On June 28, 2018, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vyxeos, intended for the treatment of acute myeloid leukemia (AML). Vyxeos was designated as an orphan medicinal product on January 11, 2012. The applicant for this medicinal product was Jazz Pharmaceuticals Ireland Limited. Vyxeos is a liposomal formulation of a fixed combination of daunorubicin and cytarabine, antineoplastic agents that inhibit topoisomerase II activity and also cause DNA damage. The strength of Vyxeos is 5 units/mL, where 1 unit equals 1.0 mg cytarabine plus 0.44 mg daunorubicin. The marketing authorization holder Jazz Pharmaceuticals had found that this was an optimal ratio for the efficacy of the product. Study CLTR0310‐301, a phase III, multicenter, randomized, trial of Vyxeos (daunorubicin‐cytarabine) liposome injection versus standard 3+7 daunorubicin and cytarabine in patients aged 60–75 years with untreated high‐risk (secondary) AML, showed a statistically significant difference between the two groups in overall survival (OS) with a median OS of 9.56 months in the daunorubicin‐cytarabine arm compared with 5.95 months for standard chemotherapy (hazard ratio, 0.69; 95% confidence interval, 0.52–0.90; one‐sided p = .003). The most common side effects were hypersensitivity including rash, febrile neutropenia, edema, diarrhea/colitis, mucositis, fatigue, musculoskeletal pain, abdominal pain, decreased appetite, cough, headache, chills, arrhythmia, pyrexia, sleep disorders, and hypotension. Implications for Practice Vyxeos has demonstrated a clinically significant improvement in overall survival compared with the standard of care 7+3 in the proposed population of patients with newly diagnosed acute myeloid leukemia (AML) with myelodysplasia‐related changes and therapy‐related AML. This is remarkable given the very poor prognosis of these patients and their unmet medical need. Secondary endpoints support the primary outcome, in particular an increased rate of hematopoietic stem cell transplantation, which is potentially the only curative treatment in AML.

Human transthyretin (TTR) is a homotetrameric protein involved in several amyloidoses. Zn2؉ enhances TTR aggregation in vitro, and is a component of ex vivo TTR amyloid fibrils. We report the first crystal structure of human TTR in complex with Zn 2؉ at pH 4.6 -7. Human transthyretin (TTR)5 is a 55 kDa, ␤-sheet-rich homotetramer found in serum and cerebrospinal fluid. It participates in thyroxine (T4) transport (1) and in the binding of holo retinol-binding protein (holo-RBP) and is believed to reduce the glomerular filtration of the relatively small (21 kDa) holo-RBP (2). In humans, TTR and its more than 100 variants are involved in amyloid diseases such as senile systemic amyloidosis (SSA) and familial amyloidotic polyneuropathy (FAP), among others (3). In SSA, deposits composed of the wild-type TTR (WT-TTR) are found in the heart. Autopsies show that at least 25% of all individuals over 80 years have such deposits, which prove fatal in 10% of these cases (4). FAP is caused by the accumulation of amyloid fibrils formed by TTR mutants, mainly around basal membranes of Schwann cells, inside the endoneurium of peripheral nerves (5, 6). Onset typically occurs in the third decade, with a life expectancy of ϳ10 years (6). Several drugs are being tested against TTR amyloidosis (3), but so far, the only treatment for FAP is liver transplantation (7).A widely accepted hypothesis for TTR amyloidogenesis presupposes tetramer dissociation into a misfolded monomer which aggregates, giving rise to amyloid fibrils. In vitro these events can be triggered by mild acidification (pH 5.0 -4.0), although amyloid formation takes several days for completion (8). In vivo these events might occur inside lysosomes during TTR turnover (8). Recently, J. W. Kelly and co-workers (9) described an engineered monomer of TTR (M-TTR) in which the introduction of two bulky amino acid residues in the protein-protein interface (F87M/L110M) avoids oligomerization into dimers or tetramers. M-TTR aggregates in solution in the same pH range as WT-TTR, although for M-TTR this occurs on a much faster time scale because tetramer dissociation into monomers is the rate-limiting step in TTR aggregation (9).Monomers (A-D) of TTR are composed of eight anti-parallel ␤-strands (A-H) arranged as a ␤-barrel (Greek key) with a short ␣-helix following strand E. The dimer (AB) is held together by hydrogen bonds involving the H and F strands located along the edge of each monomer. Two dimers (AB, CD) associate backto-back via hydrophobic interactions between residues of loops connecting strands AB and GH (10) (Fig. 1, A and B).Numerous studies with WT and variants of TTR have attempted to unravel the structural rearrangements that precede amyloid formation (10 -13). Only minor global and local changes are observed in most of these structures (10) R. L.).The atomic coordinates and structure factors (codes 3GRG, 3GRB, 3GPS, and 3DGD)

IntroductionThere is growing concern about the aggressiveness of cancer care at the end of life (ACCEoL), defined as overly aggressive treatments that compromise the quality of life at its end. Recognising the most affected patients is a cornerstone to improve oncology care. Our aim is to identify factors associated with ACCEoL for patients with cancer dying in hospitals.MethodsAll adult patients with cancer who died in public hospitals in mainland Portugal (January 2010 to December 2015), identified from the hospital morbidity database. This database provided individual clinical and demographic data. We obtained hospital and region-level variables from a survey and National Statistics. The primary outcome is a composite ACCEoL measure of 16 indicators. We used multilevel random effects logistic regression modelling (p<0·05).ResultsWe included 92 155 patients: median age 73 years; 62% male; 53% with metastatic disease. ACCEoL prevalence was 71% (95% CI 70% to 71%). The most prevalent indicators were >14 days in the hospital (43%, 42–43) and surgery (28%, 28–28) in the last 30 days. Older age (p<0·001), breast cancer (OR 0·83; 95% CI 0·76 to 0·91), and metastatic disease (0·54; 95% CI 0·50 to 0·58) were negatively associated with ACCEoL. In contrast, higher Deyo-Charlson Comorbidity Index (p<0·001), gastrointestinal and haematological malignancies (p<0·001), and death at cancer centre (1·31; 95% CI 1·01 to 1·72) or hospital with medical oncology department (1·29; 95% CI 1·02 to 1·63) were positively associated with ACCEoL. There was no association between hospital palliative care services at the hospital of death and ACCEoL.ConclusionClinical factors related to a better understanding of disease course are associated with ACCEoL reduction. Patients with more comorbidities and gastrointestinal malignancies might represent groups with complex needs, and haematological patients may be at increased risk because of unpredictable prognosis. Improvement of hospital palliative care services could help reduce ACCEoL, particularly in cancer centres and hospitals with medical oncology department, as those services are usually under-resourced, thus reaching few.

Anorectal melanoma is an uncommon cancer with a poor prognosis. We aim to describe the clinical presentation, treatment and outcome of patients with anorectal melanoma in our center. Retrospective study of patients with anorectal melanoma treated between 2000 and 2011 at a cancer center in Lisbon. Ten patients were identified, eight females and two males, with median age 70.5 years (32-79). Symptoms at presentation were rectal bleeding (8), anal pain (4) and discomfort (3). Tumor location was anal (6), rectal (3) and anorectal transition (2). Seven patients had surgery: abdomino-pelvic resection (5) and local resection (2). Among the two patients who underwent local resection, one was an incidental finding in a hemorrhoidectomy specimen. This patient had further adjuvant chemotherapy (dacarbazine). Three patients had distant metastasis at diagnosis, one had chemotherapy and two had best supportive care. Six of the seven operated patients relapsed in a median time of 5.4 months: distant metastasis (4), local recurrence (1), both (1). The two local relapse patients had surgical widening of resection margins (1) and radiotherapy (2). One-year survival was 30 %; 3-year survival was 20 %. Anorectal melanoma has a poor prognosis due to advanced disease at presentation and aggressive course, with relapse in almost all operated patients. Treatment guidelines have not been established due to the lack of randomized studies. However, recent studies show that sphincter-sparing surgical procedures along with low dose intensity radiotherapy seem to achieve a local control similar to abdomino-pelvic resection. No systemic therapy is considered standard of care for advanced disease, and regimens are extrapolated from cutaneous melanoma experience.

Breast cancer (BC) is a heterogeneous disease composed of four main subtypes with distinct clinical and epidemiological features. Although several reports have described the distribution of BC subtypes in Latin America, the majority of them have not included the cellular marker, Ki-67, in the immunohistochemical (IHC) panel. The aim of the present study was to describe the distribution of BC subtypes in a cohort of Latin American women using an IHC panel with Ki-67. A prospective cohort of 580 patients in three centers of Peru (the Hospital Nacional Edgardo Rebagliatti Martins, the Hospital Nacional Guillermo Almenara Irigoyen, the Hospital Nacional Alberto Sabogal, Lima) and one in Uruguay (Instituto Nacional del Cáncer, Montevideo) were evaluated. BC phenotypes were classified according to an IHC panel: Estrogen receptor (ER), progesterone receptor (PgR), HER2 and Ki-67. Silver in situ hybridization was used when the HER2 status, as determined by IHC, was equivocal. The associations between the BC phenotypes and their clinicopathological features were evaluated. ER was positive in 65% of the cases (n=377), and PgR in 50% (n=203). In total, 79.1% (n=459) were HER2-negative, 19.8% (n=115) were HER2-positive and 1% (n=6) had an equivocal status. With respect to Ki-67, 44.7% of the patients exhibited staining in >14% of the tumor cells (n=259). The distribution of subtypes was as follows: Luminal A, 31.9% (n=183); luminal B, 35% (n=201); HER2, 12.1% (n=70); and triple-negative, 20.9% (n=120). When Ki-67 was not included in the panel, the frequency of luminal A was 41.1% and luminal B, 25.8% (9.2% of the cases were misclassified). Ki-67 was most highly expressed in triple-negative and HER2 tumors. Inclusion of Ki-67 in the IHC panel to assign subtypes revealed a higher frequency of luminal B tumors than was reported previously for Latin American women with BC, whereas the distribution of triple-negative and HER2 tumors were similar to that previously reported. In conclusion, these results demonstrated that excluding Ki-67 from the panel of IHC markers may lead to an underestimation of the rates of luminal B tumors.