A new digital technology to reduce fungicide use in vineyards.

There is a growing demand for technologies able to decrease the environmental impact of agricultural activities without penalizing quali-quantitative characteristics of productions. In the case of viticulture, one of the key problems is represented by the spray drift during fungicide treatments. The diffusion in operational farming contexts of technologies based on variable-rate and recycling tunnel sprayers is often limited by their cost and, for the latter, by their size and lower maneuverability, representing clear disadvantages especially in case of small farms or in hilly and mountain areas. We present a new digital technology implemented in a mobile app that supports the reduction of both the number of treatments and the amount of fungicide distributed per treatment. The technology is based (i) on an alert system that prevents unneeded treatments in case of no risk of infection and (ii) on the quantification of the optimal amounts of active ingredients and dilution water based on the sprayer type/settings and on leaf area index values estimated with a common smartphone. An internal database allows to adjust (in case of need) the active ingredient dose to assure full compliance with product's legal requirements. In case of heterogeneity in leaf area index values inside the vineyard, prescription maps are generated. Results from a 2-year case study in a vineyard in northern Italy are shown, where the system allowed to reduce by 26.4 % and 27.4 % (mean of two years), respectively, the seasonal amounts of fungicides and dilution water, and by 43.8 % the copper content in must. The high usability of the technology proposed (just a common smartphone is needed) and the fact that it does not require updating the farm machine park highlights the suitability of the proposed solution for operational farming conditions, including premium wine production districts often characterized by small farms in hilly areas.

MYC rearrangements in HIV-associated large B-cell lymphomas: EUROMYC, a European retrospective study.

ABSTRACT: Large B-cell lymphoma (LBCL) carrying MYC rearrangement, alone or together with BCL2 and/or BCL6 translocations, have shown a poor prognosis when treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the HIV population. Scanty data are available on the prevalence and prognostic impact of MYC rearrangements in HIV-associated LBCL. We conducted a retrospective study to evaluate the clinical effect of MYC rearrangement in HIV-associated LBCL. We evaluated clinical characteristics, treatment received, and outcome of LBCL in patients with HIV with MYC rearrangement (MYC+) and without MYC rearrangement (MYC-). A total of 155 patients with HIV who had received fluorescence in situ hybridization analysis for MYC were enrolled in 11 European centers: 43 with MYC+ and 112 MYC-. Among patients with MYC, 10 had double-/triple-hit lymphomas, and 33 had isolated MYC rearrangement (single-hit lymphoma). Patients with MYC+ had more frequently advanced stage, >2 extranodal site at presentation, and higher proliferative index. There were no significant differences in overall survival and progression-free survival (PFS) between the 2 groups. However, patients with MYC+ received more frequently intensive chemotherapy (iCT) (44%) than (R)CHOP alone (35%) or infusional treatment (DA-EPOCH-R and R-CDE) (19%). Among patients with MYC+, those who received iCT achieved a better outcome than patients who received nonintensive treatment (complete remission, 84% vs 52%; P = .028; 5-year PFS, 66% vs 36%; P = .021). Our retrospective results suggest that HIV-associated LBCL with MYC+ could be considered for an intensive therapeutic approach whenever possible, whereas (R)CHOP seems to give inferior results in this subset of patients in terms of complete remission and PFS.

High-dose chemotherapy and autologous stem cell transplant as first salvage treatment for relapsed or refractory Hodgkin Lymphoma in the era of PET-adapted strategies.

Data on the efficacy of high-dose chemotherapy and autologous stem cell transplantation (ASCT) for classical Hodgkin lymphoma (cHL) patients who failed a PET-driven first-line therapy are limited.We retrospectively evaluated 220 adult cHL patients who underwent ASCT from 2009 to 2021 at 11 centers in Italy. Overall, 49.5% had refractory disease, 23.2% relapsed < 12 and 27.3% ≥12 months from the end of first-line chemotherapy. The 3-year progression-free survival (PFS) and overall survival (OS) were 73.8% and 89.4%. In univariable analysis for PFS events PET-2+ (HR 2.69, p = .001), anemia (HR 2.22, p = .019), refractory disease (HR 1.76, p = .045), less than CR before ASCT (HR 3.24, p < .001) and >2 lines of salvage therapy (HR 2.52; p = .004) were associated with a higher risk of failure after ASCT. In multivariable analysis, >2 lines of salvage therapy (HR 3.28, p = .004) and RT before ASCT (HR 3.00, p = 0.041) retained significance.ASCT is an effective salvage approach for cHL patients treated in the era of PET-adapted therapies.

Role of Rituximab Addition to First-line Chemotherapy Regimens in Nodular Lymphocyte-predominant Hodgkin Lymphoma: A Study by Fondazione Italiana Linfomi.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare entity whose neoplastic cells retain a B-cell phenotype with expression of CD20. Radiotherapy is recommended for favorable stage IA disease while for other stages guidelines suggest therapeutic strategies similar to those used for classic HL. The role of rituximab, although quite widespread, is not completely elucidated. We retrospectively analyzed baseline characteristics of 308 consecutive patients with NLPHL diagnosed in 19 Italian centers from 2000 to 2018. With a median follow-up of 8.4 years (interquartile range: 4.5-12.4) for treated patients, median overall survival (OS) was not reached and estimated 5-year OS was 97.8% and 5-year progression-free survival (PFS) was 84.5%. Five-year cumulative incidence of histological transformation was 1.4%, 95% confidence interval (CI), 0.5%-3.8%. After adjusting for lymphocyte count, splenic involvement, bulky disease and B symptoms (fever, drenching night sweats, unintentional loss >10% of body weight within the preceding 6 months), patients with stage II or more showed superior PFS with immunochemotherapy in comparison to chemotherapy alone (hazard ratio = 0.4, 95% CI, 0.2-0.8; P = 0.015). Our data suggest an advantage of the use of rituximab combined with chemotherapy ± radiotherapy in the treatment of stage II-III-IV NLPHL.

Explainable domain transfer of distant supervised cancer subtyping model via imaging-based rules extraction.

Image texture analysis has for decades represented a promising opportunity for cancer assessment and disease progression evaluation, evolving in a discipline, i.e., radiomics. However, the road to a complete translation into clinical practice is still hampered by intrinsic limitations. As purely supervised classification models fail in devising robust imaging-based biomarkers for prognosis, cancer subtyping approaches would benefit from the employment of distant supervision, for instance exploiting survival/recurrence information. In this work, we assessed, tested, and validated the domain-generality of our previously proposed Distant Supervised Cancer Subtyping model on Hodgkin Lymphoma. We evaluate the model performance on two independent datasets coming from two hospitals, comparing and analyzing the results. Although successful and consistent, the comparison confirmed the instability of radiomics due to an across-center lack of reproducibility, leading to explainable results in one center and poor interpretability in the other. We thus propose a Random Forest-based Explainable Transfer Model for testing the domain-invariance of imaging biomarkers extracted from retrospective cancer subtyping. In doing so, we tested the predictive ability of cancer subtyping in a validation and perspective setting, which led to successful results and supported the domain-generality of the proposed approach. On the other hand, the extraction of decision rules enables to draw of risk factors and robust biomarkers to inform clinical decisions. This work shows the potentialities of the Distant Supervised Cancer Subtyping model to be further evaluated in larger multi-center datasets, to reliably translate radiomics into medical practice. The code is available at this GitHub repository.

Can Mediterranean Diet Have a Positive Impact on Kidney Health? A Pending Answer to a Long-Time Question.

Dietary studies conducted in chronic kidney disease (CKD) patients were focused on the quantities of single nutrients, however it is possible that the excessive attention put on the restriction of proteins, sodium, potassium and phosphorus may compromise the overall quality of the diet in terms of micronutrients and palatability. Instead, concentrating on the nutritional quality healthy dietary patterns, may provide a better approach to improve nutritional prescriptions in CKD patients. All these dietary regimens share common features as reduced content of red meat, salt and saturated fatty acids, and higher fiber content, but may differ in terms of single nutrients consumption. In particular, Mediterranean Diet (Med Diet) has been associated with reduced incidence of diabetes, cardiovascular diseases and obesity, all conditions that are also strictly related to CKD. Given its low content of animal proteins and high contents of fiber it is possible that Med Diet may exert also positive effects on CKD as well as on its metabolic complications. In this review we summarize the role of Med Diet in primary prevention of CKD and on its progression.

Ibrutinib improves survival compared with chemotherapy in mantle cell lymphoma with central nervous system relapse.

Central nervous system (CNS) relapse of mantle cell lymphoma (MCL) is a rare phenomenon with dismal prognosis, where no standard therapy exists. Since the covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in relapsed/refractory MCL and penetrates the blood-brain barrier (BBB), on behalf of Fondazione Italiana Linfomi and European Mantle Cell Lymphoma Network we performed a multicenter retrospective international study to investigate the outcomes of patients treated with ibrutinib or chemoimmunotherapy. In this observational study, we recruited patients with MCL with CNS involvement at relapse who received CNS-directed therapy between 2000 and 2019. The primary objective was to compare the overall survival (OS) of patients treated with ibrutinib or BBB crossing chemotherapy. A propensity score based on a multivariable binary regression model was applied to balance treatment cohorts. Eighty-eight patients were included. The median age at study entry was 65 years (range, 39-87), 76% were males, and the median time from lymphoma diagnosis to CNS relapse was 16 months (range, 1-122). Patients were treated with ibrutinib (n = 29, ibrutinib cohort), BBB crossing chemotherapy (ie, high-dose methotrexate ± cytarabine; n = 29, BBB cohort), or miscellaneous treatments (n = 30, other therapy cohort). Both median OS (16.8 vs 4.4 months; P = .007) and median progression-free survival (PFS) (13.1 vs 3.0 months; P = .009) were superior in the ibrutinib cohort compared with the BBB cohort. Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (hazard ratio [HR], 6.8; 95% confidence interval [CI], 2.2-21.3; P < .001) and PFS (HR, 4.6; 95% CI, 1.7-12.5; P = .002), followed by CNS progression of disease (POD) >24 months from first MCL diagnosis (HR for death, 2.4; 95% CI, 1.1-5.3; P = .026; HR for death or progression, 2.3; 95% CI, 1.1-4.6; P = .023). The addition of intrathecal (IT) chemotherapy to systemic CNS-directed therapy was not associated with superior OS (P = .502) as the morphological variant (classical vs others, P = .118). Ibrutinib was associated with superior survival compared with BBB-penetrating chemotherapy in patients with CNS relapse of MCL and should be considered as a therapeutic option.

Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients.

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Immune checkpoint inhibitors in combination with radiotherapy as salvage treatment for relapsed/refractory classical Hodgkin lymphoma: A retrospective analysis in 12 patients.

The rate of complete remission (CR) with the anti-PD1 immune checkpoint inhibitors (ICI) nivolumab (N) and pembrolizumab (P) in patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) is low (20-30%), and the majority of patients eventually relapse. One strategy to improve their outcome is to combine ICI with radiotherapy (ICI-RT), taking advantage of a supposed synergistic effect. We retrospectively collected data of 12 adult patients with R/R cHL treated with ICI-RT delivered during or within 8 weeks from the start or after the end of ICI. Median age at ICI-RT was 37 years, 50% had previously received an autologous stem cell transplantation (SCT) and 92% brentuximab vedotin. RT was given concurrently, before or after ICI in 4, 1 and 7 patients. Median RT dose was 30Gy, for a median duration of 22 days. Median number of ICI administrations was 15. Overall response and CR rate were 100% and 58%. Nine patients received subsequent SCT consolidation (7 allogeneic and 2 autologous). After a median follow-up of 18 months, 92% of patients were in CR. No major concerns about safety were reported. ICI-RT combination appears to be a feasible and highly active bridge treatment to transplant consolidation.

A brief rituximab, bendamustine, mitoxantrone (R-BM) induction followed by rituximab consolidation in elderly patients with advanced follicular lymphoma: a phase II study by the Fondazione Italiana Linfomi (FIL).

Treatment for follicular lymphoma (FL) in the elderly is not well standardized. A phase II, multicentre, single arm trial was conducted in this setting with a brief chemoimmunotherapy regimen. Treatment consisted in four monthly courses of rituximab, bendamustine and mitoxantrone (R-BM) followed by 4 weekly rituximab as consolidation; rituximab maintenance was not applied because the drug was not licensed at the time of enrolment. The primary endpoint was the complete remission rate (CR). Seventy-six treatment-naive FL patients (aged 65-80 and a "FIT" score, according to the Comprehensive Geriatric Assessment) were enrolled. CR was documented in 59/76 patients (78%), partial remission in 12 (16%) and stable/progressive disease in five (6%) with an overall response rate in 71/76 (94%). Median follow-up was 44 months with 3-year progression-free-survival (PFS) and overall-survival of 67% and 92% respectively. Nine deaths occurred, three of progressive disease. The regimen was well tolerated and the most frequent severe toxicity was neutropenia (18% of the cycles). Bcl-2/IGH rearrangement was found in 40/75 (53%) of evaluated patients. R-BM was highly effective in clearing polymerase chain reaction-detectable disease: 29/31 (96%) evaluated patients converted to bcl-2/IGH negativity at the end of treatment. A brief R-BM regimen plus rituximab consolidation is effective and safe in "FIT" elderly, treatment-naïve, FL patients, inducing high CR and molecular remission rates with prolonged PFS.

Outcomes in first relapsed-refractory younger patients with mantle cell lymphoma: results from the MANTLE-FIRST study.

Patients with mantle cell lymphoma (MCL) that fail induction treatment represent a difficult-to-treat population, where no standard therapy exists. We evaluated outcomes in patients with first relapsed-refractory (r/r) MCL after upfront high dose cytarabine including standard regimens. Overall survival (OS-2) and progression-free survival (PFS-2) were estimated from the time of salvage therapy. The previously described threshold of 24 months was used to define patients as early- or late-progressors (POD). Overall, 261 r/r MCL patients were included. Second-line regimens consisted of rituximab-bendamustine (R-B, 21%), R-B and cytarabine (R-BAC, 29%), ibrutinib (19%), and others (31%). The four groups were balanced in terms of clinicopathological features. Adjusting for age and early/late-POD, patients treated with R-BAC had significantly higher complete remission (63%) than comparators. Overall, Ibrutinib and R-BAC were associated with improved median PFS-2 [24 and 25 months, respectively], compared to R-B (13) or others (7). In patients with early-POD (n = 127), ibrutinib was associated with inferior risk of death than comparators (HR 2.41 for R-B, 2.17 for others, 2.78 for R-BAC). In patients with late-POD (n = 134), no significant differences were observed between ibrutinib and bendamustine-based treatments. Ibrutinib was associated with improved outcome in early-POD patients.

Venetoclax-rituximab with or without bendamustine vs bendamustine-rituximab in relapsed/refractory follicular lymphoma.

This open-label phase 2 study (CONTRALTO) assessed the safety and efficacy of BCL-2 inhibitor venetoclax (VEN) plus rituximab (R), and VEN plus bendamustine (B) and R, vs B + R (BR) alone in relapsed/refractory (R/R) follicular lymphoma. Patients in the chemotherapy-free arm (arm A: VEN + R) received VEN 800 mg/d plus R 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 4, 6, 8, 10, and 12. After a safety run-in with VEN 600 mg, patients in the chemotherapy-containing cohort were randomized to either VEN + BR (arm B; VEN 800 mg/d for 1 year + 6 cycles of BR [B 90 mg/m2 on days 1 and 2 and R 375 mg/m2 on day 1]) or 6 cycles of BR (arm C). Overall, 163 patients were analyzed (9 in the safety run-in and 52, 51, and 51 in arms A, B, and C, respectively). Complete metabolic/complete response rates were 17% (arm A), 75% (arm B), and 69% (arm C). Of patients in arm B, only 61% received ≥90% of the planned B dose vs 96% of patients in arm C. More frequent hematologic toxicity resulted in more reduced dosing/treatment discontinuation in arm B vs arm C. Rates of grade 3/4 adverse events were 51.9%, 93.9%, and 60.0% in arms A, B, and C, respectively. VEN + BR led to increased toxicity and lower dose intensity of BR than in arm C, but efficacy was similar. Optimizing dose and schedule to maintain BR dose intensity may improve efficacy and tolerability of VEN + BR, while VEN + R data warrant further study. This study was registered at www.clinicaltrials.gov as #NCT02187861.

Primary pancreatic lymphoma: Clinical presentation, diagnosis, treatment, and outcome.

Primary pancreatic lymphoma (PPL) is a rare disease representing 0.1% of malignant lymphomas, which lacks well-defined diagnostic and therapeutic protocols. OBJECTIVES: To describe PPL clinical, diagnostic and histological characteristics, together with therapy and outcome, in a relatively large series of patients. METHODS: The study includes 39 PPL patients, aged ≥15 years, observed from January 2005 to December 2018, in 8 Italian Institutions. RESULTS: The main symptoms were abdominal pain (58%) and jaundice (47%). Lactate dehydrogenase serum levels were elevated in 43% of patients. Histological specimens were mostly obtained by percutaneous (41%) or endoscopic (36%) biopsy, with diffuse large B-cell lymphoma being the most frequent (69%) histological diagnosis. Chemotherapy was administered alone in 65% of patients, with radiotherapy in 17%, or after surgery in 9%. The 2-year overall survival (OS) was 62%, the 2-year progression-free survival (PFS) 44%. Debulking surgery (with or without chemotherapy) was associated with a significant worse OS. Three (9.4%) of 32 high-grade patients experienced a central nervous system (CNS) relapse. CONCLUSIONS: PPL is rare, often high-grade, with symptoms and localization similar to other pancreatic malignancies. Biopsy should be the preferred diagnostic method. High-grade PPL should undergo CNS prophylaxis.

Treatment of very high-risk classical Hodgkin Lymphoma: cases' selection from real life and critical review of the literature.

Over the last 4 decades, advances in radiation therapy and the addition of combination chemotherapy have significantly increased the cure rate of patients with HL, with a 5-year OS of about 90% . However, despite high rate of cure after first line of therapy, 5%-10% of HLs are refractory to the treatment, and 10-30% of patients have a disease relapse after a complete response (CR). Relapsed HL can be treated with salvage therapies with a long-lasting complete remission in 80% of cases. In recent years, novel drugs are available for the patients with relapsed/refractory HL, like Brentuximab Vedotin and immune checkpoint inhibitors. These drugs have been able to rescue a cohort of patients who subsequently could receive an allogeneic stem-cell transplant. Our cases have been chosen because they are representative of critical issues in the management of relapsed/refractory HL; our experiences are consistent with what reported by other Authors.