First-in-Class Selective HDAC6 Inhibitor (ACY-1215) Has a Highly Favorable Safety Profile in Patients with Relapsed and Refractory Lymphoma

Lessons Learned

• Oral selective HDAC6 inhibitors could allow for decreased toxicity compared to pan‐class inhibitors, and increased ease of use.
• ACY‐1215 is well tolerated and led to disease stabilization in 50% of patients treated on a twice‐daily dosing schedule.
• Rational drug combinations with ACY‐1215 improve efficacy in patients with lymphoma.
• Biomarkers such as XBP‐1 level or HDAC6‐score may improve patient selection.

BackgroundACY‐1215, ricolinostat, is an oral, first‐in‐class isoform‐selective HDAC6 inhibitor. HDAC6 is a class IIb deacetylase and plays a critical role in protein homeostasis via the unfolded protein response (UPR). Lymphocytes generate a large repertoire of antibodies and depend on an activated UPR to maintain proteostasis. Lymphomas utilize this biology to evade programmed cell death. In preclinical models of lymphoma, ACY‐1215 disrupted proteostasis, triggering apoptosis.MethodsWe translated these findings into a multi‐institution, open‐label, dose‐escalation phase Ib/II study aimed to determine the safety and efficacy in patients with relapsed and refractory lymphoma.ResultsTwenty‐one patients with heavily pretreated lymphoma were accrued. Patients in the phase Ib portion were enrolled on one of two dose cohorts [Arm A: 160 mg daily (n = 3) or Arm B: 160 mg twice daily (n = 10)]. ACY‐1215 was well tolerated. There were no dose limiting toxicities. Most adverse events were grade 1–2, including diarrhea (57%), nausea (57%), and fatigue (43%). Grade 3–4 toxicities were rare and included anemia (9.5%) and hypercalcemia (9.5%). An additional 8 patients were enrolled on the phase II portion, at 160 mg twice daily. Sixteen patients were evaluable for response. ACY‐1215 did not result in any complete or partial responses in patients treated. Eight patients had stable disease (50%) lasting a median duration of 4.5 months, all of whom were treated twice daily. Disease progressed in eight patients (50%) at cycle 2. Five patients were not evaluable due to disease progression prior to cycle 2. The median PFS was 56 days.ConclusionACY‐1215 is an oral selective HDAC6 inhibitor that was safe in patients with relapsed and refractory lymphoid malignancies and led to disease stabilization in half of the evaluable patients.     

Manual Lymphatic Drainage for Upper Limb Lymphedema: A Clinician’s Perspective for its Adaptation<br/>Adapter le Drainage Lymphatique Manuel pour le Lymphœdème du Membre Supérieur: Point de vue de Cliniciens

Upper limb lympedema is a frequent consequence of breast cancer treatment. The International Society of Lymphology recommends physical therapy for lymphedema management. This treatment includes a combination of manual lymphatic drainage and high-compression bandaging. Actually, the effectiveness of manual lymphatic drainage remains an area of controversy, especially because of the many different techniques called “manual lymphatic drainage” since 1930. The purpose of this review was to emphasise the efficacy of these different techniques according to physiological data and evidence-based practice. To improve the manual lymphatic drainage efficiency, the pressure, sometimes important, should be tailored to each edema and the techniques had to consider altered lymphatic drainage patterns. The methods used by physical therapist in the studies should be specified for higher lightness.

Résumé
Le lymphœdème du membre supérieur est une séquelle du traitement des cancers du sein. Le traitement physique des lymphœdèmes est recommandé par la Société internationale de lymphologie. Il associe drainage lymphatique manuel et bandages de décongestion. Le drainage lymphatique manuel a fait l’objet de critiques quant à son effi- cacité. Or depuis son invention dans les années 1930, de très nombreuses techniques s’intitulent « drainage lymphatique manuel ». Les auteurs distinguent l’efficacité de ces différentes techniques en fonction des données de la physiologie lymphatique et de la démonstration de ses effets basée sur les faits. Pour améliorer son efficacité, le drainage lymphatique manuel doit être appliqué sur l’œdème avec une pression adaptée à la consistance de l’œdème, parfois élevée. Les manœuvres doivent prendre en considération les trajets remaniés des collecteurs lymphatiques. Les études qui l’utilisent doivent décrire la technique utilisée.     

High frequency of K-ras mutations in normal appearing lung tissues and sputum of patients with lung cancer

To evaluate the possible use of mutant ras as a biomarker for lung cancer, we have analyzed “normal appearing” lung tissue, lung tumor, lung metastases and sputum samples from patients with non-small cell lung cancer (NSCLC). As a control, we used lung tissue and sputum samples from patients without oncological diseases or lung disorders. Our analyses were performed with the aid of enriched PCR (EPCR), a method which enables detection of ras mutation even if present at low incidence. EPCR identified K-ras codon 12 mutations in 10% of lung tissues obtained from patients with no lung diseases, whereas the same mutation was detected in 60% of samples of normal appearing lung tissues obtained from patients with NSCLC, 62% of NSCLC tumors and 80% of metastases. Analysis of sputum samples of patients with NSCLC identified 47% to harbor mutant ras allele, whereas 12.5% of controls diagnosed with non-oncological lung diseases carried this mutation. Most of these mutations were detected with the aid of EPCR only, indicating that a minority of cells in a given sample harbor this mutation. The ability to detect K-ras codon 12 mutation in 60% of lung tissue samples and in 47% of sputum samples taken from patients with lung cancer (as compared with 10% and 12.5% of respective controls) points to the potential use of ras mutation as a biomarker for exposure and possible identification of patients who may be at a higher risk of developing lung cancer. © 1995 Wiley-Liss, Inc.     

Modifications in dietary and alcohol intakes between before and after cancer diagnosis: Results from the prospective population‐based NutriNet‐Santé cohort

Postdiagnosis diet and alcohol consumption may be associated with cancer prognosis, recurrence and mortality. Our aim was to investigate food, nutrient and alcohol intake variations between before and after cancer diagnosis and their determinants in a prospective cohort. Subjects (n = 696) were incident cancer cases diagnosed in the NutriNet‐Santé cohort between 2009 and 2016. Food, nutrient and alcohol intakes were prospectively collected using repeated nonconsecutive 24‐hr dietary records since subjects' inclusion (i.e. an average of 2 y before diagnosis). Mean number of dietary records per subject was 5.9 before and 8.1 after diagnosis. All dietary data before and after diagnosis were compared by mixed models. Factors associated with the main dietary changes observed were also investigated using multivariable logistic regressions. We observed a decrease in intakes of vegetables (mean decrease in intake in patients who decreased their intake=‐102.4 ± 79.8 g/d), dairy products (–93.9 ± 82.8 g/d), meat/offal (–35.5 ± 27.8/d), soy products (–85.8 ± 104.1 g/d), sweetened soft drinks (–77.9 ± 95.4 g/d), and alcoholic drinks (–92.9 ± 119.9 g/d), and an increase in broths (42.1 ± 34.9 g/d) and fats/sauces (18.0 ± 13.4 g/d). We observed a decrease in energy intake (–377.2 ± 243.5 kcal/d) and in intakes of alcohol (–7.6 ± 9.4 g/d) proteins (–17.4 ± 12.5 g/d), and several vitamins (p < 0.05) and micronutrients (p < 0.05). Conversely, lipid (19.4 ± 14.6 g/d), SFA (9.3 ± 7.0 g/d), MUFA (8.3 ± 6.3 g/d) and vitamin E (3.9 ± 3.3 mg/d) intakes increased after diagnosis. This large prospective study suggests that cancer diagnosis is a key period for nutritional changes. It highlights some healthy behaviors such as a decrease in alcohol and sweetened drink consumption, but also less favorable trends, such as a decrease in vegetable consumption and in many vitamin and mineral intakes. These results provide insights to identify and target recommendations to put forward for better nutritional care of cancer survivors.     

Dynorphin-(1–13).

Dynorphin-(1–13) (Dyn-(1–13)) and its analogs substituted by single introduction of Ala in positions 1–11 were synthesized by the solid-phase method and purified by high pressure liquid chromatography. Relative potencies of the synthetic compounds were determined by their ability to inhibit electrically-evoked contractions of the guinea pig ileum (GPI) and of the mouse vas deferens (MVD) and to compete with [³H]-etorphine for opiate receptors in rat brain homogenates. Introduction of Ala in positions 1 and 4 of Dyn-(1–13) provoked most important decreases in the activity of the molecule in the three assays (relative potency of 0.2% or less). Substitution of Ala in positions 2 or 5, but not 3, also severely decreased the potency of the peptide in the smooth muscle preparations (0.6–5.0% activity). However, the opiate receptor binding assay was less sensitive to the replacement of residue in position 2 (20% activity) than that in positions 3 or 5 (12% and 6% relative potencies, respectively). In the GPI assay and the opiate binding test, the other substitutions which greatly lowered the potency of the molecule were seen in positions 6, 7, 9 and 11, four basic residues. Among these, Arg⁶ and Arg⁷ were demonstrated to be the most important in the three biological tests. Finally, the replacement of Ile⁸ by Ala increased the relative potency of Dyn-(1–13) up to 191% and 900% in the MVD and the opiate binding tests, respectively.     

Heteronemin, a spongean sesterterpene, inhibits TNFα-induced NF-κB activation through proteasome inhibition and induces apoptotic cell death

In this study, we investigated the biological effects of heteronemin, a marine sesterterpene isolated from the sponge Hyrtios sp. on chronic myelogenous leukemia cells. To gain further insight into the molecular mechanisms triggered by this compound, we initially performed DNA microarray profiling and determined which genes respond to heteronemin stimulation in TNFα-treated cells and which genes display an interaction effect between heteronemin and TNFα. Within the differentially regulated genes, we found that heteronemin was affecting cellular processes including cell cycle, apoptosis, mitogen-activated protein kinases (MAPKs) pathway and the nuclear factor κB (NF-κB) signaling cascade.We confirmed in silico experiments regarding NF-κB inhibition by reporter gene analysis, electrophoretic mobility shift analysis and I-κB degradation. In order to assess the underlying molecular mechanisms, we determined that heteronemin inhibits both trypsin and chymotrypsin-like proteasome activity at an IC₅₀ of 0.4 μM. Concomitant to the inhibition of the NF-κB pathway, we also observed a reduction in cellular viability. Heteronemin induces apoptosis as shown by annexin V-FITC/propidium iodide-staining, nuclear morphology analysis, pro-caspase-3, -8 and -9 and poly(ADP-ribose) polymerase (PARP) cleavage as well as truncation of Bid. Altogether, results show that this compound has potential as anti-inflammatory and anti-cancer agent.     

Iodine deficiency mitigates growth retardation and osteopenia in selenium-deficient rats

Selenium deficiency is associated with impaired bone metabolism and osteopenia in rats. However, it is not known how combined selenium and iodine deficiency affects bone metabolism. Therefore, we investigated the effect of selenium and iodine deficiency on bone metabolism in 2nd-generation selenium- and iodine-deficient rats. Selenium-deficient (Se-), iodine-deficient (I-), selenium- and iodine-deficient (Se-/I-), and control rats (Se+/I+), were pair-fed their respective diets until they were 74 d old. Each pair-fed rat was fed a selenium-adequate diet in the same amount as that consumed the day before by its selenium-deficient counterpart, taking food spillage into account. The skeletal phenotype was analyzed by dual energy X-ray absorptiometry, histomorphometry, and bone metabolism markers. Erythrocyte glutathione peroxidase activity (Gpx) and plasma thyroid hormones were measured to assess selenium and iodine status, respectively. In both Se-/I+ and Se-/I- rats, Gpx was reduced by 99% compared with pair-fed Se+/I+ and Se+/I- rats (P < 0.001). Iodine deficiency reduced plasma thyroxine by 64% in the 2 iodine-deficient groups (P < 0.001). Body weight, tail length, plasma insulin-like growth factor, pituitary growth hormone concentration, and femur and tibia bone mineral density were significantly greater in the Se-/I- rats than in the Se-/I+ rats. This study shows that iodine deficiency mitigated growth retardation and osteopenia in 2nd-generation selenium-deficient rats and suggests that adequate selenium status should be ensured before measures are taken to correct iodine deficiency.