Single-cell morphometrics reveals ancestral principles of notochord development.

Embryonic tissues are shaped by the dynamic behaviours of their constituent cells. To understand such cell behaviours and how they evolved, new approaches are needed to map out morphogenesis across different organisms. Here, we apply a quantitative approach to learn how the notochord forms during the development of amphioxus: a basally branching chordate. Using a single-cell morphometrics pipeline, we quantify the geometries of thousands of amphioxus notochord cells, and project them into a common mathematical space, termed morphospace. In morphospace, notochord cells disperse into branching trajectories of cell shape change, revealing a dynamic interplay between cell shape change and growth that collectively contributes to tissue elongation. By spatially mapping these trajectories, we identify conspicuous regional variation, both in developmental timing and trajectory topology. Finally, we show experimentally that, unlike ascidians but like vertebrates, posterior cell division is required in amphioxus to generate full notochord length, thereby suggesting this might be an ancestral chordate trait that is secondarily lost in ascidians. Altogether, our novel approach reveals that an unexpectedly complex scheme of notochord morphogenesis might have been present in the first chordates. This article has an associated 'The people behind the papers' interview.

Aggregation controlled by condensate rheology.

Biomolecular condensates in living cells can exhibit a complex rheology, including viscoelastic and glassy behavior. This rheological behavior of condensates was suggested to regulate polymerization of cytoskeletal filaments and aggregation of amyloid fibrils. Here, we theoretically investigate how the rheological properties of condensates can control the formation of linear aggregates. To this end, we propose a kinetic theory for linear aggregation in coexisting phases, which accounts for the aggregate size distribution and the exchange of aggregates between inside and outside of condensates. The rheology of condensates is accounted in our model via aggregate mobilities that depend on aggregate size. We show that condensate rheology determines whether aggregates of all sizes or dominantly small aggregates are exchanged between condensate inside and outside on the timescale of aggregation. As a result, the ratio of aggregate numbers inside to outside of condensates differs significantly. Strikingly, we also find that weak variations in the rheological properties of condensates can lead to a switch-like change of the number of aggregates. These results suggest a possible physical mechanism for how living cells could control linear aggregation in a switch-like fashion through variations in condensate rheology.

Different treatment strategies versus a common standard arm (CSA) in patients with newly diagnosed AML over the age of 60 years: a randomized German inter-group study.

A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60-87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45-64)) and the study group arms (53% (95%CI: 47-60) and 59% (95%CI: 58-63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7-14.0) in the CSA, 7.6% (95%CI: 4.5-12.8) in study group A and 11.1% (95%CI: 9.0-13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0-26.9), 17.0% (95%CI: 2.0-23.9), and 19.5% (95%CI: 16.7-22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.

Analysis of stem cell collections in adult patients with Ewing sarcoma.

BACKGROUND: Ewing sarcoma is one of the most frequent soft-tissue tumors in pediatric patients. The current treatment protocols recommend stem cell apheresis (SCA) after completion of the second course of induction therapy with vincristine, ifosfamide, doxorubicine, and etoposide (VIDE). The feasibility of SCA and graft compositions in adult patients with Ewing sarcoma have not been previously analyzed. METHODS AND MATERIALS: The authors analyzed 29 stem cell collections of 19 adult patients (9 male, 10 female) at a median age of 27 (range 19-53) years mobilized after VIDE (n = 17), cyclophosphamide/topotecan (n = 1) or vincristine, dactinomycin and ifosfamide (n = 1) chemotherapy. All patients were mobilized with filgrastim 5 µg/kg twice daily from day +7 of chemotherapy. The collections were performed if CD34+ cell count in peripheral blood was >10/µL. The target yields were ≥4×106 CD34+ cells/kg body weight. RESULTS: Median CD34+ cells/µL in peripheral blood before SCA were 45.8 (range 6.7-614.4)/µL. The median cumulative yields were 10.6 (range 1.5-38.8) CD34+ cells/kg body weight and ≥2×106 in all but two patients (89%). CD34, CD3, and CD56 yields in collections after the third VIDE and after later courses did not differ. Four patients underwent high-dose therapy with autologous transplantation, and all were engrafted. DISCUSSION: Stem cell mobilization is feasible in most Ewing sarcoma patients. Additionally, the present study's data suggest that it is safe to postpone stem cell collection to a later VIDE chemotherapy cycle if medically indicated.

Stem-cell mobilization of healthy sibling donors with pegfilgrastim-A prospective open-label phase II trial (EudraCT no: 2005-004971-39).

BACKGROUND: Pegfilgrastim is a covalently bound conjugate of filgrastim and mono-methoxypolyethylene glycol with a longer half-life. STUDY DESIGN AND METHODS: We report on phase II prospective monocentric trial examining the feasibility of stem cell mobilization with 12 mg single dose pegfilgrastim in related donors. The objectives were to determine the optimal collection day, defined as CD34+ concentration in peripheral blood (PB) >50 cells/µl, the number of donors collected with single leukapheresis, and the peak level of pegfilgrastim in donor-serum. Furthermore, the cell composition of grafts was assessed and compared to published data. RESULTS: The results included about 28 matched related donors. The median pegfilgrastim serum level remained >200 ng/mL for 48 hours before declining, with the maximal measured concentration of 259.49 ng/ml 24 h after application. The median white blood cell count and CD34 count in PB peaked on day four with 52.6 (range 22.8-85.0) Gpt/l and 66.25 (range 22.9-136.6) cells/µl, respectively. A CD34+ count >50 cells/µl on day four was detected in 75% of donors. 79% of the donors underwent a single collection. Conventional filgrastim was administered additionally in two donors, due to insufficient CD 34+ concentration in PB. 89% of donors showed CD34+ yields ≥4 (median 6.5, range 4.6-14.5) × 10/kg body weight of the recipient. All grafts were administered without rejections. DISCUSSION: The results of this trial showed that stem cell mobilization with pegfilgrastim is a feasible, and attractive option. This is the first trial presenting the kinetics of pegfilgrastim serum levels in healthy donors.

Carfilzomib, bendamustine, and dexamethasone in patients with advanced multiple myeloma: The EMN09 phase 1/2 study of the European Myeloma Network.

BACKGROUND: Combined therapy with carfilzomib, bendamustine, and dexamethasone was evaluated in this multicenter phase 1/2 trial conducted within the European Myeloma Network (EMN09 trial). METHODS: Sixty-three patients with relapsed/refractory multiple myeloma who had received ≥2 lines of prior therapy were included. The phase 1 portion of the study determined the maximum tolerated dose of carfilzomib with bendamustine set at 70 mg/m2 on days 1 and 8. After 8 cycles, responding patients received maintenance therapy with carfilzomib and dexamethasone until progression. RESULTS: On the basis of the phase 1 results, the recommended phase 2 dose for carfilzomib was 27 mg/m2 twice weekly in weeks 1, 2, and 3. Fifty-two percent of patients achieved a partial response or better, and 32% reached a very good partial response or better. The clinical benefit rate was 93%. After a median follow-up of 21.9 months, the median progression-free survival was 11.6 months, and the median overall survival was 30.4 months. The reported grade ≥3 hematologic adverse events (AEs) were lymphopenia (29%), neutropenia (25%), and thrombocytopenia (22%). The main nonhematologic grade ≥3 AEs were pneumonia, thromboembolic events (10%), cardiac AEs (8%), and hypertension (2%). CONCLUSIONS: In heavily pretreated patients who have relapsed/refractory multiple myeloma, combined carfilzomib, bendamustine, and dexamethasone is an effective treatment option administered in the outpatient setting. Infection prophylaxis and attention to patients with cardiovascular predisposition are required.

Continuum Theory of Active Phase Separation in Cellular Aggregates.

Dense cellular aggregates are common in biology, ranging from bacterial biofilms to organoids, cell spheroids, and tumors. Their dynamics, driven by intercellular forces, is intrinsically out of equilibrium. Motivated by bacterial colonies as a model system, we present a continuum theory to study dense, active, cellular aggregates. We describe the process of aggregate formation as an active phase separation phenomenon, while the merging of aggregates is rationalized as a coalescence of viscoelastic droplets where the key timescales are linked to the turnover of the active force. Our theory provides a general framework for studying the rheology and nonequilibrium dynamics of dense cellular aggregates.

Bone mineral density in patients with systemic mastocytosis: correlations with clinical and histopathological features.

OBJECTIVES: Systemic mastocytosis (SM) is a heterogeneous haematological entity characterised by proliferation of mast cells. Skeletal abnormalities of SM include osteolysis, osteopenia and osteoporosis but also osteosclerosis. A routinely used modality to assess bone density is dual-energy x-ray absorptiometry (DXA). The present study sought to elucidate possible associations between DXA findings with both clinical and bone marrow biopsy findings in SM. METHODS: Patient records of the local oncology and haematology department from 2007 to 2018 were screened for patients with SM. Overall, 39 patients (18 women and 21 men) with sufficient DXA images and clinical data were identified. We evaluated cKit mutation, tryptase level in serum, alkaline phosphatase, calcium level in serum, haemoglobin level, leucocytes and thrombocytes. Bone marrow biopsies were also evaluated. RESULTS: There were no significant differences between the different bone marrow patterns and in regard of cKit mutations. Significant lower bone mineral density (BMD) - T-score and Z-score values were identified for the indolent type compared to aggressive type. Correlation analysis revealed an association between BMD and tryptase level (r=0.35, p=0.049), mast cell proportion in bone marrow biopsy (r=0.45, p=0.01) and with the years since diagnosis (r=-0.42, p=0.02). Moreover, the correlations differed between the indolent and aggressive type. CONCLUSIONS: DXA findings are associated with clinical and bone marrow biopsy parameters in SM. A positive association with tryptase level and mast cell amount in bone marrow biopsies was identified. This corroborates the usefulness of DXA in SM beyond the sole assessment of osteopenia and osteoporosis.

Transient Howell-Jolly-body-like cytoplasmic inclusions in neutrophils after severe intoxication with alpha-lipoic acid.

After intravenous supplementation of an unintentionally high dose of the antioxidant alpha-lipoic acid (ALA), a 53-year-old female complained of myalgia, chills and nausea, and showed signs of haemorrhagic diathesis. The laboratory findings were excessive hyperferritinemia, leukoerythroblastosis, severe thrombocytopenia, elevated liver enzymes and impaired coagulation. The toxicological tests resulted in an ALA serum concentration of 10 280 µg/L. The peripheral blood film of the patient showed some neutrophil dysplasia with unusual small dark-blue stained round cytoplasmic inclusions resembling 'Howell-Jolly-body-like' (HJBL) cytoplasmic inclusions, aptly named due to the morphologic similarity to their erythrocytic counterparts. Such HJBL inclusions are occasionally associated with acquired immunodeficiency, or immunosuppressive or cytostatic treatment. An association with ALA intoxication has not been described before. There are only a few reports on unintentional, harmful and lethal intoxications with ALA. The underlying molecular background of its toxicity on liver function or haematopoiesis is not yet known in detail, but ALA seems to interact with enzyme functions, e.g. with mitochondrial enzyme-complexes, possibly due to its pro-oxidant potential at high doses.

Pretreatment CD34+/CD38- Cell Burden as Prognostic Factor in Myelodysplastic Syndrome Patients Receiving Allogeneic Stem Cell Transplantation.

Myelodysplastic syndrome (MDS) is a highly heterogeneous clonal hematopoietic disorder. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment and is of particular interest in patients at high risk for progression to acute myeloid leukemia (AML). In MDS, CD34+/CD38- cells possess MDS stem cell potential, and secondary AML (sAML) clones originate from the MDS disease stage. However, the prognostic impact of the pretreatment stem cell population burden in MDS remains unknown. We retrospectively analyzed the prognostic impact of the pretreatment CD34+/CD38- cell burden in 124 MDS patients who received allogeneic HSCT at our institution. A high pretreatment bone marrow CD34+/CD38- cell burden (≥1%) was associated with worse genetic risk and a higher incidence of blast excess. Patients with a high CD34+/CD38- cell burden had a significantly higher cumulative incidence of MDS relapse, a higher cumulative incidence of secondary AML, and a trend for shorter overall survival after allogeneic HSCT. In multivariable analyses this prognostic impact was shown to be independent of other clinical and cytogenetic risk factors in MDS. Patients suffering MDS relapse or progression to AML also had a higher pre-treatment CD34+/CD38- cell burden as a continuous variable. The observed prognostic impact is likely mediated by MDS stem cells within the CD34+/CD38- cell population initiating MDS relapse or progression to AML. New therapeutic strategies targeting MDS stem cells might improve outcomes.

Clinical and imaging features of myeloid sarcoma: a German multicenter study.

BACKGROUND: Myeloid sarcoma (MS), also known as chloroma, is an extramedullary manifestation of malignant primitive myeloid cells. Previously, only small studies investigated clinical and imaging features of MS. The purpose of this study was to elucidate clinical and imaging features of MS based upon a multicenter patient sample. METHODS: Patient records of radiological databases of 4 German university hospitals were retrospectively screened for MS in the time period 01/2001 and 06/2019. Overall, 151 cases/76 females (50.3%) with a mean age of 55.5 ± 15.1 years and 183 histopathological confirmation or clinically suspicious lesions of MS were included into this study. The underlying hematological disease, localizations, and clinical symptoms as well as imaging features on CT and MRI were investigated. RESULTS: In 15 patients (9.9% of all 151 cases) the manifestation of MS preceded the systemic hematological disease. In 43 cases (28.4%), first presentation of MS occurred simultaneously with the initial diagnosis of leukemia, and 92 (60.9%) patients presented MS after the initial diagnosis. In 37 patients (24.5%), the diagnosis was made incidentally by imaging. Clinically, cutaneous lesions were detected in 35 of 151 cases (23.2%). Other leading symptoms were pain (n = 28/151, 18.5%), neurological deficit (n = 27/151, 17.9%), swelling (n = 14/151, 9.3%) and dysfunction of the affected organ (n = 10/151, 6.0%). Most commonly, skin was affected (n = 30/151, 16.6%), followed by bone (n = 29/151, 16.0%) and lymphatic tissue (n = 21/151, 11.4%). Other localizations were rare. On CT, most lesions were homogenous. On T2-weighted imaging, most of the lesions were hyperintense. On T1-weighted images, MS was hypointense in n = 22/54 (40.7%) and isointense in n = 30/54 (55.6%). A diffusion restriction was identified in most cases with a mean ADC value of 0.76 ± 0.19 × 10- 3 mm2/s. CONCLUSIONS: The present study shows clinical and imaging features of MS based upon a large patient sample in a multicenter design. MS occurs in most cases meta-chronous to the hematological disease and most commonly affects the cutis. One fourth of cases were identified incidentally on imaging, which needs awareness of the radiologists for possible diagnosis of MS.

Comparison of non-myeloablative and reduced-intensity allogeneic stem cell transplantation in older patients with myelodysplastic syndromes.

Allogeneic stem cell transplantation (HSCT) remains the only curative treatment for myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. The introduction of reduced intensity (RIC) and non-myeloablative (NMA) conditioning enabled HSCT in older or comorbid individuals representing the majority of patients. Studies comparing RIC and NMA conditioning are limited. We retrospectively analyzed 151 MDS or MDS/MPN patients older than 50 years who received NMA- or RIC-HSCT. Patients younger or older than 65 years at HSCT were analyzed separately. Patients receiving RIC-HSCT or NMA-HSCT were balanced in factors reflecting disease aggressiveness and the HCT-CI comorbidity score. The NMA conditioned patients had a higher incidence of graft rejection and chronic graft-vs-host disease. Cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and overall survival (OS), did not differ significantly with regard to the conditioning regime in the whole cohort. In patients <65 years at HSCT, NMA conditioning associated with higher NRM and shorter OS by trend, while CIR was similar in both groups. In multivariable analyzes, the conditioning regimen remained a prognostic factor for NRM and OS in patients <65 years at HSCT. In MDS patients NMA and RIC conditioning result in similar disease control, but especially patients <65 years may benefit from RIC-HSCT.

Digital droplet PCR-based absolute quantification of pre-transplant NPM1 mutation burden predicts relapse in acute myeloid leukemia patients.

Allogeneic hematopoietic stem cell transplantation is an established consolidation therapy for patients with acute myeloid leukemia. However, relapse after transplantation remains a major clinical problem resulting in poor prognosis. Thus, detection of measurable ("minimal") residual disease to identify patients at high risk of relapse is essential. A feasible method to determine measurable residual disease may be digital droplet PCR (ddPCR) that allows absolute quantification with high sensitivity and specificity without the necessity of standard curves. Using ddPCR, we analyzed pre-transplant peripheral blood and bone marrow of 51 NPM1-mutated acute myeloid leukemia patients transplanted in complete remission or complete remission with incomplete recovery. Mutated NPM1 measurable residual disease-positive patients had higher cumulative incidence of relapse (P < 0.001) and shorter overall survival (P = 0.014). Restricting the analyses to patients receiving non-myeloablative conditioning, mutated NPM1 measurable residual disease positivity is associated with higher cumulative incidence of relapse (P < 0.001) and shorter overall survival (P = 0.006). Positive mutated NPM1 measurable residual disease status determined by ddPCR before allogeneic stem cell transplantation is associated with worse prognosis independent of other known prognostic markers-also for those receiving non-myeloablative conditioning. In the future, mutated NPM1 measurable residual disease status determined by ddPCR might guide treatment and improve patients' outcomes.

Prognostic impact of the CD34+/CD38- cell burden in patients with acute myeloid leukemia receiving allogeneic stem cell transplantation.

In acute myeloid leukemia (AML), leukemia-initiating cells exist within the CD34+/CD38- cell compartment. They are assumed to be more resistant to chemotherapy, enriched in minimal residual disease cell populations, and responsible for relapse. Here we evaluated clinical and biological associations and the prognostic impact of a high diagnostic CD34+/CD38- cell burden in 169 AML patients receiving an allogeneic stem cell transplantation in complete remission. Here, the therapeutic approach is mainly based on immunological graft-versus-leukemia effects. Percentage of bone marrow CD34+/CD38- cell burden at diagnosis was measured using flow cytometry and was highly variable (median 0.5%, range 0%-89% of all mononuclear cells). A high CD34+/CD38- cell burden at diagnosis associated with worse genetic risk and secondary AML. Patients with a high CD34+/CD38- cell burden had shorter relapse-free and overall survival which may be mediated by residual leukemia-initiating cells in the CD34+/CD38- cell population, escaping the graft-versus-leukemia effect after allogeneic transplantation. Evaluating the CD34+/CD38- cell burden at diagnosis may help to identify patients at high risk of relapse after allogeneic transplantation. Further studies to understand leukemia-initiating cell biology and develop targeting therapies to improve outcomes of AML patients are needed.

Multiscale modeling of bacterial colonies: how pili mediate the dynamics of single cells and cellular aggregates.

Neisseria gonorrhoeae is the causative agent of one of the most common sexually transmitted diseases, gonorrhea. Over the past two decades there has been an alarming increase of reported gonorrhea cases where the bacteria were resistant to the most commonly used antibiotics thus prompting for alternative antimicrobial treatment strategies. The crucial step in this and many other bacterial infections is the formation of microcolonies, agglomerates consisting of up to several thousands of cells. The attachment and motility of cells on solid substrates as well as the cell-cell interactions are primarily mediated by type IV pili, long polymeric filaments protruding from the surface of cells. While the crucial role of pili in the assembly of microcolonies has been well recognized, the exact mechanisms of how they govern the formation and dynamics of microcolonies are still poorly understood. Here, we present a computational model of individual cells with explicit pili dynamics, force generation and pili-pili interactions. We employ the model to study a wide range of biological processes, such as the motility of individual cells on a surface, the heterogeneous cell motility within the large cell aggregates, and the merging dynamics and the self-assembly of microcolonies. The results of numerical simulations highlight the central role of pili generated forces in the formation of bacterial colonies and are in agreement with the available experimental observations. The model can quantify the behavior of multicellular bacterial colonies on biologically relevant temporal and spatial scales and can be easily adjusted to include the geometry and pili characteristics of various bacterial species. Ultimately, the combination of the microbiological experimental approach with the in silico model of bacterial colonies might provide new qualitative and quantitative insights on the development of bacterial infections and thus pave the way to new antimicrobial treatments.

Lenalidomide, bendamustine and prednisolone exhibits a favourable safety and efficacy profile in relapsed or refractory multiple myeloma: final results of a phase 1 clinical trial OSHO - #077.

This phase 1 dose finding study tested a combination of lenalidomide, bendamustine and prednisolone (RBP) in 21 patients in five cohorts with advanced multiple relasped/refractory myeloma (MM) to determine the maximum tolerable dose (MTD) of the combination. The first cohort received a starting dose of lenalidomide 10 mg/d, days 1-21, bendamustine 60 mg/m(2) /d, days 1-2, and prednisolone 100 mg/d, days 1-4. Dose escalation was done in cohorts of three to six patients with lenalidomide dose increasing to 15, 20 and 25 mg, and after reaching 25 mg/d, bendamustine was increased to 75 mg/m(2) . A total of 21 patients were enrolled and all completed at least two cycles. Two patients developed dose-limiting haemotoxicity: one patient on lenalidomide 25 mg/d and bendamustine 60 mg/m(2) and another patient at the highest dose level (lenalidomide 25 mg/d and bendamustine 75 mg/m(2) ). The MTD was not reached. Sixteen patients (76%) responded after at least two cycles of RBP with one stringent complete response (CR), one near CR, five very good partial response and nine partial response. After a median observation time of 16 months, progression-free survival at 18 months was 48% and overall survival was 64%. In conclusion, RBP with lenalidomide 25 mg/d, days 1-21 and bendamustine 75 mg/m(2) days 1-2 is well tolerated in patients with relapsed/refractory MM.

CT-defined body composition as a prognostic factor in multiple myeloma.

OBJECTIVES: Body composition assessment is comprised by skeletal muscle mass (SMM) and subcutaneous and visceral adipose tissue (SAT and VAT) and can be quantified by imaging. It can be predictive of several clinically outcomes in patients with hematological diseases. Our aim was to establish the effect of body composition parameters on overall survival (OS) and progression-free survival (PFS) in patients with multiple myeloma (MM). MATERIALS AND METHODS: All patients with MM were retrospectively analyzed between 2009 and 2019. One hundred twenty-three patients were included into the analysis. Whole-body computed tomography (CT) was used to calculate SMM, VAT, and SAT. RESULTS: Overall, 22 patients (17.9%) of the patient sample died. Forty patients were sarcopenic (32.5%), 79 patients were visceral obese (64.2%), and 18 patients (14.6%) were sarcopenic obese. Parameter of body composition did not influence OS: sarcopenia, hazard ratio (HR) = 1.3 (95% CI 0.50-3.34), p = .59; visceral obesity, HR = 1.6 (95% CI 0.70-3.76), p = .26; sarcopenic obesity, HR = 2.3 (95% CI 0.90-5.63), p = 0.08. Patients with infectious complications showed higher VAT values. CONCLUSIONS: CT-defined body composition parameters have no influence on survival in patients with MM undergoing autologous stem-cell therapy. These results corroborate previous smaller studies that body composition might have a limited role in this tumor entity. VAT may predict the occurrence of infectious complications.

Varicella Zoster Virus-Specific Hyperimmunoglobulin in the Adjuvant Treatment of Immunocompromised Herpes Zoster Patients: A Case Series.

INTRODUCTION: Immunocompromised patients are at increased risk for herpes zoster (HZ)-associated complications. Despite standard therapy with systemic antiviral drugs and analgesics, complications are frequently encountered, including generalization of lesions or persistent neuropathic pain, so-called post-herpetic neuralgia (PHN). Given the scarcity of literature and awareness of therapeutic options to improve patient outcomes, especially for vulnerable patient groups, here we describe a strategy based on early intensification of treatment with a varicella zoster virus-specific hyperimmunoglobulin (VZV-IgG), which is approved in the adjuvant treatment of HZ. METHODS: For this case series, we selected four cases of HZ in patients with impaired immunity due to hemato-oncologic disease or immunosuppressive treatment who presented with either existing generalized lesions and/or severe pain or with other risk factors for a complicated HZ course such as PHN. They were considered to be representative examples of different patient profiles eligible for intensification of treatment by the addition of VZV-IgG to virostatic therapy. CASE REPORT: All patients showed a rapid response to combined treatment with VZV-IgG and a virostatic agent. In two patients who had generalized lesions, the formation of new lesions ceased 1 day after VZV-IgG infusion. One patient, with mantle cell lymphoma, achieved complete healing of the lesions 9 days after diagnosis of HZ, a rare occurrence compared to similar cases or cohorts. A patient with HZ in the cervical region showed a good response after a single dose of VZV-IgG. None of the patients developed post-zoster-related complications. Combination therapy of a virostatic agent and VZV-IgG was well tolerated in these four cases. CONCLUSION: This case series demonstrates highly satisfactory treatment effectiveness and tolerability for VZV-IgG in the adjuvant treatment of immunocompromised HZ patients and supports early intensification of HZ therapy in patients at high risk of severe disease progression.