MYC targeting by OMO-103 in solid tumors: a phase 1 trial.

Among the 'most wanted' targets in cancer therapy is the oncogene MYC, which coordinates key transcriptional programs in tumor development and maintenance. It has, however, long been considered undruggable. OMO-103 is a MYC inhibitor consisting of a 91-amino acid miniprotein. Here we present results from a phase 1 study of OMO-103 in advanced solid tumors, established to examine safety and tolerability as primary outcomes and pharmacokinetics, recommended phase 2 dose and preliminary signs of activity as secondary ones. A classical 3 + 3 design was used for dose escalation of weekly intravenous, single-agent OMO-103 administration in 21-day cycles, encompassing six dose levels (DLs). A total of 22 patients were enrolled, with treatment maintained until disease progression. The most common adverse events were grade 1 infusion-related reactions, occurring in ten patients. One dose-limiting toxicity occurred at DL5. Pharmacokinetics showed nonlinearity, with tissue saturation signs at DL5 and a terminal half-life in serum of 40 h. Of the 19 patients evaluable for response, 12 reached the predefined 9-week time point for assessment of drug antitumor activity, eight of those showing stable disease by computed tomography. One patient defined as stable disease by response evaluation criteria in solid tumors showed a 49% reduction in total tumor volume at best response. Transcriptomic analysis supported target engagement in tumor biopsies. In addition, we identified soluble factors that are potential pharmacodynamic and predictive response markers. Based on all these data, the recommended phase 2 dose was determined as DL5 (6.48 mg kg-1).ClinicalTrials.gov identifier: NCT04808362 .

Conservation of orbital angular momentum throughout amplification of high order harmonics in Ni-like krypton and silver plasmas.

In this article we present modelling results of the amplification of High Order Harmonics (HOH) carrying orbital angular momentum (OAM) in plasma amplifiers created from krypton gas and silver solid targets. The resulting amplified beam is characterized in terms of intensity, phase and decomposition in helical and Laguerre-Gauss modes. Results show that the amplification process conserves OAM, although some degradation is apparent. Several structures appear in the intensity and phase profiles. These structures have been characterized with our model and related to refraction and interference with the plasma self-emission. Thus, these results not only demonstrate the capability of plasma amplifiers to deliver HOH amplified beams carrying OAM but also pave the way towards using HOH carrying OAM as a probe beam to diagnose the dynamics of hot, dense plasmas.

Phase 1 first-in-human dose-escalation study of ANV419 in patients with relapsed/refractory advanced solid tumors.

BACKGROUND: ANV419 is a stable antibody-cytokine fusion protein consisting of interleukin-2 (IL-2) fused to an anti-IL-2 monoclonal antibody that sterically hinders binding of IL-2 to the α subunit of its receptor but has selective affinity for the receptor ßγ subunits. Thus, ANV419 preferentially stimulates CD8+ effector T cells and natural killer cells which are associated with tumor killing, while minimizing the activation of immunosuppressive regulatory T cells. METHODS: ANV419-001 is an open-label, multicenter, phase 1 study to evaluate the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ANV419. Secondary objectives were to characterize the pharmacokinetics, pharmacodynamics and tumor response. Adult patients with advanced solid tumors and disease progression after ≥1 previous line of systemic therapy were enrolled. ANV419 was administered by intravenous infusion once every 2 weeks, with a planned treatment duration of 12 months. The dose escalation part of the study explored doses 3, 6 and 12 µg/kg as single patient cohorts followed by 24-364 µg/kg in a 3+3 design. Interim results are reported here (data cut-off: March 22, 2023). RESULTS: Forty patients were enrolled and received at least one dose of ANV419. The MTD and RP2D were determined to be 243 µg/kg. The most common ANV419-related treatment-emergent adverse events were Grade 1 and 2 fever (31 (77.5%)), chills (23 (57.5%), vomiting (14 (35.0%)), cytokine release syndrome and nausea (12 (30.0%) each). Transient and self-limiting lymphopenia due to lymphocyte redistribution was observed in all patients. In the RP2D cohort, Grade ≥3 thrombocytopenia and fever were reported by one patient (12.5%) each. All events were manageable with standard supportive care. At doses of 243 µg/kg (RP2D/MTD), the estimated T1/2 was approximately 12 hours. At ANV419 doses ≥108 µg/kg, 64% of patients had a best response of at least SD (15 SD and 1 confirmed PR). CONCLUSIONS: ANV419 at doses up to 243 µg/kg (the RP2D) was well tolerated and showed signs of antitumor activity in a heavily pretreated patient population with advanced solid tumors. TRIAL REGISTRATION NUMBER: NCT04855929.

Anti-Zic4 paraneoplastic cerebellar degeneration in a patient with EGFR-mutated NSCLC: a case report.

Paraneoplastic cerebellar degeneration (PCD) is one of the most prevalent neurological paraneoplastic syndromes, typically associated with small cell lung cancer (SCLC). PCD is thought to be caused by proteins expressed by tumor cells which trigger an antibody-mediated immune response. Despite PCD being commonly associated with anti-Yo, anti-Hu and anti-Tr/DNER antibodies, PCD is the most prevalent paraneoplastic syndrome in patients harboring anti-Zic4 antibodies. We report what, to our knowledge, is the first known case of anti-Zic4 mediated PCD in a patient with EGFR-mutated metastatic non-small cell lung cancer (NSCLC). Our patient was in complete response (CR) to targeted therapy and presented to the emergency room with drowsiness, unsteady gait and memory lapses. The diagnostic work-up revealed a diffuse cerebellar atrophy in the MRI, ruling out brain metastasis and leptomeningeal carcinomatosis. A body-CT scan showed no signs of recurrent disease. The cerebrospinal fluid (CSF) was within normal parameters. An onconeural antibody panel was conducted in a peripheral blood sample, detecting high levels of anti-Zic4 antibody by indirect immunofluorescence (IFI), results later confirmed by immunoblot testing. With the suspected diagnosis of an anti-Zic4 PCD, the case was discussed with the neurology department and treatment with high dose methylprednisolone was initiated. Considering the lack of substantial clinical benefit, the patient was then treated with intravenous immunoglobulins (IVIG) for 5 days, showing modest improvement. At this time, the patient presented minor disease relapse in the form of a sub-centimetric pulmonary nodule. Despite one cycle of chemotherapy, the patient's neurological condition deteriorated leading to fatal pneumonia secondary to progressive dysphagia. There is scarce evidence of paraneoplastic syndromes in EGFR-mutated NSCLC. Further research is warranted to stablish a possible association between anti-Zic4 and the EGFR molecular pathway.

Prognostic value of circulating endothelial cells in glioblastoma patients: a pilot study.

Aim: Glioblastoma (GB) is an aggressive tumor type and the detection of circulating endothelial cells (CECs) in peripheral blood has been related to angiogenesis. Materials & methods: A prospective single-center pilot study of CEC detection at diagnosis in 22 patients with GB was performed, using the US FDA-approved CellSearch system. Results: A CEC cutoff value was estimated using a receiver operating curve (ROC) and patients were classified into two groups: <40 CEC/4 ml and >40 CEC/4 ml blood. Median overall survival was 25.33 months for group 1 and 8.23 months for group 2 cases (p = 0.02). There was no correlation between CEC and PWI (perfusion-weighted imaging) RM. Conclusion: CEC detection has a prognostic value in GB cases at diagnosis.

New horizons for uncommon mutations in non-small cell lung cancer: BRAF, KRAS, RET, MET, NTRK, HER2.

The 2004 discovery of EGFR mutations, followed by ALK rearrangements, ushered in a targeted therapy era for advanced non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors targeting gene alterations have substantially improved survival and quality of life for patients with NSCLC. In the last decade, rearrangements of the ROS1 oncogene have been incorporated into healthcare practice that are applicable to another small subgroup of patients who benefit from similar targeted strategies. Recent genome studies of lung adenocarcinoma have identified other possible therapeutic targets, including RET, NTRK fusions, c-MET alterations, and activating mutations in KRAS, BRAF, and HER2, all with frequencies greater than 1%. Lung cancers harbouring these genome changes can potentially be treated with agents approved for other indications or under clinical development. This review updates the therapeutic arsenal that especially targets those genes.

Micro- and Nanofibrillated Cellulose from Annual Plant-Sourced Fibers: Comparison between Enzymatic Hydrolysis and Mechanical Refining.

The current trends in micro-/nanofibers offer a new and unmissable chance for the recovery of cellulose from non-woody crops. This work assesses a technically feasible approach for the production of micro- and nanofibrillated cellulose (MNFC) from jute, sisal and hemp, involving refining and enzymatic hydrolysis as pretreatments. Regarding the latter, only slight enhancements of nanofibrillation, transparency and specific surface area were recorded when increasing the dose of endoglucanases from 80 to 240 mg/kg. This supports the idea that highly ordered cellulose structures near the fiber wall are resistant to hydrolysis and hinder the diffusion of glucanases. Mechanical MNFC displayed the highest aspect ratio, up to 228 for hemp. Increasing the number of homogenization cycles increased the apparent viscosity in most cases, up to 0.14 Pa·s at 100 s-1 (1 wt.% consistency). A shear-thinning behavior, more marked for MNFC from jute and sisal, was evidenced in all cases. We conclude that, since both the raw material and the pretreatment play a major role, the unique characteristics of non-woody MNFC, either mechanical or enzymatically pretreated (low dose), make it worth considering for large-scale processes.

Analysis of adverse drug events as a way to improve cancer patient care.

PURPOSE: To define the signals that a new artificial intelligence (AI) system must emit to improve adverse drug events (ADEs) management in oral antineoplastic agents (OAA). METHODS: A multidisciplinary group of experts in patient safety was set up to define what signals the new AI system must emit to improve ADEs management in OAAs. The baseline data for the new AI system were generated through an observational and ambispective study carried out in a university hospital. All patients who met the inclusion criteria were selected consecutively every working day for 6 months. The ADEs were collected by interview and by the review of health records. The ADEs were categorised according to how they could be detected: patient, analysis, examination. RESULTS: The group defined what signals the AI system must emit to improve ADEs management in OAAs: a signal to educate the patient when the possible ADEs were categorised as patient, a signal as a reminder to request a blood test or a microbiological culture when the possible ADEs were categorised as analysis, and a signal as a reminder for the necessity of a clinical examination when the possible ADEs were categorised as examination. A total of 1652 ADEs were reported in the interviews (ADE-interview) with the pharmacist, and doctors noted 1989 ADEs in the health record (ADE-HR). The most frequent ADEs were identified in the patient category. CONCLUSION: This study opens a new way for better management of ADEs and is the first step in the development of a future technology, which will improve the quality of life of patients.

Prolonged Responses With Trastuzumab Emtasine Treatment of Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer Refractory to Trastuzumab and Pertuzumab: Systematic Review of Evidence.

Amplification of human epidermal growth factor receptor 2 (HER2) occurs in around 25% of breast cancers and has been associated with aggressive disease. Here, we summarize published evidence on efficacy and prolonged responses with trastuzumab emtansine (T-DM1) after first-line trastuzumab plus pertuzumab and provide possible factors related to prolonged responses to T-DM1. We conducted a literature search using PubMed, and articles that were published in English between July 1, 2012 and December 31, 2019 were included. A review of the bibliography included in the articles found was made. Nine articles were eligible; 2 were case reports, and the remaining 7 were nonexperimental studies, all retrospective. Five were multi-center works. The total number of patients was 796 (276 received pertuzumab). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used for this systematic review. The population included was heterogeneous among studies according to hormone receptor status, de novo metastatic disease, number of metastatic sites, visceral involvement, brain metastasis, previous neoadjuvant or adjuvant trastuzumab, and line of therapy in which T-DM1 was administered. Less efficacy in terms of responses (overall response rate, 18%-33%) and progression-free survival (4-6 months) with second-line T-DM1, in patients pretreated with pertuzumab, was shown (if compared with the EMILIA trial). The results are more similar to those of the TH3RESA trial (very pretreated population). Prolonged treatments (6 months or more) were observed in at least 17% of cases. The efficacy of T-DM1 after a previous pertuzumab treatment is lower than if pertuzumab is not given, although prolonged responses are observed in this setting.

Targeting KRAS in Non-Small Cell Lung Cancer.

Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is the most frequently altered oncogene in Non-Small Cell Lung Cancer (NSCLC). KRAS mutant tumors constitute a heterogeneous group of diseases, different from other oncogene-derived tumors in terms of biology and response to treatment, which hinders the development of effective drugs against KRAS. Therefore, for decades, despite enormous efforts invested in the development of drugs aimed at inhibiting KRAS or its signaling pathways, KRAS was considered to be undruggable. Recently, the discovery of a new pocket under the effector binding switch II region of KRAS G12C has allowed the development of direct KRAS inhibitors such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, initiating a new exciting era. However, treatment with targeted KRAS G12C inhibitors also leads to resistance, and understanding the possible mechanisms of resistance and which drugs could be useful to overcome it is key. Among others, KRAS G12C (ON) tricomplex inhibitors and different combination therapy strategies are being analyzed in clinical trials. Another area of interest is the potential role of co-mutations in treatment selection, particularly immunotherapy. The best first-line strategy remains to be determined and, due to the heterogeneity of KRAS, is likely to be based on combination therapies.

Albumin-bound paclitaxel as new treatment for metastatic cholangiocarcinoma: A case report.

BACKGROUND: Cholangiocarcinomas are rare and very aggressive tumors. Most patients have advanced-stage or unresectable disease at presentation, and the systemic therapies have limited efficacy. Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free taxane that has been approved for the treatment of some cancers such as breast, non-small cell lung and pancreatic cancer, however it has not been applied to treat cholangiocarcinoma. We have both preclinical and clinical evidence of the efficacy of nab-paclitaxel in cholangiocarcinoma, yet no phase 3 trials have been made. CASE SUMMARY: A 63-year-old man was diagnosed in December 2016 with stage III B intrahepatic cholangiocarcinoma. Surgery was performed, followed by adjuvant chemotherapy treatment with capecitabine and gemcitabine; although, the gemcitabine was suspended due to allergic reaction after two cycles. In April 2019, metastatic cholangiocarcinoma relapse was diagnosed, and a first-line treatment with FOLFOX scheme was started. Eight cycles were administered, producing an initial clinical improvement and decrease in blood tumor marker levels. Radiological and serological progression was noted in September 2019. As a second-line treatment, FOLFIRI was not recommended due to risk of worsening the patient's tumor-related diarrhea. A combination therapy with gemcitabine was not feasible, as the patient had previously suffered from an allergic reaction to this treatment. We decided to use nab-paclitaxel as a second-line treatment, and four cycles were administered. Both clinical and serological responses were observed, and a radiological mixed response was also noted. CONCLUSION: Advanced cholangiocarcinoma could be treated with nab-paclitaxel monotherapy, which should be studied in combination with other types of treatment (chemotherapy, fibroblast growth factor receptor inhibitors).

Myocarditis and carotidynia caused by Granulocyte-Colony stimulating factor administration.

A 59 year-old woman was treated with adjuvant chemotherapy for triple negative breast cancer (TNBC) stage IB. She received pegfilgrastrim as secondary prophylaxis of neutropenia. After administration of pegfilgrastrim on day 11, she was hospitalised because of carotidynia and myocarditis that improved with antibiotics and steroids as an infection was suspected. Once she was recovered, another cycle of chemotherapy with pegfilgrastrim was administrated. At this time, the patient presented to our hospital with fever, odynophagia and chest pain, with diagnosis of myocarditis coupled with cardiogenic shock. She received antibiotics and steroids, advanced life support and also a pericardial window was done, with recovery of her condition. After a complete evaluation and exclusion of other possible aetiologies, we concluded that pegfilgrastrim was responsible for inducing carotidynia and myocarditis. Few cases have been published about Granulocyte-Colony stimulating factor (G-CSF) induced carotidynia and aortitis. However, this is the first reported case about G-CSF induced myocarditis and carotidynia.

Application of cellulose nanofibers to remove water-based flexographic inks from wastewaters.

Water-based or flexographic inks in paper and plastic industries are more environmentally favourable than organic solvent-based inks. However, their use also creates new challenges because they remain dissolved in water and alter the recycling process. Conventional deinking technologies such as flotation processes do not effectively remove them. Adsorption, coagulation/flocculation, biological and membrane processes are either expensive or have negative health impacts, making the development of alternative methods necessary. Cellulose nanofibers (CNF) are biodegradable, and their structural and mechanical properties are useful for wastewater treatment. TEMPO-oxidised CNF have been evaluated for the decolourisation of wastewaters that contained copper phthalocyanine blue, carbon black and diarlyide yellow pigments. CNF in combination with a cationic polyacrylamide (cPAM) has also been tested. Jar-test methodology was used to evaluate the efficiency of the different treatments and cationic/anionic demand, turbidity and ink concentration in waters were measured. Results show that dual-component system for ink removal has a high potential as an alternative bio-based adsorbent for the removal of water-based inks. In addition, experiments varying CNF and cPAM concentrations were performed to optimise the ink-removal process. Ink concentration reductions of 100%, 87.5% and 83.3% were achieved for copper phthalocyanine blue, carbon black and diarlyide yellow pigments, respectively. Flocculation studies carried out show the decolourisation mechanism during the dual-component treatment of wastewaters containing water-based inks.

Ulipristal Acetate in Myomectomy Optimization in an Infertile Patient with Giant Myomas.

The use of ulipristal acetate (UPA) has been recently introduced in the treatment of uterine leiomyomas. This drug has proven useful to control menometrorrhagia and to reduce myoma size. In the case presented here, we show the benefits of UPA treatment in facilitating surgical removal of giant myomas in an infertile patient. In addition to myoma reduction and a better control of preoperative bleeding, the treatment with UPA reduced the duration and complexity of the surgery, as well as the area of uterine wall involved and the resulting scar. No side effects were observed and the patient became pregnant 6 months after the surgery and had a normal pregnancy and delivery. This case report shows the beneficial effects of UPA in the preoperative treatment of myomas which affect uterus function.

Effect of polyelectrolyte morphology and adsorption on the mechanism of nanocellulose flocculation.

The effect of polyelectrolyte morphology, charge density, molecular weight and concentration on the adsorption and flocculation of Microfibrillated Cellulose (MFC) were investigated. Linear Cationic Polyacrylamide (CPAM) and Branched Polyethylenimine (PEI) of varying charge density and molecular weight were added at different dosages to MFC suspensions. The flocculation mechanisms were quantified by measuring gel point by sedimentation, and floc size, strength and reflocculation ability through Focussed Beam Reflectance Measurements. Polymer adsorption was quantified through zeta potential and adsorption measurements using polyelectrolyte titration. The flocculation mechanism of MFC is shown to be dependent on polyelectrolyte morphology. The high molecular weight branched polymer, HPEI formed rigid bridges between the MFC fibres. HPEI had low coverage and negative zeta potential at the optimum flocculation dosage, forming flocs of high strength. After breaking of flocs, total reflocculation was achieved because the high rigidity of polymer did not allow reconformation or flattening of the polyelectrolyte adsorbed on MFC surface. The lower molecular weight branched polymer, LPEI (2kDa) showed rapid total deflocculation, complete reflocculation and had maximum flocculation occurring at the point of zero charge. These characteristics correspond to a charge neutralisation mechanism. However, if the flocculation mechanism was purely charge neutralisation mechanism, the minimum gel point would be at the point of zero charge. Since this is not the case, this difference was attributed to the high polydispersity of the commercial LPEI used, allowing some bridges to be formed by the largest molecules, changing the minimum gel point. With the linear 80% charged 4MDa CPAM, bridging mechanism dominates since maximum flocculation occurred at the minimum gel point, negative zeta potential and low coverage required for maximum flocculation. Reflocculation was not possible as the long linear polymer reconformed on the MFC surface under a flat conformation. Flocculation with the linear 50% charged 13MDa CPAM happened by bridging with the minimum gel point and maximum flocculation corresponding to roughly half polyelectrolyte surface coverage on cellulose.

Study of the gastrointestinal tolerance of a new tablet formulation of the lopinavir/ritonavir antiretroviral in HIV-infected patients.

BACKGROUND: Preliminary studies suggest that the new film-coated tablet formulation of lopinavir/ritonavir (LPV/r-fct) could cut down the rate of adverse gastrointestinal symptoms of the conventional lopinavir/ritonavir soft gelatine capsules (LPV/r-sgc). OBJECTIVE: To ascertain the difference in the rate of adverse gastrointestinal symptoms in patients who switch from LPV/r-sgc to LPV/r-fct. METHODS: An uncontrolled, open, prospective study including a pre/post comparison using the Gastrointestinal Symptom Rating Scale (GSRS) modified to the characteristics of the protease inhibitors. RESULTS: Seventy patients were included, with a mean time of treatment, with the new formulation of 77 days [confidence interval (CI) 95%: 70 to 84]. The total GSRS score was 26.96 (CI 95%: 25.02 to 28.89) in the prechange survey and 26.27 (CI 95%: 24.08 to 28.47) in the postchange survey, with a mean difference of 0.69 points (CI 95%: -1.18 to 2.55, P = 0.47). None of the questions obtained the objective of a difference of at least 2 points, previously set as a clinically significant difference. Only 1 patient dropped the study due to gastrointestinal toxicity. CONCLUSIONS: Our study has unearthed no clinically significant differences in the gastrointestinal tolerance profile of (LPV/r-sgc) and (LPV/r-fct), measuring this tolerance level by application of the GSRS scale.