IMbrave150: Efficacy and Safety of Atezolizumab plus Bevacizumab versus Sorafenib in Patients with Barcelona Clinic Liver Cancer Stage B Unresectable Hepatocellular Carcinoma: An Exploratory Analysis of the Phase III Study.

Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis reports efficacy and safety results in patients with baseline Barcelona Clinic Liver Cancer (BCLC) stage B disease. Methods: Patients with systemic treatment-naive unresectable HCC and Child-Pugh class A liver function were randomized 2:1 to receive 1,200 mg of atezolizumab plus 15 mg/kg of bevacizumab or 400 mg of sorafenib. Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 in the BCLC stage B subgroup. Patients in this analysis had BCLC stage B disease at baseline per electronic case report form. Secondary efficacy endpoints included the objective response rate (ORR) and change in the sum of longest diameters (SLD) of target lesions from baseline per IRF RECIST 1.1 and modified RECIST (mRECIST) for HCC. Results: Of 501 enrolled patients, 74 (15%) had BCLC stage B disease at baseline (atezolizumab + bevacizumab, n = 49; sorafenib, n = 24). For this group, median follow-up was 19.7 months. A trend toward improved OS and PFS per IRF RECIST 1.1 was observed with atezolizumab + bevacizumab versus sorafenib (OS: hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.29, 1.34; PFS: HR: 0.64; 95% CI: 0.36, 1.12). ORRs per IRF RECIST 1.1 and HCC mRECIST were 43% and 50% with atezolizumab + bevacizumab and 26% and 30% with sorafenib, respectively. Percentage change in SLD of target lesions from baseline per IRF RECIST 1.1 and HCC mRECIST showed durable responses with atezolizumab + bevacizumab treatment. Safety data were consistent with known profiles of atezolizumab and bevacizumab, as seen in the overall study population. Discussion/Conclusion: Efficacy benefits were observed with atezolizumab + bevacizumab in patients with baseline BCLC stage B disease, consistent with the intention-to-treat population.

Synthesis and Properties of Aromatic-Terminated Diacetylene Organogelators and Their Application to Photopatterning of Polydiacetylenes.

A series of simply structured diacetylene-diamide-based gelators (DAGs) with aromatic terminals were synthesized, and their gelation and subsequent photopolymerization abilities were analyzed. DAGs with an adequate spacer length (n) and tolyl terminals (DA-Tn) interacted with aromatic solvents, such as benzene and xylenes, at elevated temperatures. During the subsequent cooling process, the DAGs interacted with each other through CH-π interactions at their terminal positions. They also formed one-dimensional hydrogen bonding arrays through secondary amides, leading to stable organogels. These gels polymerized into π-conjugated polydiacetylenes (PDAs) under ultraviolet irradiation. In the p-xylene gels of DA-Tn, the spacer length exerted characteristic odd-even effects on the photopolymerization rates over a certain range (n = 3-6), which can be explained by periodic changes in the uniformity of the molecular packing modes. When the gelling solvent was changed to cyclohexane, the gelation and photopolymerization abilities were greatly improved because the DA-Tn gel networks became highly crystallized and transparent to ultraviolet light (254 nm). The ultimate conversion to PDA from DA-T8/cyclohexane gels was 45.2 wt %. Applying photolithographic techniques to the DAG with excellent photopolymerizability in the film state, we successfully fabricated microscale photopatterns of PDA. We also established a convenient removal process (development process) of DA monomers in unexposed areas. The resulting PDA patterns were quite stable to ambient light stimuli.

A Series of Bisamide-Substituted Diacetylenes Exhibiting a Terminal Alkyl Odd/Even Parity Effect on Mechanoactivated Photopolymerization.

Diacetylene derivatives exhibit solid-state polymerization to polydiacetylene initiated by UV light or γ-ray irradiation. The activation of the photopolymerization relies on the monomer diynes arrangement. Recently, it has been demonstrated that the first mechanoresponsive bisamide substituted diacetylenes (DAs) show dramatic switching from light-inert to light-reactive states at a given pressure. The origin of this unique phenomenon was apparently related to the pressure-sensitive crystalline transition in DAs, but the molecular mechanism remains elusive. To obtain more insight, herein a series of DAs with varying terminal alkyl spacer length is presented, and their molecular structural effect on the intermolecular hydrogen bonding and steric repulsion is examined. In pristine states, even-parity DAs were inactive upon UV irradiation (λ=254 nm) unless external pressure was applied. By contrast, odd-parity DAs were easily polymerized upon UV irradiation without pressure application. However, the pressure-induced crystalline phase transition exhibiting photopolymerization was valid for all DAs regardless of their alkyl spacer length. A systematic investigation revealed that the terminal alkyl spacer length, especially its odd/even parity plays a key role in determining the intrinsic intermolecular hydrogen-bonding nature of DA crystals and the resultant molecular packing. In addition, the relevant thermochromic behavior was also observed from photopolymerized polydiacetylenes.

Pressure-Induced Transition of Bisamide-Substituted Diacetylene Crystals from Nonphotopolymerizable to Photopolymerizable State.

Mechanoresponsive diacetylenes (DAs) exhibiting a transition of crystalline orientation from light-inert to light-active state upon applied force are reported. Amide units are introduced to DAs where hydrogen bonding is utilized to control intermolecular interactions. Application of external pressure (2-150 MPa) to DAs results in an emergence of new crystal phases with changing the d-spacing which possibly reduces the reaction barrier. Accordingly, the dramatic crystalline transition from "perfectly off" to "on" state to undergo the light-induced topochemical polymerization of bulk DA crystals is obtained. Subsequent UV irradiation at a wavelength of 254 nm enables the polymerization of the pressed region, changing its color from white to blue which suggests the selective formation of polydiacetylene (PDA) polymorphs. In addition, by utilizing the mechanoresponsive crystallinity with low-enough activation pressure, a new strategy for PDA patterning is demonstrated based on the selective transfer of information by means of force to a DA film. This phenomenon can be applicable to a new nanoimprinting technique where no mechanical deformation of resist materials but phase transition is induced by the mold.

Epstein-Barr virus-positive diffuse large B-cell lymphoma following acute myeloid leukemia: a common clonal origin indicated by chromosomal translocation t(3;4)(p25;q21).

Secondary non-Hodgkin lymphoma following acute myeloid leukemia (AML) is extremely rare. We here describe a unique case involving a patient who developed Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) during complete remission (CR) of AML. A 75-year-old Japanese man was initially diagnosed with AML with maturation (FAB M2), bearing chromosomal translocation t(3,4)(p25;q21). After intensive chemotherapy, bone marrow aspiration revealed normal karyotype, and he achieved CR. Six years and 4 months later, he was still in CR from AML, but developed DLBCL presenting in the terminal ileum. Cytogenetic analysis of the DLBCL cells showed the same translocation as the previous AML. The rearrangements of the immunoglobulin heavy chain genes of the two malignancies were examined using polymerase chain reaction amplification, and the rearrangement patterns were found to differ from each other. Our data thus suggest that, in the present case, the AML and DLBCL arose from a common progenitor cell, as indicated by the clonal abnormality t(3,4)(p25;q21), and that different immunoglobulin heavy chain gene rearrangements occurred during each course of clonal evolution.

Non-Hodgkin's lymphoma of the vaginal wall in a hemodialysis patient with hepatocellular carcinoma.

A 66 year old woman with end-stage renal disease and liver cirrhosis due to chronic hepatitis C virus infection was introduced to hemodialysis therapy in 2003. In 2007, hepatocellular carcinoma was identified and the patient underwent radio frequency ablation (RFA) and ethanol injection therapy (EIT) under laparotomy. A large vaginal tumor was incidentally found at gynecological examination. Histological diagnosis was diffuse large B-cell lymphoma (Stage IE). During the first course of chemotherapy, the vaginal tumor began to prolapse from the vaginal wall due to an excellent response to the chemotherapy and finally was resected. The patient received another course of chemotherapy followed by radiotherapy. The vaginal tumor was undetectable in the follow-up imaging studies. Although patients with end-stage renal disease are at increased risk for several cancers, the occurrence of malignant lymphoma following hepatocellular carcinoma is rare. Furthermore, lymphomas arising from the female genital tract are very uncommon.

Crystallization and preliminary X-ray crystallographic study of phosphoglucose isomerase from Plasmodium falciparum.

Phosphoglucose isomerase (PGI) is a key enzyme in glycolysis and glycogenesis that catalyses the interconversion of glucose 6-phosphate (G6P) and fructose 6-phosphate (F6P). For crystallographic studies, PGI from the human malaria parasite Plasmodium falciparum (PfPGI) was overproduced in Escherichia coli, purified and crystallized using the hanging-drop vapour-diffusion method. X-ray diffraction data to 1.5 A resolution were collected from an orthorhombic crystal form belonging to space group P2(1)2(1)2(1) with unit-cell parameters a = 103.3, b = 104.1, c = 114.6 A. Structural analysis by molecular replacement is in progress.

Solid phase adsorption of crystal violet lactone on silica nanoparticles to probe mechanochemical surface modification.

The solid phase adsorption of crystal violet lactone (CVL) on five types of Stober silica nanopowders with BET specific surface areas in the range of 50-800 m2/g under dry milling conditions was described for the first time. The hydrogen bonding between surface silanol and the carboxylate of the ring-opened triphenylmethane dye (CVL+) led to the formation of monolayers of CVL+ in a flat-laid configuration. The lambda max of CVL+ in diffusive reflection visible spectra was influenced by the particle size of silica powders, suggesting that the microenvironmental polarity of adsorbed CVL+ is considerably reduced along with the decrease of the particle size. The solid phase adsorption of CVL obeyed Langmuir adsorption isotherms to give a saturated amount of CVL+ for every silica nanoparticle. The surface concentration of CVL+ on nanoparticles at the saturation was estimated to be 0.31 mg/m2 on average, disclosing that about 52% of the surface can be covered by CVL+ under the assumption that the BET-specific surface areas are equivalent to the real surfaces active for the CVL adsorption. The generation of the blue color of CVL provided a convenient means to estimate qualitative and quantitative analysis of the surface coverage with surface-active reagents, which conceal surface silanols. Subsequently, silica nanoparticles were milled with a surface modifier, followed by milling with CVL to observe the intensity of the blue color in order to disclose that the surface coverage with oligo- and polyethylene glycols as well as with nonionic surfactants by dry milling was specifically determined by the number of repeating oxyethylene units. Although the surface-active reagents were easily desorbed in water, the desorption was notably suppressed by milling with CVL, suggesting that the surface-modified particles with the surface-active reagents are covered with ultrathin films of CVL.

Molecular basis for peroxisomal localization of tetrameric carbonyl reductase.

Pig heart peroxisomal carbonyl reductase (PerCR) belongs to the short-chain dehydrogenase/reductase family, and its sequence comprises a C-terminal SRL tripeptide, which is a variant of the type 1 peroxisomal targeting signal (PTS1) Ser-Lys-Leu. PerCR is imported into peroxisomes of HeLa cells when the cells are transfected with vectors expressing the enzyme. However, PerCR does not show specific targeting when introduced into the cells with a protein transfection reagent. To understand the structural basis for peroxisomal localization of PerCR, we determined the crystal structure of PerCR. Our data revealed that the C-terminal PTS1 of each subunit of PerCR was involved in intersubunit interactions and was buried in the interior of the tetrameric molecule. These findings indicate that the PTS1 receptor Pex5p in the cytosol recognizes the monomeric form of PerCR whose C-terminal PTS1 is exposed, and that this PerCR is targeted into the peroxisome, thereby forming a tetramer.

Repeated relapses of acute myelogenous leukemia in the isolated extramedullary sites following allogeneic bone marrow transplantations.

Isolated extramedullary (EM) relapses of acute myelogenous leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) have been reported to be rare, and are usually followed by bone marrow relapses. We report a 49-year-old man with AML with the unfavorable chromosome abnormality 7q-, who was treated by allo-HSCT. Fifteen months after allo-HSCT, the patient initially developed a relapse only in his inguinal lymph nodes, and then bone marrow relapse became evident one month after the EM relapse. Subsequently, the patient received chemotherapy and a second allo-HSCT from another donor, but he suffered another relapse in different EM sites including the skin and central nervous system with a persistently normal marrow. This case is characterized by repeated relapses in isolated EM sites after allo-HSCT and suggests that the anti-leukemic effects of chemotherapy and/or graft-versus-leukemia effects in the EM sites might not be so uniformly effective as that in the marrow. Accordingly, we should be aware that AML relapses can occur repeatedly only in isolated EM sites post allo-HSCT, resulting in treatment failure and a poor prognosis.

Crystallization and preliminary X-ray crystallographic studies of pig heart carbonyl reductase.

Pig heart carbonyl reductase (PHCR), which belongs to the short-chain dehydrogenase/reductase (SDR) family, has been crystallized by the hanging-drop vapour-diffusion method. Two crystal forms (I and II) have been obtained in the presence of NADPH. Form I crystals belong to the tetragonal space group P4(2), with unit-cell parameters a = b = 109.61, c = 94.31 A, and diffract to 1.5 A resolution. Form II crystals belong to the tetragonal space group P4(1)2(1)2, with unit-cell parameters a = b = 120.10, c = 147.00 A, and diffract to 2.2 A resolution. Both crystal forms are suitable for X-ray structure analysis at high resolution.

Novel odd/even effect of alkylene chain length on the photopolymerizability of organogelators.

[reaction: see text] Starting from diactylene diacarboxylic acids, we have synthesized a series of photopolymerizable organogelators that possess simple amide structures, different alkylene chain lengths, and either optically active or racemic 3,7-dimethyl-1-octylamine units. The alkylene chain length of these compounds exhibits a prominent odd/even effect with respect to the photopolymerization in the gel state and is accompanied by a stereostructural effect on the gelation ability.

[Brugada syndrome occurring after autologous peripheral blood stem cell transplantation for acute myeloid leukemia].

A 74-year-old male was found to be suffering from the Brugada syndrome after undergoing high dose chemotherapy followed by autologous peripheral blood stem cell transplantation (ABSCT) for acute myeloid leukemia. A specific ECG pattern of right bundle-branch block and a coved-type ST-segment elevation in leads V1 through V3, which is compatible with the Brugada syndrome, was unmasked by febrile neutropenia on the 8th day after ABSCT. He experienced syncope on the 11th day due to ventricular tachycardia, which was immediately improved with the administration of intravenous lidocaine. The Brugada syndorome should be considered in febrile patients if they have a episode of syncope or ECG change.

Successful treatment of diffuse large B-cell lymphoma following Waldenström's macroglobulinemia with CHOP chemotherapy followed by combination therapy of CHOP with rituximab.

We report a 72-year-old man with Waldenström's macroglobulinemia (WM) in whom diffuse large B-cell lymphoma (DLCL) occurred 17 years after the diagnosis of WM. The malignant cells of both DLCL and WM expressed CD20 on their surface. CHOP plus anti-CD20 monoclonal antibody, rituximab, were effective for both diseases, and the patient remains disease-free 17 months later.

Genome and virulence determinants of high virulence community-acquired MRSA.

BACKGROUND: A new type of meticillin-resistant Staphylococcus aureus (MRSA), designated community-acquired MRSA, is becoming increasingly noticeable in the community, some strains of which cause fatal infections in otherwise healthy individuals. By contrast with hospital-acquired MRSA, community-acquired MRSA is more susceptible to non b-lactam antibiotics. We investigated the high virulence potential of certain strains of this bacterium. METHODS: We ascertained the whole genome sequence of MW2, a strain of community-acquired MRSA, by shotgun cloning and sequencing. MW2 caused fatal septicaemia and septic arthritis in a 16-month-old girl in North Dakota, USA, in 1998. The genome of this strain was compared with those of hospital-acquired MRSA strains, including N315 and Mu50. FINDINGS: Meticillin resistance gene (mecA) in MW2 was carried by a novel allelic form (type IVa) of staphylococcal cassette chromosome mec (SCCmec), by contrast with type II in N315 and Mu50. Type IVa SCCmec did not carry any of the multiple antibiotic resistance genes reported in type II SCCmec. By contrast, 19 additional virulence genes were recorded in the MW2 genome. All but two of these virulence genes were noted in four of the seven genomic islands of MW2. INTERPRETATION: MW2 carried a range of virulence and resistance genes that was distinct from those displayed on the chromosomes of extant S aureus strains. Most genes were carried by specific allelic forms of genomic islands in the MW2 chromosome. The combination of allelic forms of genomic islands is the genetic basis that determines the pathogenicity of medically important phenotypes of S aureus, including those of community-acquired MRSA strains.