Viral Population Heterogeneity and Fluctuating Mutational Pattern during a Persistent SARS-CoV-2 Infection in an Immunocompromised Patient.

Literature offers plenty of cases of immunocompromised patients, who develop chronic and severe SARS-CoV-2 infections. The aim of this study is to provide further insight into SARS-CoV-2 evolutionary dynamic taking into exam a subject suffering from follicular lymphoma, who developed a persistent infection for over 7 months. Eight nasopharyngeal swabs were obtained, and were analyses by qRT-PCR for diagnostic purposes. All of them were considered eligible (Ct < 30) for NGS sequencing. Sequence analysis showed that all sequences matched the B.1.617.2 AY.122 lineage, but they differed by few mutations identifying three genetically similar subpopulations, which evolved during the course of infection, demonstrating that prolonged replication is paralleled with intra-host virus evolution. These evidences support the hypothesis that SARS-CoV-2 adaptive capacities are able to shape a heterogeneous viral population in the context of immunocompromised patients. Spill-over of viral variants with enhanced transmissibility or immune escape capacities from these subjects is plausible.

Low-Dose Cyclophosphamide versus Intermediate-High-Dose Cyclophosphamide versus Granulocyte Colony-Stimulating Factor Alone for Stem Cell Mobilization in Multiple Myeloma in the Era of Novel Agents: A Multicenter Retrospective Study.

The optimal stem cell (SC) mobilization strategy for patients with multiple myeloma (MM) remains a matter of debate. Possible approaches include low or high doses of cyclophosphamide (Cy), other chemotherapeutic agents, or granulocyte colony-stimulating factor (G-CSF) alone. The scope of the study was to compare low-dose Cy plus G-CSF versus intermediate-high-dose Cy plus G-CSF versus G-CSF alone for SC mobilization in MM, in terms of efficacy and safety. We retrospectively analyzed 422 MM patients undergoing SC mobilization in 6 Italian centers, including 188 patients who received low-dose Cy (LD-Cy group, defined as 2 g/m2), 163 patients who received intermediate-high-dose Cy (HD-Cy group, defined as ≥ 3 g/m2), and 71 patients who received G-CSF alone (G-CSF group). The median peak of circulating CD34+ cells was 77/µL in the LD-Cy group, 92/µL in the HD-Cy group, and 55/µL in the G-CSF group (P = .0001). The median amount of SCs collected was 9.1 × 106/kg, 9.7 × 106/kg, and 5.6 × 106/kg in the 3 groups, respectively (P = .0001). The rate of mobilization failure (defined as failure to collect ≥2 × 106/kg) was 3.7% in the LD-Cy group, 3.4% in the HD-Cy group, and 4.3% in the G-CSF group (P = .9). The target SC dose of at least 4 × 106/kg was reached in 90.4%, 91.1%, and 78.6% of the patients in these 3 groups, respectively (P = .014). The "on demand" use of plerixafor was higher in the G-CSF group (76%) compared with the LD-Cy group (19%) and the HD-Cy group (6%). In multivariate analysis, G-CSF mobilization and previous use of melphalan or radiotherapy were independently associated with failure to collect the target SC dose of ≥4 × 106/kg. No impacts of age, blood counts, or previous treatment with lenalidomide, bortezomib, or carfilzomib were observed. Our results suggest that LD-Cy may be considered for successful SC mobilization in patients with MM.

Factors affecting successful mobilization with plerixafor: an Italian prospective survey in 215 patients with multiple myeloma and lymphoma.

BACKGROUND: Although the efficacy of plerixafor in peripheral blood stem cell (PBSC) mobilization has been explored in several studies, factors associated with successful plerixafor mobilization after administration of granulocyte-colony-stimulating factor (G-CSF), with or without chemotherapy, have not been investigated. We analyzed data on PBSC mobilization from a large Italian database of lymphoma and myeloma plerixafor-treated patients. STUDY DESIGN AND METHODS: Two endpoints were established to define successful mobilization: patients with at least 2 × 10(6) CD34+ cells/kg collected by three leukapheresis procedures and patients achieving a peak count of at least 20 × 10(6) CD34+ cells/L during mobilization. RESULTS: Plerixafor achieved successful mobilization in both predicted (n = 64) and proven poor mobilizers (PMs; n = 143), classified according to the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) criteria. Successful mobilization was independent of type of mobilization (steady state or chemotherapy); age; sex; disease; number or type of chemotherapy regimens preceding plerixafor; radiation therapy; prior treatment with melphalan, carmustine, lenalidomide, and radioimmune conjugates; and laboratory variables. Multivariate analysis identified previous fludarabine treatment and premobilization platelet count as predictors of successful mobilization. CONCLUSION: This large, prospective, nationwide study confirmed plerixafor efficacy for mobilizing PBSCs when added to G-CSF with or without chemotherapy. Plerixafor can overcome negative effects of most predictors of poor mobilization to achieve satisfactory harvest both in predicted and proven PM.

Lenalidomide in combination with dexamethasone in elderly patients with advanced, relapsed or refractory multiple myeloma and renal failure.

Salvage therapy of elderly patients with advanced, relapsed and refractory multiple myeloma (MM) is often limited by poor marrow reserve and multi-organ impairment. In particular, renal failure occurs in up to 50% of such patients, and this can potentially limit the therapeutic options. Both thalidomide and bortezomib have proven effective in these patients, with an acceptable toxicity, while, in clinical practice, lenalidomide is generally not considered a first-choice drug for MM patients with renal failure as early reports showed an increased hematological toxicity unless appropriate dose reduction is applied. Aim of this study was a retrospective evaluation of the efficacy of the combination Lenalidomide + Dexamethasone in a population of elderly MM patients treated in 5 Italian Centers. The study included 20 consecutive MM patients (9 M, 11 F, median age 76.5 years) with relapsed (N= 6) or refractory (N=13) MM and moderate to severe renal failure, defined as creatinine clearance (Cr Cl) < 50ml/min. Four patients were undergoing hemodyalisis at study entry. 85 % of the patients had been previously treated with bortezomib-containing regimens. Lenalidomide dose was adjusted according to renal function and patients clinical conditions Median treatment duration was 16 months (1-22), therapy was interrupted after 1 21-day cycle in 2 patients. Grade III-IV neutropenia was observed in 7 patients (35%); grade III-IV non hematological toxicity was recorded in 3 cases (28%). A > partial response was observed in 8 patients (40%), 1 of whom obtained a VGPR; 4 additional patients achieved a minor response. Median response duration was 16 months (range 2-19+ months). A complete and partial renal response was obtained in 4 and 3 patients, respectively, all of them were responsive to Lenalidomide-dexamethasone According to our data, LEN+DEX has shown efficacy and acceptable toxicity in this population of elderly patients with advanced MM and renal failure.

[Chemotherapy in extended small-cell lung cancer. Retrospective analysis of two different series of patients treated with carboplatin and etoposide or ciclophosphamide-epidoxorubicin and etoposide]. / La chemioterapia del microcitoma disseminato. Confronto tra carboplatino-etoposide e ciclofosfamide-epirubicina-etoposide.

Although cisplatin and etoposide seem to represent the treatment of choice in Small-Cell Lung Cancer, a lot of data exist in literature supporting both the use of anthracycline-containing regimens and the use of alternating regimens where platinum-containing regimens and anthracycline-containing regimens are alternatively used as first line in the same patient. In our paper we review the outcomes of two different series of patients treated with ciclophosphamide-epidoxorubicin-etoposide (CEVP16) or carboplatin-etoposide (CBE) for extended Small-Cell Lung Cancer. Sixty-three patients (53.4%) were treated with CEVP16 and 55 patients (46.6%) with CBE. Response Rate (complete plus partial responses) was greater in patients treated with CEVP16 (49.2%) when compared with the response rate in patients treated with CBE (30.9%) (p=0.04 using the Chi-Square test); no differences were observed in the median time to progression (235 vs 199 days, using the Log-Rank test). Overall survival was greater in the CEVP16 group when compared with the CBE one (281 vs 208 days and 35.6% vs 16.3% of patients alive after 2 years of follow up for CEVP16 and CBE respectively, p=0.02 using the Log-Rank test). Although our data present all the methodological limits of the "case-series", it is interesting to observe how an anthracycline-containing regimen seems to be more effective than a platinum-containing one and how it could still play a role in the treatment of extended Small-Cell Lung Cancer.

Carboplatin and gemcitabine in the palliative treatment of stage IV non-small cell lung cancer: definitive results of a phase II trial.

BACKGROUND: Cisplatin-containing regimens represent the gold standard in the treatment of advanced non-small cell lung cancer, but carboplatin is often preferred for its better toxic profile when palliation is the aim of the treatment. The synergistic effect and tolerability of carboplatin-gemcitabine combination are well known. In this phase II trial, we evaluated the activity and safety of a schedule with carboplatin and gemcitabine, defined in our previous phase I trial. METHODS: Thirty-seven patients with measurable stage IV non-small cell lung cancer were treated with carboplatin, AUC 4.5 mg/ml/min on day 1, and gemcitabine, 800 mg/m2 on days 1 and 8, every 21 days. All patients were treated until disease progression or intractable toxicity and were evaluated before each course of chemotherapy for toxicity and after every 3 courses for response. RESULTS: After a median follow-up of over 10 months, complete response, partial response, and stabilization of the disease were observed in 3 (8.1%), 9 (24.3%), and 15 patients (40.5%), respectively. Median time to progression was 7 months. At this writing, 27 patients have died, with a median survival of 10 months, and 29 (78.3%), 16 (43.2%), and 11 (29.7%) patients are alive after 6, 12, and 15 months of follow-up, respectively. Toxicity was mild, and mainly hematological, with a significant correlation with the number of courses of chemotherapy (P = 0.0003). CONCLUSIONS: Our results are comparable with those reported in the literature and confirm the good activity and tolerability of the carboplatin-gemcitabine combination. Up to 4 courses of chemotherapy with carboplatin and gemcitabine may represent an interesting option in the palliative treatment of non-small cell lung cancer.

Adjuvant chemotherapy in gastric cancer: a meta-analysis of randomized trials and a comparison with previous meta-analyses.

AIMS AND BACKGROUND: Up to now adjuvant chemotherapy after curative resection for gastric cancer (GC) has been considered an experimental approach. The results of existing phase III randomized trials comparing chemotherapy with control after surgery are controversial. Three meta-analyses have been published in recent years. It is likely that each of them presents a theoretical bias, mainly as regards the inclusion criteria of the trials. In this article we re-examine this potential bias, highlighting the differences between the present and past meta-analyses on adjuvant chemotherapy for GC. METHODS: Only randomized controlled clinical trials comparing systemic adjuvant chemotherapy with control after radical resection of GC were eligible. Total mortality was assessed as outcome measure of the treatment effect and a pooled odds ratio was calculated using the Peto-Mantel-Haenszel method. RESULTS: After the selection process 17 papers (18 comparisons) proved eligible for inclusion in the meta-analysis with a total of 3118 patients, of whom 1546 randomized to the treatment arms and 1572 to the control arms; 762 and 871 deaths occurred in the treatment and control arms, respectively. Statistical analysis suggests an absence of significant heterogeneity between the trials and a significant advantage in survival for adjuvant chemotherapy (pooled odds ratio, 0.72, 95% Cl, 0.62-0.84). CONCLUSIONS: Our meta-analysis would seem to indicate that adjuvant chemotherapy results in a significant survival advantage in patients with GC. However, this observation undoubtedly requires confirmation in large randomized controlled trials including cisplatin before adjuvant chemotherapy after curative resection for GC can be proposed for use in clinical practice.