MEKi. High VAF and BRAF amplification coexist in 7%-11% of patients.

New Screening Strategy Combining Anal Papanicolaou and Human Papillomavirus Tests for Human Papillomavirus-Related Anal Cancer: A Prospective, Single-Center Study.

BACKGROUND: The objective of this study was to evaluate the performance of a combined approach of liquid-based anal cytology and human papillomavirus (HPV) testing in predicting patients who should undergo high-resolution anoscopy for the early detection of anal cancer and anal intraepithelial neoplasia (AIN)-2+. METHODS: We conducted a prospective single-center quality improvement study. We consecutively enrolled men who had sex with men (MSM) attending our sexually transmitted disease clinic to undergo anal Papanicolaou (Pap) and HPV tests. All patients with an abnormal anal Pap test result and/or positive HPV test result underwent high-resolution anoscopy. RESULTS: We enrolled 217 MSM, 80 HIV-positive patients, and 137 HIV-negative patients. Cytology showed a sensitivity of 100%, a specificity of 64.1%, an accuracy of 66.7%, a positive predictive value (PPV) of 15.7%, and a negative predictive value (NPV) of 100% for the detection of AIN-2+. The high-risk (HR)-HPV test showed sensitivity, specificity, accuracy, PPV, and NPV of 100%, 36.4%, 40%, 9.4%, and 100%, respectively. The combination of abnormal cytology with identification of infection by at least 1 HR-HPV strain on the HPV test had a sensitivity of 100%, a specificity of 73%, an accuracy of 74.6%, a PPV of 19.1%, and an NPV of 100%. CONCLUSION: Anal HR-HPV testing, complementary to cytology, improves the diagnostic accuracy of screening for anal cancer.

Clinical, histopathological and prognostic features of primary cutaneous acral CD8+ T-cell lymphoma and other dermal CD8+ cutaneous lymphoproliferations: results of an EORTC Cutaneous Lymphoma Group workshop.

BACKGROUND: The differential diagnosis of atypical dermal nonepidermotropic CD8+ lymphocytic infiltrates includes a heterogeneous spectrum of lymphoproliferations with overlapping histological and phenotypic features, but divergent clinical manifestations and prognoses. As these neoplasms are rare, more data on their clinicopathological presentation and course are needed. OBJECTIVES: To assess the clinical, histological and immunophenotypic features; outcomes of; and differences between dermal CD8+ lymphoproliferations. METHODS: Retrospective analysis of a series of 46 patients and biopsies by the international EORTC Cutaneous Lymphoma Group. RESULTS: The dermal CD8+ lymphoproliferations (n = 46) could be assigned to one of three groups: (i) cutaneous acral CD8+ T-cell lymphoma (n = 31), characterized mostly by a solitary nodule arising at acral sites, a monotonous dermal infiltrate of small-to-medium-sized CD8+ lymphocytes with a characteristic dot-like pattern of CD68, a low proliferation rate and an excellent prognosis; (ii) primary cutaneous CD8+ peripheral T-cell lymphoma, unspecified/NOS (n = 11), presenting with one or multiple rapidly evolving tumours, mostly medium-sized pleomorphic CD8+ tumour cells with expression of several cytotoxic markers, and high proliferative activity; and (iii) cutaneous CD8+ lymphoproliferations (n = 4), associated with congenital immunodeficiency syndromes in two patients with persisting localized or disseminated violaceous to brownish plaques on the extremities, a histiocyte-rich infiltrate of mostly small CD8+ lymphocytes with subtle atypia and a protracted course; and papular CD8+ eruptions in two patients with acquired immunosuppression. CONCLUSIONS: A constellation of distinct clinical, histopathological and phenotypic features allows discrimination and assignment of dermal CD8+ infiltrates into distinct disease entities. Primary cutaneous acral CD8+ lymphoma, assigned a provisional category in current lymphoma classifications, is a distinct and reproducible entity. A correct diagnosis is essential to avoid unnecessarily aggressive treatment for indolent CD8+ lymphoproliferations and to identify cases with underlying immuno-deficiency or potential for dismal outcome.

Short-term efficacy and safety of total skin electron beam therapy in mycosis fungoides: Systematic review and meta-analysis.

Total skin electron beam therapy (TSEBT) is one of the mainstays of treatment for mycosis fungoides. The most common modalities are standard dose (30-36 Gy) and low dose (10-12 Gy). To review the literature on the efficacy and safety profiles of standard dose and low dose TSEBT. We searched electronic databases for studies that enrolled patients with Mycosis Fungoides and treated with TSEBT. We estimated the event rates associated with low dose and standard dose TSEBT. The Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline was followed. Main outcomes were complete response rate, partial response rate, mild and severe adverse events rate low dose TSEBT had a Complete Response Rate of 28% [0.19, 0.37], an Overall Response Rate of 85% [0.76, 0.93], a mild adverse events rate of 93% [0.82, 1.04] and a severe adverse events rate of 5% [-0.04; 0.14] Standard dose TSEBT had a Complete Response Rate of 57% [0.41; 0.73], the Overall Response Rate was 99% [0.97; 1.02], the mild adverse events rate was 100%, the severe adverse events rate was 7% [-0.01; 0.16]. Comparing standard dose TSEBT in the early versus advanced stages, advanced stages patients had a Risk Ratio = 0.77 in obtaining a Complete Response [0.64, 0.92](p = 0.0158). TSEBT is an associated with an excellent short term safety profile. Both schedules show high ORR, with standard dose TSEBT demonstrating highest CRR. Advanced stage of disease negatively influence the CRR.

Tolerogenic IDO1+CD83- Langerhans Cells in Sentinel Lymph Nodes of Patients with Melanoma.

Langerhans cells (LCs) are crucial regulators of anti-cancer immune responses. Cancer, however, can alter DCs functions leading to tolerance. The enzyme indoleamine 2,3-dioxygenase (IDO1) plays a crucial role in this process. In sentinel lymph nodes (SLNs) of patients with melanoma, LCs show phenotypical and functional alterations favoring tolerance. Herein we aimed to investigate IDO1 expression in SLN LCs from patients with melanoma. We showed by immunofluorescence analysis that a portion of Langerin+ LCs, located in the SLN T cell-rich area, displayed the typical dendritic morphology and expressed IDO1. There was no significant difference in the expression of IDO between SLN with or without metastases. Double IDO1/CD83 staining identified four LCs subsets: real mature IDO1−CD83+ LCs; real immature IDO1−CD83− LCs; tolerogenic mature IDO1+CD83+ LCs; tolerogenic immature IDO1+CD83− LCs. The latter subset was significantly increased in metastatic SLNs as compared to negative ones (p < 0.05), and in SLN LCs of patients with mitotic rate (MR) > 1 in primary melanoma, as compared to MR ≤ 1 (p < 0.05). Finally, immature SLN LCs, after in vitro stimulation by inflammatory cytokines, acquired a maturation profile by CD83 up-regulation. These results provide new input for immunotherapeutic approaches targeting in vivo LC of patients with melanoma.

Critical concepts and management recommendations for cutaneous T-cell lymphoma: A consensus-based position paper from the Italian Group of Cutaneous Lymphoma.

In this paper, we present a review of critical concepts, and produce recommendations on management issues in cutaneous T-cell lymphomas (CTCLs) of adults. A panel of nine experts was selected for their expertise in research and clinical practice of CTCLs. During an initial meeting, the areas of major concern in the management of CTCLs were selected by generating and rank-ordering clinical key questions using the criterion of clinical relevance, through group discussion. Recommendations were achieved by multiple-step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. The panel produced recommendations on how to facilitate the clinical suspicion of CTCL; indication of cutaneous biopsy; optimal histological diagnosis, immunohistochemistry and genetic markers; and staging pathway and up-to-date therapeutics (with particular focus on new treatments). The critical concept of integration of the different medical expertise in the management of the patients with CTCL was thoroughly examined. These recommendations are intended for use not only by expert centers but above all by "not experienced" dermatologists and hematologists as well as general practitioners.

Non-scarring patchy alopecia: What else, apart from alopecia areata?

A 67-year-old woman presented with a 3-month history of patchy alopecia areata (AA)-like hair loss and multiple painful enlarged lymph nodes at cervical, nuchal, and left axillary site. The patient was on follow-up for IgM monoclonal gammopathy of undetermined significance, stable for many years. A punch biopsy from a patch of the temporal scalp revealed the presence of B-cell lymphoid infiltrates consistent with marginal zone B-cell lymphoma (MZL). Other staging examinations were conducted to make a definitive diagnosis of nodal MZL with secondary cutaneous involvement. The patient showed a complete remission of the alopecia, without evidence of scarring, after immunochemotherapy for lymphoma.

Italian expert-based recommendations on the use of photo(chemo)therapy in the management of mycosis fungoides: Results of an e-Delphi consensus.

BACKGROUND: Phototherapy is a mainstay for the treatment of MF. However, there is scarce evidence for its use, mostly due to the lack of a unified schedule. AIMS: The primary aim of this study was to establish the first structured, expert-based consensus regarding the indications and technical schedules of NB-UVB and PUVA for MF. The secondary aim was to determine the consensus level for each specific item. MATERIALS & METHODS: E-delphi study. Item-specific expert consensus was defined as the number of "Totally Agree" results to ≥80% of the panelists. Cronbach alpha index ≥0.7 was used as a measure of homogeneity in the responses among questions related to the same topic. RESULTS: Overall, there was a high homogeneity among responders (0.78). On specific topics, the highest grade was observed for technical items (0.8) followed by indications for early (0.73) and advanced stages (0.7). CONCLUSIONS: Items related to the most canonical indications of phototherapy and to treatment schedules showed the highest agreements rates. There is consensus about the use of standardized treatment schedules for the induction and consolidation phases for NB-UVB and PUVA in MF.

Blastic plasmacytoid dendritic cell neoplasm: genomics mark epigenetic dysregulation as a primary therapeutic target.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy for which there is still no effective therapy. In order to identify genetic alterations useful for a new treatment design, we used whole-exome sequencing to analyze 14 BPDCN patients and the patient-derived CAL-1 cell line. The functional enrichment analysis of mutational data reported the epigenetic regulatory program to be the most significantly undermined (P<0.0001). In particular, twenty-five epigenetic modifiers were found mutated (e.g. ASXL1, TET2, SUZ12, ARID1A, PHF2, CHD8); ASXL1 was the most frequently affected (28.6% of cases). To evaluate the impact of the identified epigenetic mutations at the gene-expression and Histone H3 lysine 27 trimethylation/acetylation levels, we performed additional RNA and pathology tissue-chromatin immunoprecipitation sequencing experiments. The patients displayed enrichment in gene signatures regulated by methylation and modifiable by decitabine administration, shared common H3K27-acetylated regions, and had a set of cell-cycle genes aberrantly up-regulated and marked by promoter acetylation. Collectively, the integration of sequencing data showed the potential of a therapy based on epigenetic agents. Through the adoption of a preclinical BPDCN mouse model, established by CAL-1 cell line xenografting, we demonstrated the efficacy of the combination of the epigenetic drugs 5'-azacytidine and decitabine in controlling disease progression in vivo.

Clindamycin as unique antibiotic choice in Hidradenitis Suppurativa.

The rifampicin (RF)-clindamycin (CL) combination is recommended as first line therapy in moderate to severe Hidradenitis Suppurativa (HS) by European S1 guidelines. Although prolonged use of RF should be discouraged, there are currently few alternatives to this combination therapy. The aim of the present study was to assess retrospectively the efficacy of oral CL monotherapy in patients diagnosed with HS. In the period January 2017-May 2018, 31 HS patients who received a 300 mg b.i.d. oral dose of CL were studied retrospectively. Efficacy of the treatment was evaluated by comparing the main HS severity scores (Sartorius score modified by Revuz, Hidradenitis Suppurativa Physician Global Assessment [HS-PGA] and International Hidradenitis Suppurativa Severity Score System [IHS4]) before (W0) and after (W12) CL oral therapy. CL efficacy was demonstrated by the extreme and significant reduction of all three disease severity parameters during the 12-week period (p ≤ .01). There was also a statistically significant change in the mean visual analogue scale for pain. The present study demonstrates the efficacy of oral CL monotherapy as RF-sparing regimen alternative to RF-CL combination in a selected group of patients.

Management of severe bio-radiation dermatitis induced by radiotherapy and cetuximab in patients with head and neck cancer: emphasizing the role of calcium alginate dressings.

PURPOSE: Severe bio-radiation dermatitis may develop in patients treated with concurrent radiotherapy and cetuximab for head and neck squamous cell carcinoma. The aim of our work was to report on the impact of a grade-specific management approach on treatment tolerability. METHODS: Concomitant radiotherapy and cetuximab was prescribed for patients deemed ineligible for cisplatin-based chemoradiation. Since 2014, an advanced wound care nursing team was established in our clinic to implement a standardized policy for skin toxicity. A central role of calcium alginate dressings was defined in our management algorithm. The correlation between patient, disease, and treatment features with severe bio-radiation dermatitis and treatment tolerability was evaluated. RESULTS: Between 2007 and 2018, 51 patients were treated at our center with radiotherapy and cetuximab. The incidence of G3/G4 bio-radiation dermatitis was 43.1%. Comparing two consecutive cohorts of 26 and 25 patients treated before and after January 2014, respectively, the adoption of a grade-specific dermatitis management allowed to improve treatment tolerability. A mean radiation treatment interruption of 8.42 days (SD, 6.73; 95% CI 5.7-11.1) was reduced to 0.86 days (SD, 2.66; 95% CI - 0.28-2.02) in the more recent group (p < 0.0001). Mean relative dose intensity of cetuximab was also significantly higher (86.3% vs 74.5%, p = 0.0226). CONCLUSIONS: Routine involvement of an advanced wound care management team and early consideration for calcium alginate dressings in case of moist desquamation should be warranted to ensure high compliance to radiotherapy and cetuximab in patients with head and neck cancer.

Granular IgA Deposits in the Skin of Patients with Coeliac Disease: Is it Always Dermatitis Herpetiformis?

Coeliac disease is an immune-mediated enteropathy driven by gluten, which can be associated with dermatitis herpetiformis. The presence of granular IgA deposits, detected by direct immunofluorescence, is the hallmark of dermatitis herpetiformis; nevertheless, IgA deposits have also been demonstrated in healthy skin of patients with coeliac disease. The main objective of this study was to investigate whether IgA deposits could be found in the skin of patients with coeliac disease who have non-dermatitis herpetiformis inflammatory skin diseases. Direct immunofluorescence was performed on perilesional skin biopsies of 6 patients with coeliac disease with non-dermatitis herpetiformis inflammatory skin diseases and, as control, on 12 non-coeliac patients with inflammatory skin diseases. IgA deposits were found in all of the patients with coeliac disease, but were absent in the control group. In conclusion, IgA deposits may be considered an immunopathological marker for coeliac disease; therefore, patients with coeliac disease showing skin manifestations with positive direct immunofluorescence should be investigated carefully in order to make a differential diagnosis between dermatitis herpetiformis and other non-dermatitis herpetiformis inflammatory skin diseases.

Treatment of psoriasis with topical agents: Recommendations from a Tuscany Consensus.

Psoriasis is a chronic and relapsing inflammatory skin disease, clinically characterized by erythematous and scaly plaques. Treatment approach is mainly driven by disease severity, though several factors should be considered in order to identify the optimal therapeutic choice. Mild psoriasis may be treated with a wide array of topical agents including corticosteroids, vitamin D analogs, keratolytics, and calcipotriol/betamethasone propionate compound. Because guidelines may not provide practical indications regarding the therapeutic approach, the use of topical agents in psoriasis is more individually tailored. In order to homogenize the standard of care, at least in a local setting, we collected the real-life-based recommendations for the use of topical therapies from an expert panel, the Tuscany Consensus Group on Psoriasis, representing all leading centers for psoriasis established in Tuscany. With this document, this consensus group sought to define principles guiding the selection of therapeutic agents with straightforward recommendations derived from a real-life setting.

Aggressive epidermotropic cutaneous CD8+ lymphoma: a cutaneous lymphoma with distinct clinical and pathological features. Report of an EORTC Cutaneous Lymphoma Task Force Workshop.

AIMS: Aggressive epidermotropic cutaneous CD8(+) lymphoma is currently afforded provisional status in the WHO classification of lymphomas. An EORTC Workshop was convened to describe in detail the features of this putative neoplasm and evaluate its nosological status with respect to other cutaneous CD8(+) lymphomas. METHODS AND RESULTS: Sixty-one CD8(+) cases were analysed at the workshop; clinical details, often with photographs, histological sections, immunohistochemical results, treatment and patient outcome were discussed and recorded. Eighteen cases had distinct features and conformed to the diagnosis of aggressive epidermotropic cutaneous CD8(+) lymphoma. The patients typically present with widespread plaques and tumours, often ulcerated and haemorrhagic, and histologically have striking pagetoid epidermotrophism. A CD8(+) /CD45RA(+) /CD45RO(-) /CD2(-) /CD5(-) /CD56(-) phenotype, with one or more cytotoxic markers, was found in seven of 18 patients, with a very similar phenotype in the remainder. The tumours seldom involve lymph nodes, but mucosal and central nervous system involvement are not uncommon. The prognosis is poor, with a median survival of 12 months. Examples of CD8(+) mycosis fungoides, lymphomatoid papulosis and Woringer-Kolopp disease presented the typical features well documented in the CD4(+) forms of those diseases. CONCLUSIONS: Aggressive epidermotropic cutaneous CD8(+) lymphoma is a distinct lymphoma that warrants inclusion as a distinct entity in future revisions of lymphoma classifications.

Rituximab plus liposomal pegylated doxorubicin in the treatment of primary cutaneous B-cell lymphomas.

BACKGROUND: In primary cutaneous B-cell lymphomas (PCBCL), radiotherapy - or surgery in a minority of cases - is the first-line treatment in follicle center lymphoma (PCFCL) and marginal zone B-cell lymphoma (PCMZL). Conversely, patients with multifocal skin involvement or relapsed/refractory disease deserve a systemic chemotherapy. In diffuse large B-cell lymphoma, leg type (PCLBCL-LT), due its poorer outcome, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like regimens are the most commonly used frontline, although hard to propose in elderly patients. In this regard, the association of rituximab (R) and pegylated liposomal doxorubicin (PLD) can be considered a promising, alternative approach. AIMS: Based on the favorable results reported with R and PLD in several recent trials, we decided to test efficacy and safety of this combination. METHODS: Twelve patients with PCBCL were treated with R plus PLD, and 7 had relapsed disease. Treatment plan consisted of 2 monthly cycles of R 375 mg/m(2) and PLD 20 mg/m(2) day 1;15, followed (in responders) by two cycles given only at day 1. All patients received prophylactic pyridoxine to prevent palmar-plantar erythrodysesthesia (PPE). RESULTS: Ten of 12 patients had a response (eight complete; two partial), remarkably 2/3 with PCLBCL-LT. Two patients did not respond (one progressive disease, PD, and one stable disease). Three patients died after a median follow-up of 56 months, two patients due to PD, and 1 due to a second neoplasm. Two out of 10 responders relapsed after 31 and 32 months, respectively. Hematological toxicity was negligible (one case of grade 2 neutropenia), as well as extra-hematological toxicity (two cases of grade 2 PPE). CONCLUSIONS: These preliminary data suggest that R-PLD is effective and well tolerated in all subsets of PCBCL and may be offered frontline in indolent cases unsuitable for radiotherapy or surgery as well as in more aggressive cases with contraindications to CHOP-like regimens.