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Anti-CD38 monoclonal antibodies have consistently shown increased efficacy when added to standard of care for patients with multiple myeloma. We aimed to assess the efficacy of isatuximab in addition to lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed transplantation-eligible multiple myeloma.This open-label, multicentre, randomised, active-controlled, phase 3 trial was done at 67 academic and oncology practice centres in Germany. This study is ongoing and divided into two parts; herein, we report results from part 1. Eligible patients were aged 18-70 years; had a confirmed diagnosis of untreated multiple myeloma requiring systemic treatment and a WHO performance status of 0-2; and were eligible for induction therapy, high-dose melphalan and autologous haematopoietic stem-cell transplantation, and maintenance treatment. Patients were randomly assigned (1:1) to receive three 42-day cycles of induction therapy either with isatuximab plus lenalidomide, bortezomib, and dexamethasone (isatuximab group) or lenalidomide, bortezomib, and dexamethasone alone (control group) using a web-based system and permuted blocks. Patients in both groups received lenalidomide (25 mg orally on days 1-14 and 22-35), bortezomib (1·3 mg/mBetween Oct 23, 2018, and Sep 22, 2020, 660 patients were included in the ITT analysis (331 in the isatuximab group and 329 in the control group). 654 (99%) patients were White, two were African, one was Arabic, and three were Asian. 250 (38%) were women and 410 (62%) were men. The median age was 59 years (IQR 54-64). MRD negativity after induction therapy was reached in 166 (50%) patients in the isatuximab group versus 117 (36%) in the control group (OR 1·82 [95% CI 1·33-2·48]; p=0·00017). Median follow-up time from start to end of induction therapy was 125 days (IQR 125-131) versus 125 days (125-132). At least one grade 3 or 4 adverse event occurred in 208 (63%) of 330 patients versus 199 (61%) of 328 patients. Neutropenia of grade 3 or 4 occurred in 77 (23%) versus 23 (7%) patients and infections of grade 3 or 4 occurred in 40 (12%) versus 32 (10%) patients. Among 12 deaths during induction therapy, one death due to septic shock in the isatuximab group and four deaths (one cardiac decompensation, one hepatic and renal failure, one cardiac arrest, and one drug-induced enteritis) in the control group were considered treatment-related.Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone for induction therapy improved rates of MRD negativity with no new safety signals in patients with newly diagnosed transplantation-eligible multiple myeloma.Sanofi and Bristol Myers Squibb (Celgene).

Patients after heart transplantation are at increased risk for malignancy secondary to immunosuppression and oncogenic viral infections. Most common among children is posttransplant lymphoproliferative disorder (PTLD), occurring in 5% to 10% of patients. We used a national database to examine the incidence and risk factors for posttransplant malignancy.The United Network for Organ Sharing database was queried for pediatric (18 years) heart transplant recipients from October 1987 through November 2019. Freedom from malignancy after transplant was assessed with Kaplan-Meier analysis. Cox regression was performed to generate hazard ratios (HRs) and 95% CIs for risk of malignancy development.Of 8581 pediatric heart transplant recipients, malignancy developed in 8.1% over median follow-up time of 6.3 years, with PTLD compromising 86.4% of the diagnosed cancers. The incidence of PTLD development was 1.3% at 1 year and 4.5% at 5 years. Older age at the time of transplant was protective against the development of malignancy (HR, 0.98; 95% CI, 0.96-0.99; P.001), whereas a history of previous malignancy (HR, 1.9; 95% CI, 1.2-3.0; P = .007) and Ebstein-Barr virus (EBV) recipient-donor mismatch (HR, 1.7; 95% CI, 1.3-2.2; P.001) increased the risk. Induction therapy, used in 78.9% of the cohort, did not increase malignancy risk (P = .355) nor did use of maintenance tacrolimus (P = .912).PTLD occurred after 7% of pediatric heart transplants, with risk increased by younger age and EBV mismatch, highlighting the importance of PTLD monitoring in EBV-seronegative recipients. Induction therapy, used in most of the pediatric heart transplants, does not seem to increase posttransplant malignancy nor does tacrolimus, the most commonly used calcineurin inhibitor.

Introduction Lysyl oxidase-like 4 is an amine oxidase from the lysyl oxidase family that was previously shown to be overexpressed in head and neck cancer and upregulated in response to hypoxia. The possible role of lysyl oxidase-like 4 as a tumor marker in advanced stage larynx cancer was investigated. Objective To investigate the expression of lysyl Oxidase-Like 4 protein in advanced stage laryngeal cancer and elucidate its possible role as a tumor marker, predictor of treatment response and prognosticator. Methods Diagnostic specimens of 72 patients treated for stage III–IV laryngeal squamous cell carcinoma were evaluated for lysyl oxidase-like 4 expression by immunohistochemistry. Results Lysyl oxidase-like 4 expression was correlated with advanced tumor stage (p = 0.041) and better differentiation (p = 0.025) but was independent of tumor diameter (p = 0.456). Response to induction chemotherapy or the need for salvage laryngectomy were not affected by lysyl oxidase-like 4 expression (p = 0.999, p = 0.070 respectively). Increased lysyl oxidase-like 4 expression was associated with better 2 year overall survival in both univariate (p = 0.036) and multivariate analyses (p = 0.014). Conclusion Lysyl oxidase-like 4 expression emerges with advancing stages, is lost with worsening differentiation, and may have tumor suppressive properties in larynx cancer.

Acute myeloid leukemia (AML) is the most common type of leukemia in adults. There are no previous studies evaluating AML treatment patterns in Puerto Rico. We describe the first-line therapy patterns and survival of patients diagnosed with AML in Puerto Rico using the Puerto Rico Central Cancer Registry Health Insurance Linkage Database (2011-2015).We describe patient characteristics according to intensive, non-intensive, and non-treatment status. We used Cox proportional hazard models to evaluate the factors associated with the risk of death stratified by intensive and non-intensive therapy. For this study, 385 patients with AML were included.The mean age was 67 years old and 50.1% were female. Nearly half of AML patients (46.8%) received intensive treatment, 23.6% received non-intensive treatment, and 26.2% did not receive treatment. The overall 3-year survival rate was 17.9%. Among those who received intensive therapy, the risk of death among females was lower than males (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.44-0.93). Patients 60 years or older who received intensive treatment had a higher risk of death than younger patients (HR: 1.67, 95% CI: 1.09-2.55). Patients with poor/adverse risk receiving intensive (HR: 3.43, 95% CI: 1.76-6.69) or non-intensive (HR: 4.32, 95% CI: 1.66-11.28) treatment had a higher risk of death than patients with a favorable risk category.Our findings are the first step to monitor the quality of care of patients with AML in Puerto Rico, particularly related to the administration of appropriate induction therapies, which is one of the most important predictors of AML survival.

INDUCTION: chemotherapy (IC) followed by chemoradiation (CRT) is an attractive approach in high-risk locally advanced rectal cancer. Additionally, ASA has shown potential to improve outcomes alongside CRT in rectal cancer. The ICAR trial aimed to evaluate the safety and efficacy of IC followed by CRT with or without ASA on MRI tumor response.Single-center, double-blind, randomized phase II trial to evaluate induction treatment with CAPOX, followed by capecitabine-based chemoradiotherapy with ASA (arm 1) or placebo (arm 2) in high-risk stage II-III rectal adenocarcinoma staged by MRI. The primary endpoint was MRI tumor regression grade (mrTRG). Secondary endpoints were pathological response, surgical outcomes, postoperative complications, treatment tolerance, DFS, and OS.Between January 2018 and August 2019, 27 patients were eligible, 25 (92.5%) completed IC, and 23 patients were randomly assigned (12 to ASA group; 11 to placebo group). In the ASA arm, 3 pts (25%) presented distant disease progression at restaging. Seven patients (30.4%) had cCR after neoadjuvant treatment. All 13 patients submitted to surgery after neoadjuvant treatment underwent R0 resections except for 1 patient with positive CRM, and 12 patients (92.3%) had sphincter preservation. After a median follow-up of 34.9 months, the 2-year DFS was 83.1% and 3-year OS was 81.5%.There was good compliance in both treatment arms and encouraging cCR rate. ASA during CRT was safe but failed to improve on MRI tumor response. The study was closed due to the absence of benefits.

In this study, we investigated various pubertal presentations and progressions before and after estrogen induction therapy and the correlations with Turner syndrome karyotypes.We reviewed the medical records of patients with Turner syndrome diagnosed before the age of 18 years between 2000 and 2019. Sixty-six patients were enrolled and distributed into 45,X monosomy group, X chromosome structural abnormalities group and X mosaicism group. The pubertal presentations were classified into spontaneous puberty, arrested puberty and no spontaneous puberty. All patients' karyotypes, pubertal progressions and laboratory data were collected and analyzed.The karyotypes were highly correlated with pubertal presentations. No spontaneous puberty was noticed in 58.3% 45,X monosomy patients, 50% patients with X chromosome structural abnormalities had arrested puberty, whereas 70% patients with X mosaicism had spontaneous puberty. Estrogen induction therapy in patients with no spontaneous puberty could induce puberty and the tempo of puberty may approximate to the spontaneous puberty group (median, 2.3 vs. 2.2 years, P = 0.95). In both interventional groups, the FSH level was distinguishable before treatment (median, 65.1 vs. 100.4 mIU/mL, P = 0.02). After long term estrogen therapy, the FSH could be suppressed to similar level in both interventional groups (median, 37.5 vs 34.5 mIU/mL, P = 0.84). Neither LH nor E2 level provided valuable information before and after treatment.The karyotypes were highly correlated with pubertal presentations at Turner syndrome patients. The integrity of 2nd X chromosome plays an important role. Low dose estrogen could mimic the tempo of puberty even delay induction age at Taiwan. The FSH data could provide predictive information of pubertal induction for both interventional groups.

Purpose We report our experience of 86 consecutive patients with locally advanced nasopharyngeal carcinoma who were treated with volumetric modulated arc therapy. Materials and methods We retrospectively reviewed the medical records of 86 patients with histologically proven primary nasopharyngeal carcinoma treated with volumetric modulated arctherapy technique radiotherapy. Primary endpoints were local, regional, distant control, and overall survival, second endpoint was late toxicity. Results The median age was 47.5 years (range: 13–79 years) with sex ratio 1.09. At diagnosis, rhinologic symptoms represented the most common clinical presentation, reported by 61 patients (70.9%). Almost 88.4% of patients presented non-keratinizing undifferentiated carcinoma histology (n = 76). Most of the patients presented a locally advanced disease defined by stage III and IVa (95.3%). Therefore, 31 patients were treated by concurrent chemoradiation (36%), 52 patients received induction chemotherapy followed by concurrent chemoradiotherapy (57%), three patients received induction chemotherapy followed by exclusive radiotherapy (3.5%). and three patients treated with exclusive irradiation (3.5%). With a median follow up of 15.7 months (range: 4–33.3 months), nine patients died (10.4%), three presented local or locoregional relapse (3.4%), while nine patients presented distant recurrences (10.4%). The two years overall and disease-free survival rates were 88.7% and 83.1% respectively, locoregional control was 100% at 12 months and 96.2% at 24 months, and the two years distant failure-free survival was 86.7%. Time to relapse was the only prognostic factor in univariate analysis for overall survival in our study. The therapeutic tolerance was good with 61.7% of grade 3 and 2.3% grade 4 hyposialia respectively, 46.5% of otological disorders and no radionecrosis was noted. Conclusion Volumetric modulated arctherapy technique with concurrent chemoradiotherapy is an effective treatment for nasopharyngeal carcinoma with excellent overall and locoregional control without severe toxicity. Distant metastasis is the major site of failure, so induction chemotherapy added to chemoradiotherapy must be discussed in multidisciplinary consultation meeting because it significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone.

Venetoclax combined with intensive chemotherapy has been shown to be safe with promising activity in fit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to compare the activity of venetoclax plus intensive chemotherapy with intensive chemotherapy alone.This was a post-hoc propensity score matched analysis of prospective clinical trials (NCT03214562, NCT02115295, and NCT01289457) in patients at The University of Texas MD Anderson Cancer Center, Texas, USA between March 29, 2010, and June 15, 2021. Eligible patients were aged 18 years and older, and had newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, and were treated within trials incorporating purine analogues with an anthracycline and cytarabine either with venetoclax plus intensive chemotherapy or with intensive chemotherapy alone. Patients in the venetoclax plus intensive chemotherapy cohort were matched with patients in the intensive chemotherapy cohort. Morphological response and measurable residual disease (MRD) was assessed using bone marrow aspiration and biopsy and eight-colour multiparameter flow cytometry. The primary objectives were rate of MRD negative composite complete response and cumulative incidence of transition to allogeneic haematopoietic stem-cell transplantation (HSCT). All patients who had response within two treatment cycles (induction and re-induction) were included in the analyses. Secondary objectives included assessment of event-free and overall survival.The propensity matched cohort included 279 patients (median age 49 years [IQR 39-57]; 131 [47%] were men and 148 [53%] were women); 85 in the venetoclax plus intensive chemotherapy cohort and 194 in the intensive chemotherapy cohort. After a median follow up of 30 months (95% CI 26-36), 64 (86%) of 74 patients in the venetoclax plus intensive chemotherapy cohort had an MRD-negative composite complete response rate compared with 86 [61%] of 140 patients in the intensive chemotherapy cohort (odd ratio 3·2 [95% CI 1·5-6·7]; p=0·0028). The overall cumulative incidence of allogeneic HSCT in responding patients was higher with venetoclax plus intensive chemotherapy than intensive chemotherapy (79% [95% CI 67-88] vs 57% [49-65]; hazard ratio [HR] 1·52 [95% CI 1·11-2·08]; p=0·012). Venetoclax plus intensive chemotherapy improved event-free survival (median not reached [NR; 95% CI NR-NR] vs 14·3 months [10·7-33·5]; HR 0·57 [95% CI 0·34-0·95]; p=0·030), but overall survival did not significantly differ between the two cohorts (median NR [95% CI 24-NR] vs 32 months [19-NR]; HR 0·63 [95% CI 0·35-1·1], p=0·13).Venetoclax combined with intensive induction chemotherapy induced deep MRD-negative remissions, allowing transition to allogeneic HSCT in first remission, and improvement in event-free survival. These results highlight the incremental benefit of venetoclax added to intensive induction chemotherapy across European LeukemiaNet risk groups, and serve as a benchmark to inform enrolment on future confirmatory prospective clinical trials.None.

BACKGROUND: Treatment for adults with acute lymphoblastic leukaemia requires improvement. UKALL14 was a UK National Cancer Research Institute Adult ALL group study that aimed to determine the benefit of adding the anti-CD20 monoclonal antibody, rituximab, to the therapy of adults with de novo B-precursor acute lymphoblastic leukaemia.METHODS: This was an investigator-initiated, phase 3, randomised controlled trial done in all UK National Health Service Centres treating patients with acute lymphoblastic leukaemia (65 centres). Patients were aged 25-65 years with de-novo BCR-ABL1-negative acute lymphoblastic leukaemia. Patients with de-novo BCR-ABL1-positive acute lymphoblastic leukaemia were eligible if they were aged 19-65 years. Participants were randomly assigned (1:1) to standard-of-care induction therapy or standard-of-care induction therapy plus four doses of intravenous rituximab (375 mg/m2 on days 3, 10, 17, and 24). Randomisation used minimisation and was stratified by sex, age, and white blood cell count. No masking was used for patients, clinicians, or staff (including the trial statistician), although the central laboratory analysing minimal residual disease and CD20 was masked to treatment allocation. The primary endpoint was event-free survival in the intention-to-treat population. Safety was assessed in all participants who started trial treatment. This study is registered with ClincialTrials.gov, NCT01085617.FINDINGS: Between April 19, 2012, and July 10, 2017, 586 patients were randomly assigned to standard of care (n=292) or standard of care plus rituximab (n=294). Nine patients were excluded from the final analysis due to misdiagnosis (standard of care n=4, standard of care plus rituximab n=5). In the standard-of-care group, median age was 45 years (IQR 22-65), 159 (55%) of 292 participants were male, 128 (44%) were female, one (INTERPRETATION: Standard of care plus four doses of rituximab did not significantly improve event-free survival over standard of care. Rituximab is beneficial in acute lymphoblastic leukaemia but four doses during induction is likely to be insufficient.

Epigenetic dysregulation leads to aberrant DNA hypermethylation and is common in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). A large number of clinical trials in AML, MDS, and other hematologic malignancies have assessed hypomethylating agents (HMAs), used alone or in combination with other drugs, in the frontline, maintenance, relapsed/refractory, and peritransplant settings. Effective maintenance therapy has long been a goal for patients with AML in remission. Previous large, randomized clinical trials of maintenance with HMAs or other agents had not shown meaningful improvement in overall survival. Oral azacitidine (Oral-AZA [CC-486]) is approved in the United States, Canada, and European Union for treatment of adult patients with AML in first complete remission (CR) or CR with incomplete blood count recovery (CRi) following intensive induction chemotherapy who are ineligible for hematopoietic cell transplant. Regulatory approvals of Oral-AZA were based on outcomes from the randomized, phase III QUAZAR AML-001 trial, which showed a median overall survival advantage of 9.9 months with Oral-AZA versus placebo. Oral-AZA allows convenient extended AZA dosing for 14 days per 28-day treatment cycle, which is not feasible with injectable AZA. Focusing on AML and MDS, this report reviews the rationale for the use of orally bioavailable AZA and its potential use in all-oral combination therapy regimens; the unique pharmacokinetic and pharmacodynamic profile of Oral-AZA compared with injectable AZA; the clinical safety and efficacy of Oral-AZA maintenance therapy in patients with AML in first remission and for treatment of patients with active MDS; and ongoing Oral-AZA clinical trials.

Induction immunosuppressive therapy is used to prevent rejection and maintain allograft function in transplantation. Rabbit antithymocyte globulin (rATG), a T-cell depleting antibody, is the most commonly used induction agent for kidney transplantation. To date there is still limited data on outcomes of pediatric kidney transplants with rATG as induction therapy.Retrospective single-center study of first-time kidney transplant recipients ≤18 years old who received rATG induction between 2005 and 2019 at the National Kidney and Transplant Institute. Data were collected up to 1 year post transplant.Eleven patients were included in the study. They received rATG at 1.5 mg/kg/dose (±0.3 mg/kg/dose) once a day for 3 days. Patient survival was 100% at 6 months, and 90.9% at 1 year. Graft survival was 90.9% at 6 months, and 81.8% at 1 year. Four patients (36.4%) had a glomerular filtration rate of60 at 1 year. One died of sepsis at 7 months. One patient (9.1%) had acute allograft rejection with recurrence of disease, C3 glomerulopathy, on day 13. A total of 3 patients (27.3%) developed leukopenia and 4 patients (36.4%) developed thrombocytopenia. The majority were anemic at baseline (9.7 mg/dL), and a significant increase in the mean hemoglobin was seen at 4 weeks (11.6 mg/dL) to 1 year (13 mg/dL). Incidence of recurrent infections was 9.1% (with culture growth) and 36.4% (no culture growth). Hypertension remained unchanged before and after transplant.Induction with single dose rATG at 1.5 mg/kg/dose (±0.3 mg/kg/dose) for 3 days provided effective and safe outcomes in pediatric kidney transplant patients in this study.

Metastasis is the primary cause of treatment failure in nasopharyngeal carcinoma (NPC); however, the current tumour-node-metastasis staging system has limitations in predicting distant metastasis and guiding induction chemotherapy (IC) application. Here, we established a transcriptomics-based gene signature to assess the risk of distant metastasis and guide IC in locoregionally advanced NPC.Transcriptome sequencing was performed on NPC biopsy samples from 12 pairs of patients with different metastasis risks. Bioinformatics and qPCR were used to identify differentially expressed genes (DEGs), while univariate and multivariate analyses were used to select prognostic indicators for the gene signature. A signature-based nomogram was established in a training cohort (n = 191) and validated in an external cohort (n = 263).Eleven DEGs were identified between metastatic and non-metastatic NPC. Four of these (AK4, CPAMD8, DDAH1 and CRTR1) were used to create a gene signature that effectively categorised patients into low- and high-risk metastasis groups (training: 91.1 versus 70.4%, p 0.0001, C-index = 0.752; validation: 88.4 versus 73.9%, p = 0.00057, C-index = 0.741). IC with concurrent chemoradiotherapy (CCRT) improved distant metastasis-free survival in low-risk patients (94.4 versus 85.0%, p = 0.043), whereas patients in the high-risk group did not benefit from IC (72.6 versus 74.9%, p = 0.946).Our transcriptomics-based gene signature was able to reliably predict metastasis in locoregionally advanced NPC and could be used to identify candidates that could benefit from IC + CCRT.

This article reviews the various treatment options, by primary or postoperative external radiotherapy and by brachytherapy for the p16-negative oropharyngeal squamous cell carcinoma. Dose levels, fractionation and association with systemic treatments are presented. The need for neck node dissection post local treatment is discussed, as well as specificities for the management of p16-positive tumours. Guidelines for target volume selection and delineation are thoroughly elaborated. Last, the management by radiotherapy of locoregional recurrences is discussed.

Background: Mirikizumab is a humanized monoclonal antibody targeting interleukin 23p19 with demonstrated efficacy in psoriasis and ulcerative colitis. We investigated the safety and efficacy of mirikizumab in patients with moderate-to-severe Crohn's disease (CD). Methods: Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12. Results: At Week 12, endoscopic response was significantly higher by the predefined 2-sided significance level of 0.1 for all mirikizumab groups compared with PBO (200 mg: 25.8%, 8/31, 95% confidence interval [CI], 10.4–41.2, P = .079; 600 mg: 37.5%, 12/32, 95% CI, 20.7–54.3, P = .003; 1000 mg: 43.8%, 28/64, 95% CI, 31.6–55.9, P < .001; PBO: 10.9 %, 7/64, 95% CI, 3.3–18.6). Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C and SC groups, respectively. Frequencies of adverse events (AE) in the mirikizumab groups were similar to PBO. Through Week 52, frequencies of treatment-emergent AEs were similar across all groups. Frequencies of serious AE and discontinuations due to AE were higher in the nonrandomized maintenance cohort. Conclusion: Mirikizumab effectively induced endoscopic response after 12 weeks in patients with moderate-to-severe CD and demonstrated durable efficacy to Week 52. A detailed summary can be found in the Video Abstract. ClinicalTrials.gov, Number: NCT02891226

Benefit from maintenance in advanced non-squamous non-small cell lung cancer (NS-NSCLC) might favor switch maintenance after disease stabilization (SD) and continuation after objective response (OR). This trial assessed a maintenance strategy conditioned by response to cisplatin-gemcitabine (CG) with G continuation for patients with OR or switch to pemetrexed (P) for patients with SD as compared with a control arm based on the Paramount regimen.Eligibility criteria: age 18-70 years, ECOG PS 0-1, untreated stage IV NS-NSCLC without EGFR or ALK alteration, ineligibility to bevacizumab. Patients were randomized 1:1 to receive either CG (4 cycles) followed by G maintenance in case of OR followed by P at progression, or switch to P for patients with SD, or 4 cycles of CP followed by P (control arm). Primary endpoint: overall Survival.Between 2012 and 2016, 932 patients were randomized (CG: 467, CP: 465) with well-balanced characteristics. 257 patients (56.7%) in the CG arm received maintenance (G: 142, P: 113) versus 277 patients (59.7%) in the CP arm. Median number of maintenance cycles was 5 for G and P (CG induction) and 4 for P (CP induction). OS adjusted HR was 0.97 (95% CI 0.84, 1.13; p = 0.71) with a median of 10.9 months (CG) versus 10.4 (CP). HR for PFS was 0.95 (95% CI 0.83, 1.09; p = 0.45) with a median of 4.8 months for CG versus 4.5 for CP. Safety profile was as expected.Adapting maintenance strategy according to response to induction chemotherapy does not improve patient outcome.NCT01631136.

We present the update of the recommendations of the French society of oncological radiotherapy on radiotherapy of pancreatic tumors. Currently, the use of radiation therapy for patients with pancreatic cancer is subject to discussion. In the adjuvant setting, the standard treatment is six months of chemotherapy with 5-fluorouracile, irinotecan and oxaliplatin. Chemoradiation may improve the survival of patients with incompletely resected tumours (R1). This remains to be confirmed by a prospective trial. Neoadjuvant chemoradiation is a promising treatment especially for patients with borderline resectable tumours. For patients with locally advanced tumours, there is no standard. An induction chemotherapy followed by chemoradiation for non progressive patients reduces the rate of local relapse. Whereas in the first trials of chemoradiation large fields were used, the treated volumes have been reduced to improve tolerance. Tumour movements induced by breathing should be taken in account. Intensity modulated radiation therapy allows a reduction of doses to the organs at risk. Whereas widely used, this technique has poor evidence-based recommendation. Stereotactic body radiation therapy is also being studied, as a neoadjuvant or exclusive treatment.

Background Several observational studies on Tofacitinib (TOFA) in ulcerative colitis (UC) have been published over the last 2 years. Aims To estimate effectiveness and safety of TOFA arising from real-world experience. Methods PubMed Central/Medline and Embase were systematically searched for real-world observational studies on TOFA for the treatment of UC through November 2020. Results Seven studies comprising 759 patients met the inclusion criteria. The pooled estimate rates were 49% for clinical response, 40% for clinical remission, and 34% for corticosteroid-free clinical remission at induction, while the rates of endoscopic response and endoscopic remission were 37% and 19%, respectively. At maintenance, the pooled estimate rates of clinical response, clinical remission, and corticosteroid-free clinical remission were 36%, 35%, and 24%, respectively. The pooled estimate of incidence rate of adverse events was 53.0 per 100 person-years (PY), while the pooled estimate of incidence rate of withdrawal of TOFA due to adverse events was 9.3 per 100 PY, with a pooled rate of infections of 17.6 per 100 PY. Conclusions Cumulative analysis of data from real-world studies confirmed the good efficacy of TOFA in UC shown by randomized controlled trials for both induction and maintenance, while the safety profile was consistent with previous reports.

ObjectiveIn the Phase 3 VELIA trial (NCT02470585), veliparib added to carboplatin plus paclitaxel concomitantly and as maintenance for women with newly-diagnosed advanced ovarian cancer significantly improved progression-free survival (PFS) versus chemotherapy alone. Here we present exploratory analyses by paclitaxel dosing schedule and germline BRCA (gBRCA) status.MethodsWomen with untreated ovarian carcinoma were randomized (1:1:1) to: veliparib during chemotherapy and maintenance (veliparib-throughout), veliparib during chemotherapy followed by placebo maintenance (veliparib-combination only), or placebo during chemotherapy and maintenance (control). Chemotherapy included carboplatin plus dose-dense (DD; weekly) or every-3-week (Q3W) paclitaxel (a stratification factor at randomization), selected at the investigator's discretion pre-randomization. PFS was assessed by paclitaxel dosing schedule using a Cox proportional hazard model adjusted by treatment arm and stratification factors; safety was analyzed based on paclitaxel dosing schedule and gBRCA status.Results1132 patients were analyzed by paclitaxel schedule. Pooled treatment arms demonstrated longer median PFS with DD (n=586) versus Q3W (n=546) paclitaxel (ITT: 20.5 vs 15.7months, hazard ratio [HR] 0.77; homologous recombination proficient cancer: 15.1 vs 11.8months, HR 0.64; BRCAwt: 18.0 vs 12.9months, HR 0.70). Comparison between arms favored veliparib-throughout versus control in both DD (PFS, 24.2 vs 18.3months, hazard ratio 0.67) and Q3W (19.3 vs 14.6, hazard ratio 0.69) subgroups. DD paclitaxel was associated with higher incidence of Grade 3/4 neutropenia, fatigue, and anemia versus Q3W. There were no differences in toxicity between gBRCAm (n=211) and gBRCAwt (n=902) subgroups.ConclusionsDD paclitaxel was tolerable and associated with longer PFS in the HR proficient and gBRCAwt groups, versus Q3W. gBRCA status did not impact safety.

The most widely practiced (standard) treatment of non-metastatic rectal cancer is based on proctectomy with mesorectal excision (partial or total according to the location of the tumor and commonly called TME). Surgery is preceded by CAP50-type chemoradiotherapy (capecitabineand 50 Grays radiation) and performed 6-8 weeks after the end of chemoradiotherapy. The development of new endoscopic, surgical, radiation-based and chemotherapeutic modalities leads surgeons to envisage customized treatment to find the best compromise between functional and oncologic results according to the locoregional extension of the tumor. Superficial lesions are amenable to transanal excision. T2-3 tumors4cm are amenable to rectal preservation when neoadjuvant treatment obtains a complete response, allowing local excision or close surveillance. Intensification endocavitary radiotherapy and induction and consolidation chemotherapy regimens to avoid recourse to salvage abdomino-perineal resection (APR) are under investigation. For locally advanced rectal cancers (T3-4 and all N+ irrespective of T), the following scenarios can be envisaged: for initially resectable tumors (T3N0, T1-T3N+, circumferential resection margin2mm), neoadjuvant chemotherapy alone aims to minimize the risk of local recurrence while avoiding the sequelae of radiotherapy. In case of initially non-resectable tumors (T4, circumferential resection margin1mm), induction chemotherapy before chemoradiotherapy and consolidation chemotherapy after short course radiotherapy provide better results than standard treatment in terms of complete response and recurrence-free survival, and should be routinely proposed in this indication.

International audience; PurposeThe purpose of this study was to assess the efficacy in terms of neck failure of an initial neck dissection before definitive chemoradiotherapy in N2-3 oropharyngeal squamous cell carcinomas, as well as the dosimetric impact and the acute and delayed morbidity of this approach.Materials and methodsAll patients consecutively treated between 2009 and 2018 with definitive chemoradiotherapy using intensity-modulated conformal radiotherapy (IMRT) for a histologically proven N2-3 oropharyngeal squamous cell carcinomas were retrospectively included. The therapeutic approach consisted of induction chemotherapy, followed by cisplatine-based chemoradiotherapy preceded or not by neck dissection. Neck dissection was discussed on a case-by-case basis in a dedicated multidisciplinary tumour board for patients with a dissociated response to induction chemotherapy, defined as a better response on the primary than on the node. Chemoradiotherapy without neck dissection was systematically performed in case of a major lymph node response to induction chemotherapy (decrease in size of 90% or more). Intensity-modulated radiotherapy using a simultaneous-integrated boost delivered 70 Gy in 35 fractions on macroscopic tumour volumes, 63 Gy on intermediate-risk levels or extra-nodal extension and 54 Gy on prophylactic lymph node areas.ResultsTwo groups were constituted: 47 patients without an initial neck dissection (62.7%), and 28 patients with a neck dissection prior to definitive chemoradiotherapy (37.3%). Initial patient characteristics were not statistically different between the two groups. The median follow-up was 60.1 months (range: 3.2–119 months). Incidence of neck failure was higher in patients without neck dissection (P = 0.015). The neck failure rate at 5 years was 19.8% (95% confidence interval: 7.4–30.6%; P = 0.015) without neck dissection versus 0% following neck dissection. All lymph node failures occurred in the planned target volume at 70 Gy. Upfront neck dissection suggested a decrease in the mean dose received by the homolateral parotid gland (P = 0.01), mandible (P = 0.02), and thyroid gland (P = 0.02). Acute toxicity of chemoradiotherapy after neck dissection suggested a reduction in grade ≥ 3 adverse events (P = 0.04), early discontinuation of concomitant chemotherapy (P = 0.009) and feeding tube-dependence (P = 0.008) in univariate analysis. During follow-up, there was no difference between the two groups in terms of xerostomia, dysgeusia, dysphagia or gastrostomy dependence in univariate analysis.ConclusionNeck dissection prior to definitive chemoradiotherapy in N2-3 oropharyngeal squamous cell carcinoma was associated with high neck control without additional mid and long-term morbidity.; Objectif de l’étudeIl s’agissait d’évaluer l’efficacité en termes d’échec ganglionnaire du curage ganglionnaire cervical initial dans les carcinomes épidermoïdes de l’oropharynx de stade N2-3 pris en charge par chimioradiothérapie exclusive, ainsi que l’impact dosimétrique et la tolérance aiguë et tardive de cette approche.Matériels et méthodesTous les patients consécutivement pris en charge entre 2009 et 2018 par chimioradiothérapie exclusive à l’aide d’une radiothérapie conformationelle avec modulation d’intensité (RCMI) pour un carcinome épidermoïde de l’oropharynx de stade N2-3 selon la septième édition de la classification TNM American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) ont été rétrospectivement inclus. La stratégie thérapeutique consistait en une chimiothérapie d’induction, suivie d’une chimioradiothérapie exclusive à base de cisplatine précédée ou non d’un curage ganglionnaire cervical. Le curage ganglionnaire cervical a été discuté au cas par cas en réunion de concertation multidisciplinaire dédiée chez les patients en situation de réponse dissociée à la chimiothérapie d’induction, à savoir une réponse de meilleure qualité sur la tumeur primitive que sur les ganglions. Une chimioradiothérapie sans curage ganglionnaire cervical a été systématiquement réalisée en cas de réponse ganglionnaire majeure à la chimiothérapie d’induction (diminution en taille de 90 % ou plus). La RCMI délivrait en boost intégré une dose de 70 Gy en 35 fractions dans les volumes tumoraux macroscopiques, 63 Gy dans les aires ganglionnaires à risque intermédiaire ou en rupture capsulaire et 54 Gy dans celles irradiées à visée prophylactique.RésultatsDeux groupes ont été constitués : 47 (62,7 %) patients sans curage ganglionnaire cervical initial, et 28 (37,3 %) patients avec un curage ganglionnaire cervical avant la chimioradiothérapie. Les caractéristiques initiales des patients n’étaient pas statistiquement différentes entre les deux groupes. Le recul médian était de 60,1 [3,2–119] mois. L’incidence des échecs ganglionnaires était plus élevée chez les patients n’ayant pas eu de curage ganglionnaire cervical (p = 0,015). Le taux d’échec ganglionnaire à 5 ans était de 19,8 % (intervalle de confiance à 95 % : 7,4–30,6) en l’absence de curage ganglionnaire cervical contre aucune rechute (0 %) après curage ganglionnaire cervical. Tous les échecs ganglionnaires se trouvaient dans le volume cible prévisionnel à 70 Gy. Le curage ganglionnaire cervical a permis une diminution de la dose moyenne reçue par la parotide homolatérale (p = 0,01), la mandibule (p = 0,02) et la thyroïde (p = 0,02). La tolérance aiguë de la chimioradiothérapie avait tendance à être meilleure chez les patients ayant eu un curage ganglionnaire avec une réduction des événements indésirables de grade ≥ 3 (p = 0,04), de l’arrêt précoce de la chimiothérapie concomitante (p = 0,009) et du recours à une gastrostomie (p = 0,008) en analyse unifactorielle. Au cours du suivi, il n’existait aucune différence entre les deux groupes en termes de xérostomie, de dysgueusie, de dysphagie ou de dépendance à la gastrostomie en analyse unifactorielle.ConclusionLe curage ganglionnaire cervical avant la chimioradiothérapie exclusive dans les carcinomes épidermoïdes de l’oropharynx de stade N2-3 était associé à un très bon taux de contrôle ganglionnaire sans morbidité supplémentaire à moyen et long termes.

The standard treatment of locally advanced rectal cancer comprises neoadjuvant chemoradiation followed by total mesorectal excision. This strategy provides low local recurrence rate, however distant recurrence is still an issue and may impact on survival rates. Novel approaches in the neoadjuvant setting have been tested to improve early and late outcomes, as well as to reduce treatment-related toxicity and morbidity. In this review, we discuss the current literature of neoadjuvant treatment in locally advanced rectal cancer, including total neoadjuvant methods, protocols for radiation delivery, chemotherapy regimen and efforts to add novel targeted therapies, selective withdrawal of surgery or radiotherapy, and future perspectives. Moreover, we highlight relevant issues that have emerged with these new treatment possibilities.

Despite therapeutic advances and improvement in outcomes of patients with acute lymphoblastic leukemia, as reported by specialized centers, healthcare disparities exist. This is a retrospective cohort analysis of the clinical outcomes of 146 patients with newly diagnosed acute lymphoblastic leukemia treated in the safety-net hospital system of the third most populous county in the US. Addressing social factors which may limit access to health care, adopting effective and less costly therapies and improving patient diversification in clinical trials may all improve the outcomes of underserved patient populations. BACKGROUND: Major advances in the treatment of acute lymphoblastic leukemia (ALL) over the past decade have resulted in 5-year overall survival (OS) rates of 80% in mature B cell ALL, 50% in precursor B cell ALL, 50%–60% in T cell ALL, and 60%–70% in Philadelphia chromosome–positive (Ph+) ALL, as reported in studies from large, specialized centers. However, many patients treated in the community have limited access to novel therapies and stem cell transplantation (HSCT). PATIENTS AND METHODS: The purpose of this retrospective cohort analysis was to evaluate the clinical outcomes of patients ≥ 16 years with newly diagnosed ALL treated from October 2007 to June 2019 in the Harris County Health System, Houston, TX. RESULTS: One hundred forty-six patients were included, with newly diagnosed pre-B-ALL (n=127), T-ALL (n=18), and chronic myeloid leukemia / lymphoid blast crisis (n=1). Median age was 35 years (16–82) at diagnosis, and 81(55%) were male. The majority of patients with pre-B ALL identified as Hispanic (n=118, or 92%). Ninety-eight (67%) of patients were uninsured or indigent, receiving care under the county’s financial assistance programs. Hyper-CVAD-based induction chemotherapy was administered in 134(92%) of patients, while 9 (6%) were treated on different protocols, and 3 (2%) were not treated due to early death, or patient refusal. Imatinib was the most common TKI used in 17/30 or 57% of patients with Ph+ disease. Out of 137 evaluable for response patients, 117 (85%) achieved complete remission (CR+CRi), 19 (14%) had refractory disease, and 1 (1%) died within 4 weeks of diagnosis. Median follow-up time was 50 months (1.5–135). For the entire study cohort, the median duration of CR/CRi was 15.4 months. Out of 62 patients who were eligible for consolidative HSCT at first CR, 52 (89%) did not receive it, with lack of insurance being the most common reason (n=29, or 56%). Barriers to utilization of novel therapies such as blinatumomab or CAR-T were also observed. Patient-caused delays in administration of chemotherapy and treatment interruptions of at least 30 days were seen in 31(23%) patients. At 1, 2, and 5 years, relapse rates were 37%, 56%, and 70%. Recurrent/refractory disease was the cause of death in most patients (n=69 [85%]). Five-year EFS and OS rates were 22% and 38% for patients with pre-B ALL, 24% and 44% for patients with T ALL, and 13% and 27% for patients with Ph+ ALL. Median OS was significantly increased (not reached [NR] vs. 24 months; p=0.00088) in patients with an indication for HSCT in first CR due to high-risk features who underwent HSCT, versus those who did not. CONCLUSION: Addressing barriers raised by socioeconomic disparities, increasing access to effective therapies, and including patients with ALL treated in the community in clinical trials may improve survival for underserved populations.

Purpose Among oral squamous cell carcinoma (OSCC) patients who receive docetaxel, cisplatin, and 5-fluorouracil (TPF) induction chemotherapy, those with a favorable pathological response tend to obtain satisfactory clinical outcomes, while the total population exhibit no survival benefit. Thus, there is an urgent need to improve the therapeutic effect of TPF by applying personalized treatment according to distinct biomarkers. Methods and materials In the present study, we collected oral rinse samples from 44 OSCC patients enrolled in our prospective multicenter random phase II trial before TPF induction chemotherapy to conduct 16S rRNA gene sequencing and metagenomic analysis. Patients were administrated with two cycles of TPF induction chemotherapy (75 mg/m2 cisplatin and 75 mg/m2 docetaxel on day 1 and 750 mg/m2 fluorouracil from the first to the fifth day), and then divided into responsive and nonresponsive groups according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results In the 16S rRNA gene sequence analysis, Fusobacterium and Mycoplasma were more enriched in the nonresponsive group, while Slackia was more enriched in the responder group at the genus level. In the metagenomic shotgun sequencing analysis, Fusobacterium nucleatum was more enriched in the nonresponsive group. Functional analysis showed that the platinum drug resistance pathway and microRNAs in cancer and RNA degradation pathways were remarkably associated with patient sensitivity to induction chemotherapy. Conclusions Our data suggest that the oral microbiome may play an important role in the OSCC patient sensitivity to TPF induction chemotherapy and offer novel potential biomarkers for predicting the response to TPF induction chemotherapy.

Background Patients diagnosed with locoregionally advanced head and neck squamous cell carcinoma (LAHNSCC) regularly undergo staging with 18F-FDG PET/CT in our center. In cases of delays in radiotherapy (RT) planning CT more than 4 weeks after initial PET/CT or clinically suspected progress, PET/CT is repeated for restaging and as an RT planning reference. Our aim was to determine the impact of second-look PET/CT on stage migration, treatment change and RT planning. Methods Consequent treatment changes were categorized as minor and major. Minor changes were defined as PET/CT-based modifications of RT plans, e.g., the addition of anatomical compartments, changes in high- and low-risk dose levels or both. Major changes included changes from curative to palliative treatment intent and alterations of interdisciplinary treatment plans, such as the addition of induction chemotherapy, switch to primary surgery, no treatment and/or the necessity of additional diagnostic work-up resulting in the postponement or cancellation of treatment. Results Thirty-two newly diagnosed LAHNSCC patients who were treated between 2014 and 2018 underwent second-look PET/CT (median interval 42.5 days). Second-look PET/CT led to locoregional and distant upstaging in 3/32 and 1/32 patients, respectively. In 1/32 patients (3%), second-look PET/CT led to a palliative approach with systemic treatment. New lymph node metastases were discovered in 16 patients, 6 of whom also showed significant progression of the primary tumor, resulting in minor changes in 16 of the remaining 31 patients (52%) who were treated curatively. Conclusion If RT treatment planning of LAHNSCC was delayed by more than 4 weeks after initial PET/CT staging or when progression was clinically suspected, a second look at 18FDG-PET/CT was performed. This led to changes in treatment planning in more than half of the cases, which is expected to directly influence oncologic outcomes.

Background Unsatisfactory tumor response to induction chemotherapy (IC) is an adverse prognostic factor of locoregionally advanced nasopharyngeal carcinoma (LANPC). A re-induction strategy which applies additional cycles of an alternative IC regimen prior to radiotherapy (RT) has been adopted. Methods A total of 419 LANPC patients who attained suboptimal response (stable disease or disease progression) according to the Response Evaluation in Solid Tumors (RECIST) guideline after initial IC were retrospectively included. They were divided into those who received additional cycles of re-induction regimen prior to RT (re-induction group, n = 87) and those who had no additional chemotherapy (direct to RT group, n = 332). Propensity score matching (PSM) was used to adjust for potential confounders. Tumor response and long-term survival were compared between two groups. Results After receiving a second IC regimen, 39.1% of the patients in re-induction group attained partial response; however, the tumor control of subsequent RT was not significantly improved when compared with direct to RT group (patients attaining complete response after RT 55.2% vs. 52.5%, P = 0.757). Patients who received re-induction therapy showed worse locoregional relapse-free survival (LRFS) and progression-free survival (PFS) than those proceeded directly to RT (3-year LRFS 75.7% vs. 83.1%, P = 0.005; 3-year PFS 62.4% vs. 68.3%, P = 0.037). The increased hematological toxicities were observed in re-induction group that included grade 3–4 anemia, thrombocytopenia and liver enzyme increase. Conclusion Re-induction therapy decreased LRFS and PFS and increased toxicities among patients who attain suboptimal response to initial IC regimen, as compared with direct to RT strategy.

Background Autoimmune mediated encephalitis (AME), which includes autoantibody-associated encephalitis and acute disseminated encephalomyelitis, is a common cause of encephalitis as well as infectious encephalitis in children. AME may be triggered by autoimmune responses to paraneoplastic syndromes and infections. Infectious encephalitis associated with an immunocompromised status caused by anti-cancer chemotherapy is well recognized; however, there have been few reports on the relationship between AME and chemotherapy. Case report A ten-year-old previously healthy, developmentally normal girl was diagnosed with a pure germinoma in the suprasellar region. Following 30 days of induction chemotherapy, she developed a depressed level of consciousness with accompanying right hemiplegia, aphasia, and unexplained fever. Cerebrospinal fluid (CSF) analysis revealed positive oligoclonal bands and elevated neopterin levels. Neither atypical cells suggesting tumor exacerbation nor pathogens known to cause encephalitis were identified in the CSF. She was administrated immunosuppressive therapy and her symptoms rapidly improved. No known autoantibodies associated with autoantibody-associated encephalitis were identified in blood or CSF. However, the presence of oligoclonal bands and elevated neopterin levels in the CSF, and the favorable response to immunosuppressive therapy were consistent with an AME diagnosis. Thirteen days after the third course of chemotherapy, the patient developed a depressed level of consciousness again. Due to the recurrence of encephalitis, re-administration of immunosuppressive therapy was performed, which led to improvement in her symptoms. Recurrence of encephalitis has not occurred for 1 year after completion of chemotherapy. Conclusion The chemotherapy-induced abnormal immune response might have triggered the AME.

Background Cytomegalovirus (CMV) infection is an important complication after kidney transplantation (KT). Antithymocyte globulin (ATG) increases the risk for CMV infection, and universal prophylaxis is recommended during the first 3 to 6 months after ATG induction in CMV-seropositive recipients. However, following this recommendation is not easy because the cost is high. The aim of this study was to determine who, among high-risk KT recipients, are more vulnerable to CMV infections. Methods We retrospectively analyzed the medical records of patients who underwent KT with ATG induction therapy at a single institute from April 2014 to June 2019. We assessed pretransplant recipient characteristics to determine the CMV infection risk factors. Cell-mediated immunity was evaluated with a lymphocyte subset test before transplantation and at the time of discharge. We included 227 patients in the study. Results CMV-DNAemia was associated with donor type (deceased donor), the duration of renal replacement therapy, and the ATG dose. Multivariable analysis revealed that donor type is the primary risk factor for CMV-DNAemia. We also found that CD4+ cell counts were significantly lower in CMV-DNAemia recipients at the time of discharge. Conclusion The risk for CMV infection in CMV-seropositive KT recipients with ATG induction therapy increases when a graft is received from a deceased donor with renal impairment and when insufficient CD4+ cells are present during recovery.

Introduction: The addition of induction chemotherapy (ICT) to neoadjuvant chemoradiotherapy (CRT) has the potential to improve outcomes in patients with locally advanced rectal cancer (LARC). However, patient selection is essential to prevent overtreatment. This study compared the complete response (CR) rate after treatment with and without ICT of LARC patients with prognostically poor characteristics. Methods: All LARC patients who were treated with neoadjuvant CRT, whether or not preceded by ICT, and who underwent surgery or were considered for a wait-and-see strategy between January 2016 and March 2020 in the Catharina Hospital Eindhoven, were retrospectively selected. LARC was defined as any T4 tumour, or a T2/T3 tumour with extramural venous invasion and/or tumour deposits and/or N2 lymph node status, and/or mesorectal fascia involvement (T3 tumours only). Case-control matching was per -formed based on the aforementioned characteristics. Results: Of 242 patients, 178 (74%) received CRT (CRT-group) and 64 patients (26%) received ICT followed by CRT (ICT-group). In the ICT-group, 3 patients (5%) did not receive the minimum of three cycles. In addition, in this selected cohort, compliance with radiotherapy was 100% in the ICT-group and 97% in the CRT-group. The CR rate was 30% in the ICT-group and 15% in the CRT-group (p = 0.011). After case-control matching, the CR rate was 28% and 9%, respectively (p = 0.013). Conclusion: Treatment including ICT seemed well tolerated and resulted in a high CR rate. Hence, this treatment strategy may facilitate organ preservation and improve survival in LARC patients with prog-nostically poor characteristics. (c) 2021 Elsevier Ltd, BASO -The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

This study aimed to address the prognostic relevance of CD34+/CD38-/TIM3+ leukemic stem cell (LSC) frequency in patients with acute myeloid leukemia (AML) and its impact on patient outcome. We analyzed the expression of LSC markers (CD34+/CD38-/TIM3+) using flow cytometry in bone marrow samples of 53 AML cases before and after induction chemotherapy. The LSC frequency at diagnosis was significantly higher compared with that postinduction (P < .001). Patients were categorized into high LSC expressers (≥ median) and low expressers (< median). Patients with AML with high number of LSCs at diagnosis had significantly lower induction of remission response (P = .0104), shorter disease-free survival, and shorter overall survival (P < .001 for both) compared with those with lower LSC count. Cox regression analysis revealed that LSC frequency at diagnosis is an independent prognostic factor in AML. Assessment of LSCs (CD34+/CD38-/TIM3+) at diagnosis is recommended for refining of AML risk stratification.

Background Radical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control. Methods We performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7). Patients were randomised (1:1) to DE-IMRT or standard dose IMRT (ST-IMRT) using a minimisation algorithm, balancing for centre, tumour site, nodal status and chemotherapy use. DE-IMRT was 67.2 gray (Gy) in 28 fractions (f) to the primary tumour and 56Gy/28f to at-risk nodes; ST-IMRT was 65Gy/30f to primary tumour and 54Gy/30f to at-risk nodes. Suitable patients received 2 cycles of concomitant cisplatin and up to 3 cycles of platinum-based induction chemotherapy. The primary end-point was time to locoregional failure analysed by intention-to-treat analysis using competing risk methodology. Findings Between February 2011 and October 2015, 276 patients (138 ST-IMRT; 138 DE-IMRT) were randomised. A preplanned interim futility analysis met the criterion for early closure. After a median follow-up of 47.9 months (interquartile range 37.5–60.5), there were locoregional failures in 38 of 138 (27.5%) ST-IMRT patients and 42 of 138 (30.4%) DE-IMRT patients; an adjusted subhazard ratio of 1.16 (95% confidence interval: 0.74–1.83, p = 0.519) indicated no evidence of benefit with DE-IMRT. Acute grade 2 pharyngeal mucositis was reported more frequently with DE-IMRT than with ST-IMRT (42% vs. 32%). No differences in grade ≥3 acute or late toxicity rates were seen. Conclusion DE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer. The trial is registered: ISRCTN01483375.

Background Late relapse (LR) of nonseminomatous germ cell tumour (NSGCT) is uncommon, with limited data published. LR is defined as relapse occurring after a disease-free interval of 2 yr. Objective To review features of NSGCT LR in a UK tertiary centre. Design, setting, and participants A total of 3064 patients were referred from January 2005 to December 2017. We identified patients who experienced LR after initial pathology demonstrated NSGCT and reviewed data for their original and LR presentation and management. Outcome measurements and statistical analysis Outcomes included time to LR measured from the date of diagnosis, and overall survival. This was assessed using Cox proportional Hazards modelling, with stratification or adjustment for potential confounders. Results and limitations We identified 101 patients with LR; the median time to LR was 96 mo. Forty-three patients (42.6%) experienced relapse after 10 yr. Univariable log-rank testing revealed that the median time to LR was significantly shorter for patients who had not received induction chemotherapy (iCTx; 54 mo, 95% confidence interval [CI] 48–108) than for those who did (112 mo, 95% CI 84–186; p = 0.04). Patients who had received iCTx were less likely to have elevated tumour markers (36% vs 46%) and more likely to undergo initial surgical resection at LR compared to CTx-naïve patients. Postpubertal teratoma (PPT), yolk sac, and dedifferentiated elements predominated for patients with iCTx exposure, whereas active GCT or fibrosis predominated in postchemotherapy resections for CTx-naïve patients at LR. Forty-one men underwent postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) as part of their initial treatment for metastatic disease. Of these, 20 experienced LR in the retroperitoneum, with 18 undergoing repeat RPLND as part of their LR management. Fifteen of the repeat RPLND histopathology specimens had a PPT component. There have been 23 deaths overall; survival was worse for patients presenting with symptoms (13/36, 33%) and those receiving CTx and no surgery (10/17, 59%) at LR. Conclusions When LR of NSGCT occurs, it is frequently after an extended interval and is later among patients with prior iCTx, with PPT predominating. The high frequency of LR within the retroperitoneum following PC-RPLND reinforces the need for good-quality PC-RPLND. Patient summary We reviewed data for patients who had a late relapse of testicular cancer. We found that patients who did not receive chemotherapy as the first treatment for their initial diagnosis had a shorter time to relapse. Our results highlight the importance of long-term follow-up for testicular cancer., Take Home Message Late recurrence of nonseminomatous germ cell tumours most frequently occurs more than 10 yr after the initial diagnosis.

Purpose The LAP07 multicenter randomized study assessed whether chemoradiation therapy increases overall survival versus continuation chemotherapy in patients whose locally advanced pancreatic cancer was controlled after 4 months of induction chemotherapy. This analysis investigated whether failure to adhere to radiation therapy (RT) guidelines influenced survival and toxicity. Methods and Materials This is a planned analysis of secondary objectives in the framework of a randomized international phase 3 trial. The protocol included detailed written RT guidelines. All participating institutions undertook an initial benchmark case to check adherence to protocol guidelines. Centers with major deviation were not allowed to include patients until they achieved a significant improvement and rigorously followed the guidelines. On-trial RT quality assurance consisted of a central review of treatment plan with dose-volume histograms for each patient. Adherence to guidelines was graded as per protocol (PP), minor deviation (MiD), or major deviation (MaD). Results Fifty-seven benchmark cases were evaluated, 26% were classified as PP, 60% were MiD, and 14% were MaD. Among the 442 included patients, 133 patients were randomized in the chemoradiation therapy arm, and 117 patients were assessable for RT quality analysis. RT quality was graded as PP in 38.5% of patients, MiD in 43.6% of patients, and MaD in 17.9% of patients. The most frequent protocol violations were dose distribution heterogeneities. Median overall survival was 17 months with PP and MiD versus 13.4 months with MaD (hazard ratio [HR], 1.63; 95% confidence interval [CI], 0.99-2.71; P = .055). There was no difference in terms of progression-free survival (HR, 1.09; 95% CI, 0.66-1.8; P = .72). Patients with MaD had more nausea than patients treated PP or with MiD (P = .0045). Conclusions MaD was associated with a trend for worst survival. There was no difference in terms of progression-free survival. Because of the low rate of major deviations, their effects on the LAP07 trial results may be negligeable.

BACKGROUND: Decreased peripheral lymphocyte counts are associated with outcome after RT in several solid tumors, though appear late during or after the radiation course and often correlate with other clinical factors. Here we investigate if absolute lymphocyte counts (ALC) are independently associated with recurrence in pediatric medulloblastoma early during RT. METHODS: We assessed 202 medulloblastoma patients treated between 2000 and 2016 and analyzed ALC throughout therapy, focusing on both early markers (ALC during week 1 – ALC(wk1); grade 3+ Lymphopenia during week 2 – Lymphopenia(wk2)) and late markers (ALC nadir). Uni- and multivariable regressions were used to assess association of clinical and treatment variables with ALC and of ALC with recurrence. RESULTS: Thirty-six recurrences were observed, with a median time to recurrence of 1.6 years (Range 0.2–10.3) and 7.1 years median follow-up. ALC during RT was associated with induction chemotherapy (p

Summary Background Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Primary analysis of the phase 3 trial in adults aged 60–75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia provided support for approval of CPX-351 by the US Food and Drug Administration and European Medicines Agency. We describe the prospectively planned final 5-year follow-up results. Methods This randomised, open-label, multicentre, phase 3 trial was done across 39 academic and regional cancer centres in the USA and Canada. Eligible patients were aged 60–75 years and had a pathological diagnosis of acute myeloid leukaemia according to WHO 2008 criteria, no previous induction therapy for acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned 1:1 (stratified by age and acute myeloid leukaemia subtype) to receive up to two induction cycles of CPX-351 (100 units/m2 administered as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the second induction) or standard chemotherapy (cytarabine 100 mg/m2 per day continuous intravenous infusion for 7 days plus intravenous daunorubicin 60 mg/m2 on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the second induction [5+2]). Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery could receive up to tw cycles of consolidation therapy with CPX-351 (65 units/m2 90-min infusion on days 1 and 3) or chemotherapy (5+2, same dosage as in the second induction cycle). The primary outcome was overall survival analysed in all randomly assigned patients. No additional adverse events were collected with long-term follow-up, except data for deaths. This trial is registered with ClinicalTrials.gov , NCT01696084 , and is complete. Findings Between Dec 20, 2012, and Nov 11, 2014, 309 patients with newly diagnosed high-risk or secondary acute myeloid leukaemia were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients). At a median follow-up of 60·91 months (IQR 60·06–62·98) in the CPX-351 group and 59·93 months (59·73–60·50) in the 7+3 group, median overall survival was 9·33 months (95% CI 6·37–11·86) with CPX-351 and 5·95 months (4·99–7·75) with 7+3 (HR 0·70, 95% CI 0·55–0·91). 5-year overall survival was 18% (95% CI 12–25%) in the CPX-351 group and 8% (4–13%) in the 7+3 group. The most common cause of death in both groups was progressive leukaemia (70 [56%] of 124 deaths in the CPX-351 group and 74 [53%] of 140 deaths in the 7+3 group). Six (5%) of 124 deaths in the CPX-351 group and seven (5%) of 140 deaths in the 7+3 group were considered related to study treatment. Interpretation After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall survival in patients aged 60–75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia. Funding Jazz Pharmaceuticals.

Aim report primary results from the first multicentre randomised trial evaluating induction chemotherapy prior to trimodality therapy in patients with oesophageal or gastro-oesophageal junction adenocarcinoma. Notably, recent data from a single-institution randomised trial reported that induction chemotherapy prolonged overall survival (OS) in patients with well/moderately differentiated tumours. Methods In this phase 2 trial (28 centres in the U.S. NCI-sponsored North Central Cancer Treatment Group [Alliance]), trimodality-eligible patients (T3-4N0, TanyN+) were randomised to receive induction (docetaxel, oxaliplatin, capecitabine; Arm A) or no induction chemotherapy (Arm B) followed by oxaliplatin/5-fluorouracil/radiation and subsequent surgery. The primary endpoint was the rate of pathologic complete response (pathCR). Secondary/exploratory endpoints were OS and disease-free survival (DFS). Results Of 55 patients evaluable for the primary endpoint, the pathCR rate was 28.6% (8/28) in A versus 40.7% (11/27) in B (P = .34). Given interim results indicating futility, accrual was terminated, but patients were followed. After a median follow-up of 60.4 months, a longer median OS in Arm A versus B was unexpectedly observed (3-year rates 57.1% versus 41.7%, respectively) driven by longer DFS after margin-free surgery. In posthoc analysis, induction (versus no induction) chemotherapy was associated with significantly longer OS and DFS among patients with well/moderately differentiated tumours, but not among patients with poorly/undifferentiated tumours (Pinteraction = 0.037). Conclusions Adding induction chemotherapy prior to trimodality therapy did not improve the primary endpoint, pathCR. However, induction chemotherapy was associated with longer median OS, particularly among patients with well/moderately differentiated tumours. These findings may inform further development of curative-intent trials in this disease.

International audience; Background: The aim of this study was to assess the impact of the initial therapeutic strategy on oncologic outcomes in patients with HPV-positive OPSCC.Methods: All p16-positive OPSCCs treated from 2009 to 2014 in 7 centers were retrospectively included and classified according to the therapeutic strategy: surgical strategy (surgery ± adjuvant radiotherapy and chemotherapy) vs. non-surgical strategy (definitive radiotherapy ± chemotherapy). Univariate, multivariate propensity score matching analyses were performed to compare overall (OS), disease-specific (DSS) and recurrence-free survival (RFS).Results: 382 patients were included (surgical group: 144; non-surgical group: 238). Five-year OS, DSS and RFS were 89.2, 96.8 and 83.9% in the surgical group and 84.2, 87.1 and 70.4% in the non-surgical group, respectively. These differences were statistically significant for DSS and RFS after multivariate analysis, but only for RFS after propensity score matching analysis.Conclusion: In p16+ OPSCC patients, upfront surgery results in higher RFS than definitive radiotherapy ± chemotherapy but does not impact OS.

The objective of our study was to clarify the clinical features of EGFR-mutated sinonasal squamous cell carcinoma (SNSCC) and human papilloma virus (HPV)-related SNSCC. Patients with SNSCC treated from April 2008 to June 2019 at our institution were retrospectively reviewed. We examined EGFR mutation and HPV status for all patients. Main outcomes were overall survival, recurrence, and outcome of each treatment modality. A total of 85 patients with SNSCC were enrolled in this study. EGFR mutations and HPV DNA were detected in 24 (28%) and 7 (8%) patients, respectively. Patients with EGFR-mutated SNSCC showed a worse overall survival (OS) than those with EGFR wild-type in the multivariate analysis (p = 0.037). No death was observed in HPV-positive SNSCC. The cumulative incidence of local recurrence was significantly higher in EGFR mutant than EGFR wild-type tumors (p = 0.03). In patients with EGFR mutations, treatment with induction chemotherapy significantly improved OS (p = 0.01). EGFR-mutated SNSCC have a high-risk feature for recurrence and requires intensive attention for treatment and observation. A new treatment approach, such as EGFR tyrosine kinase inhibitors, may be needed.

Background The incidence and risk factors for invasive mold infections (IMI) in acute myeloid leukemia (AML) patients carrying FLT3 mutations have not been addressed. Patients and Methods This retrospective cohort included FLT3-mutated AML patients (2008-2018). Primary outcome was IMI incidence within 6 months after first induction or salvage therapy. Results We included 108 patients receiving fluconazole or micafungin prophylaxis. IMI incidence after induction and salvage therapy was 4.8% and 14.8%, respectively, and did not differ between patients receiving 3+7 regimen or 3+7 plus midostaurin (4.3% vs 4.5%). In a bivariate analysis, age (odds ratio, 1.11; P = .027) and FLT3 ITD mutation (odds ratio, 0.05; P = .023) were independently associated with IMI after induction chemotherapy. Gilteritinib was more frequently prescribed in patients with relapsed/refractory disease who developed IMI (50% vs 27.3%, P = .563). Conclusion FLT3 ITD mutation may be a preventive factor for IMI. Neither midostaurin nor salvage gilteritinib significantly increased the risk of IMI in this population.

Neutrophil-to-lymphocyte ratio has been correlated with clinical outcomes in many cancers. We investigated whether the delta-NLR (ΔNLR) following radiation therapy (RT) could predict achieving surgical resection and the overall survival (OS) of patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC), and whether the splenic radiation dose impacted ΔNLR.101 patients with biopsy-proven BRPC or LAPC who received induction chemotherapy followed by RT were retrospectively enrolled. Following contouring of spleens, dose-volume histograms (DVHs) for splenic dosimetric parameters were calculated. Pre- and post-RT complete blood counts (CBC) within two weeks were recorded. Delta (Δ) values were calculated by subtracting the post-RT value from the pre-RT value. Cox regression survival analysis for pre and postradiation CBC values and OS was performed. Receiver operating curves (ROC) were generated and optimal cutoff points for highest sensitivity and specificity were identified. Kaplan-Meier curves for OS were generated.On univariate Cox regression analysis, the only significant CBC value associated with OS was ΔNLR (HR 1.06, CI 1.03-1.09, p 0.001). On multivariate analysis, ΔNLR, age, and completed resection all significantly predicted for worse OS (p 0.05). ΔNLR significantly predicted achieving surgical resection (p = 0.04) and the optimal cutoff point for ΔNLR was 2.5. Patients with ΔNLR 2.5 had significantly longer OS (log rank p = 0.046). Spleen radiation dose parameters were all significantly higher in patients with a ΔNLR ≥ 2.5. Optimal radiation cutoff points to predict a ΔNLR ≥ 2.5 were splenic Dmean of 308 cGy and V5 of 10.3%.Among patients with BRPC or LAPC who have received induction chemotherapy, elevated ΔNLR after RT significantly predicts worse OS and decreased odds of achieving resection. Furthermore, ΔNLR is correlated with higher splenic doses, suggesting the spleen may be an important organ at risk.

Acute myeloid leukemia (AML) is a rare malignancy with increased incidence in the kidney transplantation (KT) population for which immunosuppression has been implicated as a putative cause. The average time interval from KT to AML development is 5 years. We present the case of a 61-year-old man who was found to have peripheral blood blasts on a postoperative day 20 routine blood draw after an uneventful unrelated living donor kidney transplant. He subsequently had a bone marrow biopsy and next-generation sequencing (NGS)-based molecular testing, which demonstrated AML characterized by SMC1A and TET2 mutations. He received induction chemotherapy followed by hematopoietic cell transplantation (HCT) from the kidney donor, who happened to be matched at one haplotype. At 12 months after his HCT and 15 months after his KT, his AML remained in remission, normal renal function was preserved, no active graft-versus-host disease was present, and immunosuppression was tapering. With full donor-derived hematopoietic chimerism, we expect to be able to discontinue immunosuppression shortly, thereby achieving tolerance. The short time interval between KT and development of AML suggests the malignancy was likely present before KT. Modern NGS-based analysis offers a promising method of identifying transplant candidates with unexplained hematologic abnormalities on pre-KT testing who may benefit from formal hematologic evaluation.

Accelerated and blast phase myeloproliferative neoplasms are advanced stages of the disease with historically a poor prognosis and little improvement in outcomes thus far. The lack of responses to standard treatments likely results from the more aggressive biology reflected by the higher incidence of complex karyotype and high-risk somatic mutations, which are enriched at the time of transformation. Treatment options include induction chemotherapy (7 + 3) as that used on de novo acute myeloid leukemia or hypomethylating agent-based therapy, which has shown similar outcomes. Allogeneic stem cell transplantation remains the only potential for cure.

Detectable minimal residual disease (MRD) after therapy for acute lymphoblastic leukemia (ALL) is the strongest predictor of hematologic relapse. The objective of the study was to assess disease-free survival (DFS) and overall survival (OS) of patients with ALL according with MRD status at the end of induction therapy in a Colombian population.We assessed a retrospective cohort to compare DFS and OS in adults with de novo ALL according to MRD status at the end of induction chemotherapy, and the type of postinduction consolidation strategy used.A total of 165 adults with ALL were included in the MRD part of the study, 73 patients in the MRD-negative group and 92 in the MRD-positive group. Median DFS for the MRD-positive group was 11 months (95% confidence interval, 11.7-22.2) and was not reached for the MRD-negative group (P .001). At 3 years, DFS was 18% and 55%, respectively (P .001). The median OS for MRD-positive patients was 16 months (95% confidence interval, 8.8-23.15) and was not reached in the MRD-negative group. At 3 years, OS was 26% and 51% for the former and latter group, respectively. Among subjects who did not receive a transplant, median DFS was 21 months for MRD-negative patients and 9 months for MRD-positive patients (P .001). The median DFS was not reached in either group, whereas 3-year DFS was 64% for MRD-negative and 70% for MRD-positive patients who underwent transplantation in first remission (P = .861).MRD status at the end of induction is an independent prognostic factor for DFS and OS in adult ALL. Allogeneic transplantation in first remission could overcome the adverse prognostic impact of MRD.

Purpose Radiation therapy dose escalation using stereotactic body radiation therapy may significantly improve both local control (LC) and overall survival (OS) for patients with inoperable pancreas cancer. However, ablative dose cannot be routinely offered because of the risk of causing severe injury to adjacent normal organs. Stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) represents a novel technique that may achieve safe delivery of ablative dose and improve long-term outcomes. Methods and Materials We performed a single institution retrospective analysis of 35 consecutive pancreatic cancer patients treated with SMART in mid-inspiration breath hold on an MR-linear accelerator. Most had locally advanced disease (80%) and received induction chemotherapy (91.4%) for a median 3.9 months before stereotactic body radiation therapy. All were prescribed 5 fractions delivered in consecutive days to a median total dose of 50 Gy (BED10 100 Gy10), typically with a 120% to 130% hotspot. Elective nodal irradiation was delivered to 20 (57.1%) patients. No patient had fiducial markers placed and all were treated with continuous intrafraction MR visualization and automatic beam triggering. Results With median follow-up of 10.3 months from SMART, acute (2.9%) and late (2.9%) grade 3 toxicities were uncommon. One-year LC, distant metastasis-free survival, progression-free survival, cause-specific survival, and OS were 87.8%, 63.1%, 52.4%, 77.6%, and 58.9%, respectively. Conclusions To our knowledge, this is the first report of 5-fraction pancreas SMART delivered on an MR-linear accelerator. We observed minimal severe treatment-related toxicity and encouraging early LC. Prospective confirmation of feasibility and long-term clinical outcomes of dose intensified SMART is warranted.

Background and purpose The FiGaRO trial assessed the feasibility and safety of using an FDG-PET-based dose-painting technique to deliver a radiotherapy (RT) boost to the FDG-avid primary tumour in patients with locally advanced high and intermediate risk oropharyngeal cancer. Materials and method Patients underwent a planning 18FDG-PET-CT scan, immobilised in the treatment position, after one cycle of induction chemotherapy. The volume of persistent FDG-avidity in the primary tumour was escalated to 71.5 Gy in30 fractions delivered using a simultaneous integrated boost Intensity Modulated RT (SIB-IMRT) technique. RT was delivered with concomitant Cisplatin following 2 cycles of induction chemotherapy. The primary outcome was the incidence of grade ≥ 3 late mucosal toxicity 12 months post-treatment, with an excess rate of >10% regarded as unacceptable. Results Twenty-nine patients were included and twenty-four were treated between 2014 and 2018, in two UK centres. Median follow-up was 36 months (range 4–56 months). Pre-defined planning target volume objectives and organ at risk dose constraints were met in all cases. There were no incidents of acute grade 4 toxicity. There were 4 cases of grade ≥ 3 mucosal toxicity at 12 months post-treatment (19.1%). There were no cases of persistent mucosal ulceration at 12 months. Overall survival at 3-years was 87.5%, 92.9% for intermediate and 70.0% for high risk patients. Conclusion Late toxicity rates, although higher than anticipated, are comparable to contemporary published data for standard dose chemo-IMRT. Results suggest improved 3y survival rates for high risk patients. This approach merits further investigation. ClinicalTrials.gov Identifier: NCT02953197.

Our patient was a 4-year-old female with acute myeloid leukemia complicated with right calcaneal osteomyelitis due to Mycobacterium abscessus with subcutaneous abscesses extending to the popliteal and groin regions after two courses of induction chemotherapy according to NOPHO-AML 2012 protocol. She required multiple operations and prolonged anti-mycobacterial therapy. A high index of suspicion for mycobacterial infection is required for immunocompromised patients with prolonged fever or unusual presentation. Mycobacterial osteomyelitis is rare, difficult to diagnose and treat, and may necessitate prolonged interruption of anti-leukemic therapy. Multidisciplinary collaboration in patient management is crucial. Long-term toxicity of antimicrobials with uncertain efficacy should not be overlooked.

Reversible cerebral vasoconstriction syndrome (RCVS) is an uncommon disorder characterised by thunderclap headache and self-resolving angiographic vasospasm in the presence or absence of neurological deficit. We present the first case of RCVS likely precipitated by a complex array of confounding factors including a hyperosmolar hyperglycaemic state (HHS), induction chemotherapy with cyclophosphamide, non-Hodgkin's lymphoma, pancytopenia and previous blood transfusions. However, the clinical presentation in this case of altered conscious state followed by thunderclap headache was highly suggestive of HHS being the crucial inciting factor. This report of RCVS associated with HHS lends unique insight into key underlying pathophysiological mechanisms, and warns of the need to maintain a high index of suspicion for this elusive condition given the dynamic and transient nature of its clinical and radiological features.

This Review focuses on the use of 18F-fluorodeoxyglucose (18F-FDG) PET in the assessment of diffuse large B-cell lymphoma, follicular lymphoma, and peripheral T-cell lymphoma. PET is important for staging and prognostication with stage migration compared with CT. Better outcomes for patients with early stage diffuse large B-cell lymphoma and follicular lymphoma suggests better delineation of disease has translated to improved outcomes in such patients beyond simple stage migration. The aim of treatment of diffuse large B-cell lymphoma and peripheral T-cell lymphoma is potential cure, during which PET is mainly used to assess remission. Interim PET can assess chemosensitivity in these lymphomas, but it does not predict treatment success sufficiently well to enable treatment modification, particularly in the absence of more effective therapies for patients who remain PET-positive on interim scanning. In follicular lymphoma, traditionally viewed as an incurable lymphoma, the aim of treatment is to control disease for several years, while maintaining quality of life. PET can predict prognosis for patients with follicular lymphoma with high tumour burden at the end of induction chemotherapy, and it is being evaluated as a platform for response-adapted treatment of follicular lymphoma.

Purpose To investigate the effects of mitoxantrone and daunorubicin in induced chemotherapy on complete remission (CR), death during induction therapy, overall survival (OS), disease-free survival (DFS), and relapse in patients of all ages with acute myeloid leukemia (AML). Methods We searched published reports at the Medline, Embase, and Cochrane Databases as well as other databases from inception through July 2019. There was no restriction on date of publication or language (PROSPERO registration CRD42018095843). Results We enrolled 12 randomized controlled trials that included data of 4583 AML patients whose disease was untreated or relapsed/refractory, and compared the CR, death during induction therapy, DFS, and OS between mitoxantrone and daunorubicin. Mitoxantrone significantly increased the CR rate (relative risk = 1.07; 95% confidence interval [CI], 1.01, 1.14; P = .03) and DFS (hazard ratio = 0.87; 95% CI, 0.79, 0.96; P = .005) compared to daunorubicin. However, there was no significant difference in death during induction therapy (relative risk = 1.00; 95% CI, 0.81, 1.24; P = .99) and OS (hazard ratio = 0.94; 95% CI, 0.87, 1.01; P = .077) between the two drugs. Conclusion Although more studies are needed to compare mitoxantrone with higher-dose daunorubicin, the results showed that compared to daunorubicin, mitoxantrone can significantly improve CR and DFS in patients of all ages. These findings suggest that mitoxantrone may be a better choice than daunorubicin as an induction chemotherapy agent for AML patients, especially in developing countries.