Treatment Relapse Research Articles

The role of minimally invasive surgery in epithelial ovarian cancer treatment: a narrative review.

The aim of this narrative review is to summarize the available evidence on the use of minimal invasive surgery (MIS) in the management of epithelial ovarian cancer (EOC). MIS is currently performed to stage and treat EOC at different stage of presentation. We will evaluate risks and benefits of minimally invasive surgery for early stage EOC treatment, then potential advantages provided by staging laparoscopy in identifying patients suitable for primary cytoreductive surgery (PDS) will be discussed. Finally we will investigate the growing role of MIS in the treatment of advanced EOC after neoadjuvant chemotherapy (NACT) and in the treatment of EOC recurrence. An electronic database search was performed on PubMed, Medline, and Google Scholar for relevant studies up to December 2022. LPS represents a feasible surgical procedure for the staging and treatment in early, advanced and EOC relapse in selected patients treated in high-volume oncological centers by surgeons with adequate experience in advanced surgical procedures. Despite the increasing use of MIS over the last few years, randomized clinical trials are still needed to prove its effectiveness.

In Silico Analysis Predicts Nuclear Factors NR2F6 and YAP1 as Mesenchymal Subtype-Specific Therapeutic Targets for Ovarian Cancer Patients

Background: Tumour heterogeneity in high-grade serous ovarian cancer (HGSOC) is a proposed cause of acquired resistance to treatment and high rates of relapse. Among the four distinct molecular subtypes of HGSOC, the mesenchymal subtype (MES) has been observed with high frequency in several study cohorts. Moreover, it exhibits aggressive characteristics with poor prognosis. The failure to adequately exploit such subtypes for treatment results in high mortality rates, highlighting the need for effective targeted therapeutic strategies that follow the idea of personalized medicine (PM). Methods: As a proof-of-concept, bulk and single-cell RNA data were used to characterize the distinct composition of the tumour microenvironment (TME), as well as the cell–cell communication and its effects on downstream transcription of MES. Moreover, transcription factor activity contextualized with causal inference analysis identified novel therapeutic targets with potential causal impact on transcription factor dysregulation promoting the malignant phenotype. Findings: Fibroblast and macrophage phenotypes are of utmost importance for the complex intercellular crosstalk of MES. Specifically, tumour-associated macrophages were identified as the source of interleukin 1 beta (IL1B), a signalling molecule with significant impact on downstream transcription in tumour cells. Likewise, signalling molecules tumour necrosis factor (TNF), transforming growth factor beta (TGFB1), and C-X-C motif chemokine 12 (CXCL12) were prominent drivers of downstream gene expression associated with multiple cancer hallmarks. Furthermore, several consistently hyperactivated transcription factors were identified as potential sources for treatment opportunities. Finally, causal inference analysis identified Yes-associated protein 1 (YAP1) and Nuclear Receptor Subfamily 2 Group F Member 6 (NR2F6) as novel therapeutic targets in MES, verified in an independent dataset. Interpretation: By utilizing a sophisticated bioinformatics approach, several candidates for treatment opportunities, including YAP1 and NR2F6 were identified. These candidates represent signalling regulators within the cellular network of the MES. Hence, further studies to confirm these candidates as potential targeted therapies in PM are warranted.

RARE-07. BONE MARROW ABLATIVE CHEMOTHERAPY ASSOCIATED WITH IMPROVED OUTCOMES AMONG PATIENTS WITH RELAPSED CENTRAL NERVOUS SYSTEM NON-GERMINOMATOUS GERM CELL TUMORS

Abstract PURPOSE Patients with relapsed/refractory central nervous system (CNS) non-germinomatous germ cell tumors (NGGCTs) have poor outcomes. There is no universal agreement on managing these patients secondary to the rarity of the disease and lack of prospective trials. We aim to explore prognostic factors that may help guide the management of patients with relapsed/refractory CNS NGGCTs. METHODS We performed a multinational retrospective study of relapsed/refractory CNS NGGCTs. We summarized all data using standard descriptive statistics. Overall survival (OS) was evaluated using Kaplan-Meier and Fisher’s exact test to estimate odds ratios (OR) and 95% confidence intervals (CI) using SPSS software. RESULTS We identified 28 patients from 7 centers. Twenty-three patients (82%) were males. The median age at initial diagnosis was 11 years (range: 8-15). Twelve patients (43%) suffered from relapse, and 16 patients (57%) had an initial refractory disease. The median time to first relapse/progression was 29 months (range: 5-26). Eight patients (29%) received bone marrow ablative chemotherapy (HDCx) at relapse/progression. Sixteen patients (57%) received re-irradiation at relapse/progression. Six patients (21%) achieved complete remission (CR) at relapse. Only eight patients (29%) were alive at the last follow-up. The median follow-up time since relapse/progression was 16 months (range: 1 -153 months). HDCx (OR=25, 95%CI: 2.9-2223) – not re-irradiation (OR=7.8 95%CI: 0.795-76.1) – was associated with being alive at the last follow-up. All patients who achieved CR at the end of relapse treatment survived. Only one patient with the refractory disease was alive at the last follow-up. CONCLUSIONS Patients with refractory CNS NGGCTs have dismal outcomes. HDCx and achieving CR at the end of relapse therapy are associated with improved survival. A multinational registry is needed to collate standardized data to inform future prospective clinical trials and improve the outcomes of patients with relapsed/refractory CNS NGCCTs.

PSMA guided approach for bIoCHEmical relapse after prostatectomy- (PSICHE) trial (NCT05022914). Detection rate and treatment decision after 68Ga-PSMA PET/CT within a prospective study.

Ultrasensitive imaging has been demonstrated to influence biochemical relapse treatment. PSICHE is a multicentric prospective study, aimed at exploring detection rate with 68Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) and outcomes with a predefined treatment algorithm tailored to the imaging. Patients affected by biochemical recurrence after surgery (prostate specific antigen [PSA] > 0.2 < 1 ng/mL) underwent staging with 68Ga-PSMA PET/CT. Management followed this treatment algorithm accordingly with PSMA results: prostate bed salvage radiotherapy (SRT) if negative or positive within prostate bed, stereotactic body radiotherapy (SBRT) if pelvic nodal recurrences or oligometastatic disease, androgen deprivation therapy (ADT) if nonoligometastatic disease. Chi-square test was used to evaluate the relationship between baseline features and rate of positive PSMA PET/CT. One hundred patients were enrolled. PSMA results were negative/positive in the prostate bed in 72 patients, pelvic nodal or extrapelvic metastatic disease were detected in 23 and 5 patients. Twenty-one patients underwent observation because of prior postoperative radiotherapy (RT)/treatment refusal. Fifty patients were treated with prostate bed SRT, 23 patients underwent SBRT to pelvic nodal disease, five patients were treated with SBRT to oligometastatic disease. One patient underwent ADT. NCCN high-risk features, stage > pT3 and ISUP score >3 reported a significantly higher rate of positive PSMA PET/CT after restaging (p = 0.01, p = 0.02, and p = 0.002). By quartiles of PSA, rate of positive PSMA PET/CT was 26.9% (>0.2; <0.29 ng/mL), 24% (>0.3; <0.37 ng/mL), 26.9% (>0.38; <0.51 ng/mL), and 34.7% (>0. 52; <0.98 ng/mL). PSICHE trial constitute a useful platform to collect data within a clinical framework where modern imaging and metastasis-directed therapy are integrated.

The Contribution of Society of Social Psychiatry P. Sakellaropoulos to the Psychiatric Reform in Rural Greece

The present paper aims to describe the structure, function, and goals of two of the oldest Mobile Mental Health Units in Greece, namely, the Mobile Mental Health Unit in Fokida (MMHU-F) and the Mobile Mental Health Unit in Thrace (Alexandroupolis, MMHU-T). Information about their historical background, catchment areas, and current staffing, as well as the services provided by each MMHU is discussed. The focus of the paper is slightly biased towards the MMHU-F because it is the only available mental health service in the whole Fokida prefecture. The major goals of the MMHUs are the diagnosis, treatment, and prevention of relapse of severe mental illness within the community. Other important goals of the MMHUs are psychoeducation, psychological support for the family/caregivers, as well as vocational training and support for patients with severe mental illness. Statistical data depicting the demographic characteristics and diagnostic profiles of patients in each MMHU is also provided, and the differences between the two MMHUs are briefly discussed.

Whole-genome informed circulating tumor DNA analysis by multiplex digital PCR for disease monitoring in B-cell lymphomas: a proof-of-concept study.

Analyzing liquid biopsies for tumor-specific aberrations can facilitate detection of measurable residual disease (MRD) during treatment and at follow-up. In this study, we assessed the clinical potential of using whole-genome sequencing (WGS) of lymphomas at diagnosis to identify patient-specific structural (SVs) and single nucleotide variants (SNVs) to enable longitudinal, multi-targeted droplet digital PCR analysis (ddPCR) of cell-free DNA (cfDNA). In 9 patients with B-cell lymphoma (diffuse large B-cell lymphoma and follicular lymphoma), comprehensive genomic profiling at diagnosis was performed by 30X WGS of paired tumor and normal specimens. Patient-specific multiplex ddPCR (m-ddPCR) assays were designed for simultaneous detection of multiple SNVs, indels and/or SVs, with a detection sensitivity of 0.0025% for SV assays and 0.02% for SNVs/indel assays. M-ddPCR was applied to analyze cfDNA isolated from serially collected plasma at clinically critical timepoints during primary and/or relapse treatment and at follow-up. A total of 164 SNVs/indels were identified by WGS including 30 variants known to be functionally relevant in lymphoma pathogenesis. The most frequently mutated genes included KMT2D, PIM1, SOCS1 and BCL2. WGS analysis further identified recurrent SVs including t(14;18)(q32;q21) (IGH::BCL2), and t(6;14)(p25;q32) (IGH::IRF4). Plasma analysis at diagnosis showed positive circulating tumor DNA (ctDNA) levels in 88% of patients and the ctDNA burden correlated with baseline clinical parameters (LDH and sedimentation rate, p-value <0.01). While clearance of ctDNA levels after primary treatment cycle 1 was observed in 3/6 patients, all patients analyzed at final evaluation of primary treatment showed negative ctDNA, hence correlating with PET-CT imaging. One patient with positive ctDNA at interim also displayed detectable ctDNA (average variant allele frequency (VAF) 6.9%) in the follow-up plasma sample collected 2 years after final evaluation of primary treatment and 25 weeks before clinical manifestation of relapse. In summary, we demonstrate that multi-targeted cfDNA analysis, using a combination of SNVs/indels and SVs candidates identified by WGS analysis, provides a sensitive tool for MRD monitoring and can detect lymphoma relapse earlier than clinical manifestation.

Clinical safety and efficacy observation of ex vivo-expanded peripheral blood-derived allogeneic NK cells in the treatment of refractory or recurrent ovarian cancer.

e17553 Background: Ovarian cancer is the most lethal gynecologic malignancy. Nearly 75% of patients were diagnosed at advanced stages. Despite 60%-80% of patients achieve complete remission after treatment with surgery combined with chemotherapy, about 60% of patients relapse within two years, more than 50% of patients develop chemotherapy tolerance with only 30% five-year survival rate. Platinum resistance-induced recurrence and platinum intolerance result in poor prognosis. Thus, there is an unmet need for innovative therapy of advanced ovarian cancer. We have developed a novel non-genetically modified ex vivo-expanded allogeneic NK cells from peripheral blood (PB). The expanded PB-NK cells have highly cytolytic activity and have the capacity to preferentially reside in ovary. We conducted a phase I clinical trial for evaluation of safety and efficacy of allogeneic NK cells in treatment of patients with refractory or recurrent ovarian cancers. Methods: Patients with advanced ovarian cancer who failed after multiline treatment were enrolled and received the treatment with allogeneic NK cells. The treatment was divided into low, medium and high dose groups with a 28-day cycle. safety and efficacy were evaluated after receiving two cycles of allogeneic NK cell infusion. Results: A total of 4 patients with advanced ovarian cancer who failed multiline therapy completed two courses of cell infusion therapy and evaluation. The median age of patients was 58 years (range 50 to 71 years). The median number of lines of treatment was 6 (range 3-7). One recurrent patient with platinum intolerance received low dose of NK cells and three relapse or refractory patients with platinum resistance received medium dose of allogeneic NK cell therapy. The patient in low-dose group and one patient in medium-dose group were evaluated for stable disease (SD), the other two patients in medium-dose group were disease progression after two courses of treatment. Notable, the patient in low-dose group continued to receive treatment with the same dose and achieved partial response (PR) after three courses of treatment. Upon receiving continuous NK cell therapy, the tumor lesions continued to shrink, with the best result was 60% reduction. It was re-evaluated as progressive disease (PD) 6 months after treatment was discontinued. Adverse events during the follow-up period included grade I fever in 4 (100%), grade I drowsiness in 1 (25%), grade I chills in 1 (25%), and grade I malaise in 1 (25%). No CRS or GVHD occurred. Conclusions: We report the safety and efficacy of allogeneic PB-NK cells in treatment of relapse or refractory ovarian cancer. The results showed that the allogeneic PB-NK cells are safe and feasible for the treatment of ovarian cancer, indicating a promising curative effect. There is no host versus graft reaction upon receiving continuous allogeneic NK cell therapy. Clinical trial information: NCT03619954 .

Therapeutic Approaches to Penile Cancer: Standards of Care and Recent Developments.

Penile cancer is a rare malignancy, most commonly diagnosed in older men, associated with poor outcomes, dramatic decline in quality of life and sexual function. Squamous cell carcinoma is the most common histopathology of penile cancer, accounting for 95% of all cases. Localized, early-stage penile cancer can be effectively managed through penile-sparing techniques in many cases, though advanced stages of penile cancer carry a poor prognosis. Current innovative treatments are exploring the role of targeted therapy, HPV-directed therapy, immune checkpoint inhibitors and adoptive T-cell therapies in treatment and prevention of relapse of penile cancer. Clinical trials are investigating the potential of targeted therapies and immune checkpoint inhibitors in advanced penile cancer. This review examines the current management of penile cancer and highlights future directions in research and treatment.

Circulating tumor DNA methylation marker-based minimal residual diseases detection and recurrence monitoring of cancer.

e15172 Background: Circulating tumor DNA (ctDNA) has been heralded as a promising tool to detect residual disease, relapse, and monitor treatment response by detecting molecular residual disease (MRD) in solid tumors. Numerous previous studies have demonstrated the molecular characteristics of ctDNA, such as the mutational landscape, single-nucleotide variations, copy number variations, and methylation landscape. Based on the methylation characteristics of ctDNA, we developed a novel MRD evaluation system (PcMM-qMSP) with ctDNA methylation markers, and evaluated the association of changes in ctDNA level with clinical outcome. Methods: We used sequencing data from public databases for data mining by clinical Natural Language Processing (NLP) to screen the pan-cancer ctDNA methylation markers (PcMM). A PcMM-based MRD detection method was established by quantitative methylation-specific PCR (qMSP). Moreover, 99 clinical blood samples [lung cancer (41), colorectal cancer (18), gastric cancer (5), pancreatic adenocarcinoma (16), liver cancer (6), cervical cancer (3), ovarian cancer (4), breast cancer (3), and unknown (3)] were collected to evaluate the consistency of ctDNA level between PcMM-qMSP and next-generation sequencing (NGS). Results: We evaluated the precision, including within-batch (intra) and between-batch (inter) reproducibility. PcMM-qMSP showed coefficients of variation (CVs) of the intra- and inter-batch assay of 0.42-0.65% and 0.05-0.27%, the accuracies were 100%. Best-in-class assays demonstrated a limit of detection (LoD) of approximately 30 copies of methylated DNA, with lower LoD at 10 copies. The evaluation results of 99 pan-solid tumor blood samples showed that the consistency of PcMM-qMSP and NGS in ctDNA level assessment was 0.82. The specific data are shown in the Table. Conclusions: PcMM is a pan-tumor specific methylation biomarker. The results demonstrated that PcMM-qMSP and NGS were highly functionally consistent for estimating ctDNA level. PcMM-qMSP detection time is less than 24 hours and costs USD 300 as compared to NGS, which takes seven days and costs USD 900. Hence, PcMM-qMSP is economical, rapid, accurate and highly sensitive for detecting pan-solid tumors. [Table: see text]

Azacitidine, lenalidomide and donor lymphocyte infusions for relapse of myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia after allogeneic transplant: the Azalena-Trial.

Azacitidine combined with donor lymphocyte infusions (DLI) is an established treatment for relapse of myeloid malignancies after allogeneic transplantation. Based on its immunomodulatory and anti-leukemic properties we considered Lenalidomide to act synergistically with Azacitidine/DLI to improve outcome. We therefore prospectively investigated tolerability and efficacy of this combination as first salvage therapy for adults with post-transplant relapse of AML, MDS and CMML. Patients were scheduled for 8 cycles Azacitidine (75 mg/m2 day 1-7), Lenalidomide (2.5 or 5mg, day 1-21) and up to 3 DLI with increasing T cell dosages (0.5×106-1.5×107 cells/kg). Primary endpoint was safety, while secondary endpoints included response, graft-versus-host disease (GvHD) and overall survival (OS). Fifty patients with molecular (52%) or hematological (48%) relapse of MDS (n=24), AML (n=23) or CMML (n=3) received a median of 7 (range, 1 to 8) cycles including 14 patients with 2.5mg and 36 with 5mg Lenalidomide daily dosage. Concomitantly, 34 patients (68%) received at least one DLI. Overall response rate was 56% and 25 patients (50%) achieved complete remission being durable in 80%. Median OS was 21 months and 1-year OS rate 65% with no impact of type of or time to relapse and Lenalidomide dosages. Treatment was well tolerated indicated by febrile neutropenia being the only grade ≥3 non-hematologic adverse event in >10% of patients and modest acute (grade II-IV 24%) and chronic (moderate/severe 28%) GvHD incidences. In summary, Lenalidomide can be safely added to Azacitidine/DLI without excess of GvHD and toxicity. Its significant anti-leukemic activity suggests that this combination is a novel salvage option for post-transplant relapse. (NCT02472691).

Activation of trace amine-associated receptor 1 (TAAR1) transiently reduces alcohol drinking in socially housed mice.

Alcohol dependence is characterized by the abnormal release of dopamine in the brain reward-related areas. Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that negatively regulates dopamine neurotransmission and thus is a promising target in the treatment of drug addiction. However, the role of TAAR1 in the regulation of alcohol abuse remains understudied. Here, we assessed the effect of TAAR1 activation on alcohol drinking behaviours of C57Bl/6J female mice housed in IntelliCages. The animals were administered with either vehicle or TAAR1 full selective agonist, RO5256390, and tested for alcohol consumption, alcohol preference and motivation for alcohol seeking. We found that mice with the highest preference for alcohol (high drinkers) in the RO5256390 group consumed less alcohol and had lower alcohol preference in comparison with high drinkers in the vehicle group, during 20 h of free alcohol access (FAA). We also found decreased alcohol consumption and alcohol preference comparing all animals in the RO5256390 to all animals in the vehicle group, during 20 h of FAA performed after the abstinence. These effects of RO5256390 lasted for the first 24 h after administration that roughly corresponded to the compound level in the brain, measured by mass spectrometry. Finally, we found that administration of RO5256390 may attenuate motivation for alcohol seeking. Taken together, our findings reveal that activation of TAAR1 may transiently reduce alcohol drinking; thus, TAAR1 is a promising target for the treatment of alcohol abuse and relapse.

Diagnosis and management of adult central nervous system leukemia.

Central nervous system leukemia (CNSL) is a prominent infiltration reason for therapy failing in acute leukemia. Recurrence rates and the prognosis have alleviated with current prophylactic regimens. However, the accurate stratification of relapse risk and treatment regimens for relapsed or refractory patients remain clinical challenges yet to be solved. Recently, with hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor-T (CAR-T) cellular therapy showing encouraging effects in some CNSL patients, advances in treating CNSL have already been reported. The development of molecular targeted agents as well as antibody-based drugs will provide patients with more personalized treatment. This article summarized recent research developments about risk factors, diagnosis, prevention, and treatment in adults with CNSL.

Treatment of pediatric relapsed and refractory acute myeloid leukemia

Background. Despite the modern therapy programs including hematopoietic stem cell transplantation, the treatment outcomes for children with acute myeloid leukemia (AML) remain unsatisfactory. The 5‑year overall survival rate is about 70 %. The 5‑year overall survival rate for patients with relapsed and refractory AML is 2 times lower (about 35 %). The treatment failure rate in primary AML and unsatisfactory results in relapsed and refractory AML make it necessary to optimize therapy protocols.Aim was a long-term retro- and prospective analysis of clinical and laboratory characteristics and treatment outcomes in patients with relapsed and refractory forms of AML.Materials and methods. This article presents the treatment results of 54 patients from 1 to 18 years of age, with relapsed and refractory AML treated at the N. N . Blokhin National Medical Research Center of Oncology from 1997 to 2022.Results. A comparison of 5 different programs revealed that patients who received second remission induction with the FLA + FLA scheme had 81.8 % of response (complete or partial) achievement. Analysis of the results in achievement the second remission in patients received epigenetic agents (azacytidine, decitabine, valproic and all-trans retinoid acids) with second-line chemotherapy found that treatment response rate was 100 % (n = 27), in contrast to patients received only second-line chemotherapy (n = 27) – 81.5 % (p = 0.003). The best treatment results were in group of patients whose treatment included epigenetic agents and allogenic hematopoietic stem cell transplantation after second remission induction – 5‑year overall survival was 51.3 ± 9.7 %.Conclusion. Intensive polychemotherapy with fludarabine- and cytarabine-containing regiments with following allogeneic hematopoietic stem cell transplantation and epigenetic agents are current trend and pathogenetically based approach for relapsed and refractory pediatric AML. Probable, the definition of the role and place of targeted drugs (gemtuzumab ozogamicin) could continue the advances in treatment of such unfavorable patient group.

High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4+ T cell arrest on the inflamed BBB under flow in vitro

IntroductionThe humanized anti-α4 integrin blocking antibody natalizumab (NTZ) is an effective treatment for relapsing–remitting multiple sclerosis (RRMS) that is associated with the risk of progressive multifocal leukoencephalopathy (PML). While extended interval dosing (EID) of NTZ reduces the risk for PML, the minimal dose of NTZ required to maintain its therapeutic efficacy remains unknown.ObjectiveHere we aimed to identify the minimal NTZ concentration required to inhibit the arrest of human effector/memory CD4+ T cell subsets or of PBMCs to the blood–brain barrier (BBB) under physiological flow in vitro.ResultsMaking use of three different human in vitro BBB models and in vitro live-cell imaging we observed that NTZ mediated inhibition of α4-integrins failed to abrogate T cell arrest to the inflamed BBB under physiological flow. Complete inhibition of shear resistant T cell arrest required additional inhibition of β2-integrins, which correlated with a strong upregulation of endothelial intercellular adhesion molecule (ICAM)-1 on the respective BBB models investigated. Indeed, NTZ mediated inhibition of shear resistant T cell arrest to combinations of immobilized recombinant vascular cell adhesion molecule (VCAM)-1 and ICAM-1 was abrogated in the presence of tenfold higher molar concentrations of ICAM-1 over VCAM-1. Also, monovalent NTZ was less potent than bivalent NTZ in inhibiting T cell arrest to VCAM-1 under physiological flow. In accordance with our previous observations ICAM-1 but not VCAM-1 mediated T cell crawling against the direction of flow.ConclusionTaken together, our in vitro observations show that high levels of endothelial ICAM-1 abrogate NTZ mediated inhibition of T cell interaction with the BBB. EID of NTZ in MS patients may thus require consideration of the inflammatory status of the BBB as high levels of ICAM-1 may provide an alternative molecular cue allowing for pathogenic T cell entry into the CNS in the presence of NTZ.

Reduction of Cancer Stem Cells and Invasiveness of Human Melanoma and Breast Cancer by Cucurbitacin B from Lagenaria siceraria

Cucurbitacins are secondary metabolites that are commonly found in the Cucurbitacae family. Many biological properties have been reported for cucurbitacins, including anti-inflammatory, antioxidant, antiviral, anti-malaria, and anticancer properties. While studies for the anticancer property of cucurbitacins focus mostly on the cell-cycle progression and apoptosis, no study has considered the effect of cucurbitacin on other cancer behaviors. Here, we report cell-proliferation-based drug testing on random herbal extracts leading to the identification of cucurbitacin B as an anticancer compound. Interestingly, cucurbitacin B had no effect on the proliferation of rat embryonic myoblast cells. We also found that cucurbitacin B significantly reduced the invasiveness of at least two highly metastatic breast cancer and melanoma cells. Using known cancer stem-cell markers, we observed a significant reduction of the melanoma stem cells. Molecularly, cucurbitacin B caused reduction of the metastasis-promoting gene Snail in melanoma and one of the cancer stem cell markers, ALDH1A1 (aldehyde dehydrogenase 1 A1), in breast cancer. Finally, we report the potential toxicity of cucurbitacin B in developing skin tissue and the olfactory organ using zebrafish embryo. In summary, our study suggests the potential use of cucurbitacin B for cancer metastasis and relapse treatment.

Complex, atypical clubfoot: follow-up after up to 16years reveals a high risk of relapse but good functional and radiological outcomes.

The treatment of complex atypical clubfoot poses many challenges. In this paper, we report on the course of complex clubfoot, primary correction using the modified Ponseti method and midterm outcomes. Special consideration is given to clinical and radiological changes in cases of relapse. Twenty-seven cases of complex, atypical, non-syndromic clubfoot were treated in 16 children between 2004 and 2012. Patient data, treatment data, functional outcomes and, in the relapse cohort, radiological findings were documented during the course of treatment. The radiological findings were correlated with the functional outcomes. All atypical complex clubfeet could be corrected using a modified form of the Ponseti method. Over an average study period of 11.6years, 66.6% (n = 18) of clubfeet relapsed. Correction after relapse showed an average dorsiflexion of 11.3° during a 5-years' follow-up period. Radiological results showed residual clubfoot pathologies such as a medialized navicular bone in four clubfeet. There were no instances of subluxation or dislocation of the talonavicular joint. Extensive release surgery was not necessary. Nevertheless, after 2.5 preoperative casts (1-5 casts), bone correction was performed in n = 3 feet in addition to Achilles tendon lengthening and tibialis anterior tendon transfer. Good primary correction of complex clubfoot using the modified Ponseti technique results in a high recurrence rate in the medium term. Relapse treatment without peritalar arthrolysis procedures produces good functional results even though minor residual radiological pathologies did persist in a minor number of cases.

Second haploidentical stem cell transplantation (HAPLO-SCT2) after relapse from a first HAPLO-SCT in acute leukaemia—a study on behalf of the Acute Leukaemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

For patients with acute myeloid and lymphoblastic leukaemia (AML/ALL) lacking a matched sibling or unrelated donor, haploidentical stem cell transplantation (HAPLO-SCT) is increasingly used. However, available data on the treatment of relapse after HAPLO-SCT, including feasibility and efficacy of a second HAPLO-SCT (HAPLO-SCT2), is scarce. Hence, adults with AML/ALL, that had undergone HAPLO-SCT2 without ex-vivo manipulation after haematologic relapse from HAPLO-SCT1 were selected for a retrospective registry analysis. Eighty-two patients (AML, n = 63, ALL, n = 19, median follow-up: 33 months) were identified. Engraftment rate was 87%. At day +180, cumulative incidences of acute GvHD II-IV°/chronic GvHD were 23.9%/22.6%, respectively. Two-year overall survival/leukaemia-free survival (OS/LFS) were 34.3%/25.4%; 2-year non-relapse mortality (NRM) and relapse incidence (RI) were 17.6% and 57%. Leukaemia was the most frequent cause of death. Separated by disease, 2-year OS/LFS/NRM/RI were 28.7%/22.3%/16.2%/61.6% in AML, and 55.3%/38.4%/23.5%/38.2% in ALL patients. In a risk-factor analysis among patients with AML, stage at HAPLO-SCT1 and HAPLO-SCT2, and interval from HAPLO-SCT1 to relapse significantly influenced outcome. Our data demonstrate that HAPLO-SCT2 is a viable option in acute leukaemia relapse after HAPLO-SCT1. Engraftment, toxicity, risk factors and long-term outcome are comparable to data reported after allo-SCT2 in a matched donor setting.

Clinical, Laboratory and Imaging Findings in the Selection of Treatment and Determination of Relapse in Subacute Thyroiditis

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A case of alemtuzumab-induced thyroid disease with a fluctuating course

Alemtuzumab (ALZ) is a humanized monoclonal antibody licensed for the treatment of relapsing–remitting multiple sclerosis (RRMS). One of its common side effects is autoimmune thyroid disease, most commonly Graves' disease (GD). Here, we present a case of a 39-year-old female that was on ALZ for the treatment of RRMS. After two cycles, she developed GD, which later converted to severe hypothyroidism.

A systematic review of isotretinoin dosing in acne vulgaris

AbstractHow does low‐dose oral isotretinoin compare with recommended and high‐dose oral isotretinoin in terms of efficacy, adverse effect profile, duration of remission, economic profile and rate and severity of relapse? A systematic literature search of EMBASE, MEDLINE, PubMed and The Cochrane Library from 1983 to July 2022 was conducted to identify randomised control trials (RCTs), cohort studies and cross‐sectional studies investigating the treatment of acne vulgaris with oral isotretinoin. This systematic review of the literature sought to explore and compare the use of different isotretinoin dosing regimens. Primary outcomes were efficacy, relapse, and safety profiles of oral isotretinoin of varying doses. Secondary outcomes included adverse events and economic considerations. The quality of studies, including risk of bias was assessed using GRADE (Grading of Recommendations, Assessment, Development and Evaluations). A total of 32 studies were included. Severe acne responds better to conventional or high fixed daily doses of isotretinoin. In cases of mild to moderate acne, where oral isotretinoin was prescribed, clearance rates were comparable with low, conventional or high dosage regimens. Despite this, relapse was more frequent in those treated with a lower dose. The severity of mucocutaneous adverse effects worsens as the dose of isotretinoin is increased. Comparison between studies was challenging due to differing methods of assessment, outcome measures and duration of follow‐up. This review highlights the need for an adequately powered RCT comparing low, conventional and high doses of oral isotretinoin to establish optimal dosing for treatment and prevention of relapse in acne vulgaris.