Evaluation of Metronomic Therapy as a Low-Cost, Sustainable, Standard-of-Care Option in Desmoid Fibromatosis: Real-World Data From a Tertiary Care Center in India.

PURPOSE: Desmoid fibromatosis (DF) is a locally aggressive tumor with low mortality but significant morbidity. There is a lack of standard of care, and existing therapies are associated with significant barriers including access, cost, and toxicities. This study aimed to explore the efficacy and safety of the metronomic therapy (MT) in DF in a large, homogenous cohort from India. PATIENTS AND METHODS: This study involved histologically confirmed DF cases treated with MT comprising vinblastine (6 mg) and methotrexate (15 mg) both once a week, and tamoxifen (40 mg/m2) in two divided doses once daily between 2002 and 2018. RESULTS: There were 315 patients with a median age of 27 years; the commonest site was extremity (142 of 315; 45.0%). There were 159 (50.1%) male patients. Of the 123 (39.0%) prior treated patients, 119 had surgery. Of 315 patients, 263 (83.5%) received treatment at our institute (MT-151, 77-local treatment, 9-tyrosine kinase inhibitor, and 26 were observed). Among the MT cohort (n = 163, 61.2%), at a median follow-up of 36 (0.5-186) months, the 3-year progression-free and overall survival were 81.1% (95% CI, 74.3 to 88.4) and 99.2% (95% CI, 97.6 to 100), respectively. There were 35% partial responses. Ninety-two patients (56.4%) completed 1-year therapy, which was an independent prognosticator (P < .0001; hazard ratio, 0.177 [95% CI, 0.083 to 0.377]). MT was well tolerated. Predominant grade ≥3 toxicities were febrile neutropenia, 12 (7.4%) without any chemotoxicity-related death. The annual cost of MT was $130 US dollars. CONCLUSION: The novel, low-cost MT qualifies as one of the effective, less toxic, sustainable, standard-of-care options for the treatment of DF with global reach and merits wide recognition.

Crosstalk between melatonin and nitric oxide restrains Cadmium-induced oxidative stress and enhances vinblastine biosynthesis in Catharanthus roseus (L) G Don.

KEY MESSAGE: Nitric oxide functions downstream of the melatonin in adjusting Cd-induced osmotic and oxidative stresses, upregulating the transcription of D4H and DAT genes, and increasing total alkaloid and vincristine contents. A few studies have investigated the relationship between melatonin (MT) and nitric oxide (NO) in regulating defensive responses. However, it is still unclear how MT and NO interact to regulate the biosynthesis of alkaloids and vincristine in leaves of Catharanthus roseus (L.) G. Don under Cd stress. Therefore, this context was explored in the present study. Results showed that Cd toxicity (200 µM) induced oxidative stress, decreased biomass, Chl a, and Chl b content, and increased the content of total alkaloid and vinblastine in the leaves. Application of both MT (100 µM) and sodium nitroprusside (200 µM SNP, as NO donor) enhanced endogenous NO content and accordingly increased metal tolerance index, the content of total alkaloid and vinblastine. It also upregulated the transcription of two respective genes (D4H and DAT) under non-stress and Cd stress conditions. Moreover, the MT and SNP treatments reduced the content of H2O2 and malondialdehyde, increased the activities of superoxide dismutase and ascorbate peroxidase, enhanced proline accumulation, and improved relative water content in leaves of Cd-exposed plants. The scavenging NO by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxy l-3-oxide (cPTIO) averted the effects of MT on the content of total alkaloid and vinblastine and antioxidative responses. Still, the effects conferred by NO on attributes mentioned above were not significantly impaired by p-chlorophenylalanine (p-CPA as an inhibitor of MT biosynthesis). These findings and multivariate analyses indicate that MT motivated terpenoid indole alkaloid biosynthesis and mitigated Cd-induced oxidative stress in the leaves of periwinkle in a NO-dependent manner.

Vanishing bile duct syndrome as a presentation of Hodgkin's lymphoma.

Vanishing bile duct syndrome is an uncommon condition characterised by the progressive loss and disappearance of bile ducts. It is an acquired form of cholestatic liver disease presenting with hepatic ductopenia (loss of >50% bile ducts in the portal areas). We present a case of vanishing bile duct syndrome as a presentation of Hodgkin's lymphoma who was treated with standard-of-care chemotherapy-doxorubicin, bleomycin, vinblastine and dacarbazine (along with brief administration of rituximab), which led to complete response and normalisation of liver function.

Characterization of a CrPME indicates its possible role in determining vindoline accumulation in Catharanthus roseus leaves.

The leaf-specific Catharanthus roseus alkaloid, vindoline, is the major bottleneck precursor in the production of scarce and costly anticancer bisindoles (vincristine and vinblastine). The final steps of its biosynthesis and storage occur in the laticifers. Earlier, we have shown that vindoline content is directly related to laticifer number. Pectin remodeling enzymes, like pectin methylesterase (PME), are known to be involved in laticifer development. A search in the croFGD yielded a leaf-abundant CrPME isoform that co-expressed with a few vindoline biosynthetic genes. Full-length cloning, tissue-specific expression profiling, and in silico analysis of CrPME were carried out. It was found to possess all the specific characteristics of a typical plant PME. Transient silencing (through VIGS) and overexpression of CrPME in C. roseus indicated a direct relationship between its expression and vindoline content. Comparative analysis of transcript abundance and enzyme activity in three familial C. roseus genotypes differing significantly in their vindoline content and laticifer count (CIM-Sushil > Dhawal > Nirmal) also corroborated the positive relationship of CrPME expression with vindoline content. This study highlights the possible role of CrPME, a cell wall remodeling enzyme, in modulating laticifer-associated secondary metabolism.

Nimotuzumab-vinorelbine combination therapy versus other regimens in the treatment of pediatric diffuse intrinsic pontine glioma.

PURPOSE: Pediatric diffuse intrinsic pontine glioma (DIPG) is a fatal disease associated with a median survival of < 1 year despite aggressive treatments. This retrospective study analyzed the treatment outcomes of patients aged < 18 years who were diagnosed with DIPG between 2012 and 2022 and who received different chemotherapy regimens. METHODS: After radiotherapy, patients with DIPG received nimotuzumab-vinorelbine combination or temozolomide-containing therapy. When nimotuzumab was unavailable, it was replaced by vincristine, etoposide, and carboplatin/cyclophosphamide (VECC). Temozolomide was administered as a single agent or a part of the combination chemotherapy comprising temozolomide, irinotecan, and bevacizumab. Furthermore, 1- and 3-year overall survival (OS), progression-free survival (PFS), and median OS and PFS were analyzed. RESULTS: The median age of 40 patients with DIPG was 97 ± 46.93 (23-213) months; the median follow-up time was 12 months. One and 3-year OS were 35.0% and 7.5%, respectively. Median OS was 12 months in all patients (n = 40), and it was 16, 10, and 11 months in those who received first-line nimotuzumab-vinorelbine combination (n = 13), temozolomide-based (n = 14), and VECC (n = 6) chemotherapy regimens, respectively (p = 0.360). One patient who received gefitinib survived for 16 months. Conversely, patients who never received radiotherapy and any antineoplastic medicamentous therapy (n = 6) had a median OS of 4 months. CONCLUSION: Nimotuzumab-vinorelbine combination therapy prolonged OS by 6 months compared with temozolomide-containing chemotherapy, although the difference was not statistically significant.

Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: Clinical Practice Guidelines for the Use of G-CSF 2022.

Granulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression and thereby relieve symptoms, such as hematuria, infection, bleeding, and pain, as well as to prolong the survival. In this clinical question, we compared treatment with primary prophylactic administration of G-CSF to maintain therapeutic intensity with conventional standard therapy without G-CSF and examined the benefits and risks as major outcomes. A detailed literature search for relevant studies was performed using PubMed, Ichu-shi Web, and Cochrane Library. Data were extracted and evaluated independently by two reviewers. A qualitative analysis of the pooled data was performed, and the risk ratios with corresponding confidence intervals were calculated and summarized in a meta-analysis. Seven studies were included in the qualitative analysis, two of which were reviewed in the meta-analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, and one randomized controlled study showed a reduction in the incidence of FN. Primary prophylactic administration of G-CSF may be beneficial, as shown in a randomized controlled study of dose-dense MVAC therapy. However, there are no studies on other regimens, and we made a "weak recommendation to perform" with an annotation of the relevant regimen (dose-dense MVAC).

Single-agent metronomic versus weekly oral vinorelbine as first-line chemotherapy in patients with HR-positive/HER2-negative advanced breast cancer: The randomized Tempo Breast study.

INTRODUCTION: Single-agent oral vinorelbine is a standard of care for hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) that has progressed on endocrine therapy. Metronomic administration may offer a better balance of efficacy and safety than standard regimens, but data from previous trials are scarce. METHODS: In this open-label, multicenter, phase II trial, patients were randomized to oral vinorelbine administered on a metronomic (50 mg three times weekly) or weekly (60 mg/m2 in cycle 1, increasing to 80 mg/m2 if well tolerated) schedule. Treatment was continued until disease progression or intolerance. The primary endpoint was disease control rate (DCR, the proportion of patients with a best overall confirmed response of CR, PR, or stable disease lasting 6 months or more). RESULTS: One-hundred sixty-three patients were randomized and treated. The DCR was 63.4% (95% confidence interval [CI]: 52.0-73.8) with metronomic vinorelbine and 72.8% (95% CI: 61.8-82.1) with weekly vinorelbine. Weekly vinorelbine was also associated with longer progression-free survival (5.6 vs 4.0 months) and overall survival (26.7 vs 22.3 months) than metronomic vinorelbine, but was associated with more adverse events. CONCLUSIONS: In this randomized phase II trial, single-agent metronomic oral vinorelbine was effective and well tolerated as first-line chemotherapy for patients with HR-positive/HER2-negative ABC. Formal comparisons are not done in this phase II study and one can simply observe that confidence intervals of all endpoints overlap. When deciding for a chemotherapy after failure of endocrine therapy and CDK 4/6 inhibitors, oral vinorelbine might be an option to be given with either schedule. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2014-003860-19.

Co-treatment With Aripiprazole and Vincristine Sensitizes P-Glycoprotein-Overexpressing Drug-resistant MCF-7/ADR Breast Cancer Cells.

BACKGROUND/AIM: Evidence supports that use of aripiprazole sensitizes drug-resistant oral cancer cells. The aim of the study was to investigate whether aripiprazole can achieve sensitization of highly drug-resistant breast cancer cells, as well as identify its relevant mechanisms of action. MATERIALS AND METHODS: MCF-7/ADR, KB, and KBV20C breast cancer cells were treated with aripiprazole, vincristine (VIC), vinorelbine, vinblastine and their combination. Cell viability assay, annexin V analyses, cellular morphology and density observation with a microscope, western-blotting, fluorescence-activated cell sorting (FACS), and analysis for P-gp inhibitory activity were performed to investigate the drugs' mechanism of action. RESULTS: We found that high drug resistance in MCF-7/ADR cells results from high P-gp inhibitory activity via overexpression of P-gp. Aripiprazole reduced cell viability, increased G2 arrest, and upregulated apoptosis when used as a co-treatment with VIC. Furthermore, we demonstrated that co-treatment with vinorelbine and vinblastine increased the sensitization of MCF-7/ADR breast cancer cells to aripiprazole. We confirmed that VIC-aripiprazole combination has much higher sensitization effects than either VIC-thioridazine or VIC-trifluoperazine co-treatment in MCF-7/ADR cells, since the previously known bipolar drugs (thioridazine and trifluoperazine) has lower P-gp inhibitory activity. However, aripiprazole-induced sensitization was not observed in VIC-treated MDA-MB-231 breast cancer cells suggesting that combination therapy with aripiprazole is specific for P-gp-overexpressing drug-resistant breast cancer cells. CONCLUSION: Co-treatment with low doses of aripiprazole sensitized MCF-7/ADR cells to VIC. Combination therapy with aripiprazole may be a valuable tool for delaying or reducing cancer recurrence by targeting P-gp-overexpressing drug-resistant breast cancer cells.

De novo biosynthesis of antiarrhythmic alkaloid ajmaline.

The antiarrhythmic drug ajmaline is a monoterpenoid indole alkaloid (MIA) isolated from the Ayurvedic plant Rauvolfia serpentina (Indian Snakeroot). Research into the biosynthesis of ajmaline and another renowned MIA chemotherapeutic drug vinblastine has yielded pivotal advancements in the fields of plant specialized metabolism and engineering over recent decades. While the majority of vinblastine biosynthesis has been recently elucidated, the quest for comprehending ajmaline biosynthesis remains incomplete, marked by the absence of two critical enzymes. Here, we show the discovery and characterization of these two elusive reductases, alongside the identification of two physiologically relevant esterases that complete the biosynthesis of ajmaline. We show that ajmaline biosynthesis proceeds with vomilenine 1,2(R)-reduction followed by its 19,20(S)-reduction. This process is further modulated by two root-expressing esterases that deacetylate 17-O-acetylnorajmaline. Expanding upon the successful completion of the ajmaline biosynthetic pathway, we engineer the de novo biosynthesis of ajmaline in Baker's yeast.

METRO-PD1: Phase 1 study of nivolumab in combination with metronomic chemotherapy in children and adolescents with relapsing/refractory solid tumors.

BACKGROUND: This multicenter Phase I study (NCT03585465) evaluated nivolumab in combination with 3 metronomic chemotherapy (MC) regimens in children with refractory/relapsing solid tumors. OBJECTIVES: To evaluate the feasibility and safety of the three regimens METHODS: Patients aged < 18 years were enrolled. Nivolumab was combined with cyclophosphamide and vinblastine (arm A), capecitabine (arm B), or cyclophosphamide, vinblastine and capecitabine (arm C). Arm A and B were allocated sequentially. Arm C opened only if A and B were deemed safe. Dose-limiting toxicities (DLTs) were evaluated over the first two cycles. Patients were evaluable if they received > 2 cycles and > 70% of the planned dose. POPULATION: Sixteen patients were enrolled, 3 in arm A, 6 in arm B, and 7 in arm C. Median age was 11.5 years (range, 5-19). Patients previously received a median of 3.5 (range, 1-4) lines of systemic treatment, 14 patients had surgery and 11 had radiotherapy. RESULTS: Median number of cycles was 2 (1-24), median treatment duration was 56 days (18-714). In arm C, median number of cycles was 4 with median treatment duration of 95 days. No DLT was observed. Grade 3 adverse events (AE) and serious AE were observed in 8 patients (50%) and 1 patient (6%), respectively, over the first 2 cycles. No grade 4 AE occurred. The 6-month PFS and OS were 12% and 44%, respectively, in the whole population. Prolonged stable disease was observed in a high-grade glioma and an atypical teratoid rhabdoid tumor. CONCLUSION: Arm C appears safe. A randomized phase II trial evaluating the addition of nivolumab to the triple MC is ongoing.

The Impact of Bleomycin Deficit on Survival in Hodgkin's Lymphoma Patients: A Retrospective Study.

PURPOSE: Hodgkin's lymphoma is currently treated with a chemotherapy protocol consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine. Due to Brazil facing a bleomycin shortage in 2017, and this drug's high toxicity, this retrospective study evaluates the effect that the absence of bleomycin had on treatment response and overall survival of Hodgkin's lymphoma patients. METHODS: The medical records of 126 HL patients treated between 2007 and 2021 were reviewed and their data collected, followed by grouping into ABVD and AVD groups according to bleomycin use. Data concerning the patient's characteristics, cancer type, and treatment plan were analyzed with proportion tests, Kaplan-Meier curves. univariate Cox regression, and χ2 tests. RESULTS: No discernible differences were found in this study between the overall survival and recurrence rate of patients treated with bleomycin compared to those without. Additionally, there was an increased risk of death in each subsequent cycle of chemotherapy of the complete ABVD protocol, demonstrating a risk of toxicity. Among the variables analyzed, hypertension and the presence of B symptoms were also associated with an increased risk of death, while the use of radiotherapy significantly improved survival. CONCLUSION: The results of this study suggest that bleomycin did not impact the outcome of Hodgkin's lymphoma treatment. Moreover, the increased risk of death associated with its toxicity during each cycle of treatment raises concerns about its role as an essential component of the gold standard for Hodgkin's lymphoma treatment. Therefore, further research and consideration are needed to reassess the use of bleomycin in Hodgkin's lymphoma treatment protocols.

The Impact of an Enrolment in Clinical Trial on Tolerance and Pathological Response for Patients Treated by Neoadjuvant MVAC Against an Invasive Bladder Cancer. A Retrospective Comparative Study.

INTRODUCTION: MVAC (Methotrexate, Vinblastine, Adriamycin, and Cisplatin) neoadjuvant chemotherapy a standard treatment for invasive bladder cancer is associated with mainly haematological toxicities. Randomized clinical trials remain a gold standard for treatment outcomes and efficacy assessment. Patients enrolled in clinical trials are selected and tend to benefit from a stricter follow-up unlike everyday clinical practice patients. Conversely, real-life observational studies better define the effectiveness of treatments in clinical routine practice. The aim of this study is to analyse the impact of clinical trial monitoring on MVAC-related toxicities. MATERIAL AND METHODS: Patients with an infiltrative localized bladder cancer treated by MVAC neoadjuvant chemotherapy between 2013 and 2019 were enrolled, and divided into 2 groups: patients included in a clinical trial namely "VESPER study" during their treatment and patients treated in clinical routine practice. RESULTS: Out of 59 patients were enrolled in this retrospective study, 13 patients were included in a clinical trial. Clinical characteristics were similar between the 2 groups. Comorbidities were more frequent in the nonclinical trial group (NCTG). Completed 6 cures treatment proportion was higher in the clinical trial group (CTG) (69.2% vs. 50%). Yet, in this group, patients had more doses reduction (38.5% vs. 19.6%). The proportion of complete pathologic response was higher in patients enrolled in clinical trial (53.8% vs. 39.1%). Statistically, the expected stricter monitoring due to clinical trial enrolment had no impact on the complete pathologic response and clinically relevant toxicities. DISCUSSION: When compared to conventional clinical practice, clinical trial enrolment induced no significant difference on the pathologic complete response or toxicity rate. Further large prospective studies are needed to confirm these data.

Genome-wide identification and characterization of wall-associated kinases, molecular docking and polysaccharide elicitation of monoterpenoid indole alkaloids in micro-propagated Catharanthus roseus.

Wall-associated kinases (WAKs) are a unique family of proteins that are predominantly localized on the plasma membrane and simultaneously bound to the cell wall. WAKs play a pivotal role in signal transduction to regulate growth, defense, and response to environmental stimuli in plants. These kinases have been identified and characterized in various plant species, however, similar information for Catharanthus roseus is scarce. C. roseus is an evergreen ornamental plant that produces a repertoire of biologically active compounds. The plant is best characterized for the production of antineoplastic monoterpenoid indole alkaloids (MIAs) namely vinblastine and vincristine. Owing to the diverse composition of phytochemicals, C. roseus is known as a "model non-model" plant for secondary metabolite research. Genome analyses showed 37 putative CrWAK genes present in C. roseus, largely localized on the plasma membrane. Phylogenetic analysis revealed six clusters of CrWAKs. Diverse cis-acting elements, including those involved in defense responses, were identified on the promotor regions of CrWAK genes. The highest binding affinity (- 12.6 kcal/mol) was noted for CrWAK-22 against tri-galacturonic acid. Tri-galacturonic acid stimulated 2.5-fold higher production of vinblastine, sixfold upregulation of the expression of ORCA3 transcription factor, and 6.14-fold upregulation of CrWAK-22 expression. Based on these results it was concluded that the expression of CrWAK genes induced by biotic elicitors may have an important role in the production of MIAs. The current findings may serve as a basis for functional characterization and mechanistic explanation of the role of CrWAK genes in the biosynthesis of MIAs upon elicitation.

Tislelizumab monotherapy in patients with previously untreated early-stage classical Hodgkin lymphoma: a real-world study.

The anti-PD-1 antibodies have been reported to show a striking effect in relapsed and refractory(R/R) classical Hodgkin lymphoma (cHL), however, there is still limited real-world data assessing the role of anti-PD-1 antibody monotherapy in early-stage cHL. In this retrospective analysis, we reported the effectiveness and safety of tislelizumab monotherapy in the first-line therapy of early-stage cHL. Twenty-three consecutive patients (10 males and 13 females) with previously untreated stage I A-II B cHL were included. At interim evaluation after 2 doses of tislelizumab monotherapy, 11 of 23 patients (47.8%) achieved complete response (CR). At the end of tislelizumab monotherapy (EOTM), objective response was observed in 22 of 23 patients (95.7%), with CR in 16 patients (69.6%). Among six patients with PR-EOTM, two patients underwent 4 cycles of ABVD chemotherapy and one patient underwent 4 cycles of tislelizumab plus AVD. One patient who developed progressive disease (PD) after 4 doses of tislelizumab subsequently underwent 4 cycles of ABVD chemotherapy. Except for four patients with CR-EOTM, consolidative radiotherapy was given to 19 patients. All patients obtained CR at the end of all treatments. With a median follow-up time of 21.3 months (range, 6.9-32.7 months), the estimated 2-year PFS rate and 2-year OS rate were 95.65% and 100%, respectively. Except for grade 3 lymphocyte count decreased, no other grade 3/4 TRAE was observed. In addition, no serious AE was reported. Our preliminary data observed that tislelizumab monotherapy was safe and highly effective in previously untreated early-stage cHL.

Long-Term Follow-Up of the Response-Adapted Intergroup EORTC/LYSA/FIL H10 Trial for Localized Hodgkin Lymphoma.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary analysis of the Early positron emission tomography (ePET) Response-Adapted Treatment in localized Hodgkin Lymphoma H10 Trial demonstrated that in ePET-negative patients, the risk of relapse increased when involved-node radiotherapy (INRT) was omitted and that in ePET-positive patients, switching from doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) to bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) significantly improved 5-year progression-free survival (PFS). Here, we report the final results of a preplanned analysis at a 10-year follow-up. In the favorable (F) ePET-negative group, the 10-year PFS rates were 98.8% versus 85.4% (hazard ratio [HR], 13.2; 95% CI, 3.1 to 55.8; P value for noninferiority = .9735; difference test P < .0001) in favor of ABVD + INRT; in the unfavorable (U) ePET-negative group, the 10-year PFS rates were 91.4% and 86.5% (HR, 1.52; 95% CI, 0.84 to 2.75; P value for noninferiority = .8577; difference test P = .1628). In ePET-positive patients, the difference in terms of PFS between standard ABVD and intensified BEACOPPesc was no longer statistically significant (HR, 0.67; 95% CI, 0.37 to 1.20; P = .1777). In conclusion, the present long-term analysis confirms that in ePET-negative patients, the omission of INRT is associated with lower 10-year PFS. Instead, in ePET-positive patients, no significant difference between standard and experimental arms emerged although intensification with BEACOPPesc was safe, with no increase in late adverse events, namely, second malignancies.

Long-Term Follow-Up of the Response-Adjusted Therapy for Advanced Hodgkin Lymphoma Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We analyzed long-term results of the response-adapted trial for adult patients with advanced-stage Hodgkin lymphoma. The aim was to confirm noninferiority of treatment de-escalation by omission of bleomycin from doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for interim fluorodeoxyglucose positron emission tomography (iPET)-negative patients and assess efficacy and long-term safety for iPET-positive patients who underwent treatment intensification with escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP/BEACOPP14). The median follow-up is 7.3 years. For all patients, the 7-year progression-free survival (PFS) and overall survival (OS) are 78.2% (95% CI, 75.6 to 80.5) and 91.6% (95% CI, 89.7 to 93.2), respectively. The 1.3% difference in 3-year PFS (95% CI, -3.0 to 4.7) between ABVD and doxorubicin, vinblastine, and dacarbazine (AVD) now falls within the predefined noninferiority margin. Among 172 patients with positive iPET, the 7-year PFS was 65.9% (95% CI, 58.1 to 72.6) and the 7-year OS was 83.2% (95% CI, 76.2 to 88.3). The cumulative incidence of second malignancies at 7 years was 5.5% (95% CI, 4.0 to 7.5) for those receiving ABVD/AVD and 2.5% (95% CI, 0.8 to 7.7) for those escalated to BEACOPP. With extended follow-up, these results confirm noninferiority of treatment de-escalation after a negative iPET. Escalation with BEACOPP for iPET-positive patients is effective and safe, with no increase in second malignancies.