Margetuximab with retifanlimab as first-line therapy in HER2+/PD-L1+ unresectable or metastatic gastroesophageal adenocarcinoma: MAHOGANY cohort A.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA. PATIENTS AND METHODS: MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR). RESULTS: As of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA. CONCLUSIONS: The chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches.

Changes in the flexor pollicis longus tendon during spontaneous resolution of pediatric trigger thumb.

The present study aimed to evaluate conformational changes in the flexor pollicis longus (FPL) tendon and inner space of the A1 pulley during spontaneous resolution of pediatric trigger thumb (PTT) and to compare them versus the normal contralateral side. We enrolled 36 patients with unilateral PTT who underwent ultrasonography twice between January 2016 and July 2020 and showed >10° improvement in thumb interphalangeal (IP) joint extension lag. Ultrasonography was used to measure the anteroposterior (AP) and radioulnar (RU) diameters of the FPL tendon proximal to the A1 pulley and of the inner space of the A1 pulley. On the side of the PTT, the average extension lag in the thumb IP joint significantly improved, from 35.6° to 14.2°. The AP and RU diameters of the FPL tendon increased by 0.3% and 1.9%, respectively, and those of the inner space of the A1 pulley increased by 15.3% and 5.0%, respectively. In the contralateral normal thumb, the AP and RU diameters of the FPL tendon increased by 12% and 9.3%, respectively, and those in the inner space of the A1 pulley increased by 9.9% and 4.6%. During improvement in IP joint extension lag, the mismatch between the enlarged FPL tendon and the inner space of the A1 pulley was reduced by their asymmetric growth.

A longitudinal histologic evaluation of vitamin D receptor expression in the skeletal muscles of patients with a distal radius fracture.

We investigated the effect of vitamin D supplementation on the expression of muscle vitamin D receptor (VDR) and cross-sectional area (CSA) in patients with a distal radius fracture (DRF). Significant increases in VDR expression and CSA were observed, especially in vitamin D-deficient patients. PURPOSE: Vitamin D supplementation is known to enhance muscle mass and function, but whether the VDR is essential in this process remains unknown. We evaluated the change in VDR expression and CSA in the forearm muscles following vitamin D supplementation in patients with a DRF. METHODS: We prospectively recruited 18 women with a median age of 63.5 years who have a DRF. We obtained two biopsies of the forearm muscle, first at the time of fracture repair and then during hardware removal. We supplemented 1000 IU of vitamin D per day during a median interval of 8 months. We examined the changes in VDR expression and CSA by immunohistochemistry. RESULTS: The median serum 25-hydroxyvitamin D [25(OH)D] increased from 14.3 to 32.1 ng/mL (P = 0.001). The median VDR expression increased from 0.72 to 0.78 (P = 0.002), and the median CSA increased from 1290.0 to 1685.8 µm2 (P = 0.022). Significant increases in VDR expression and CSA were observed in vitamin D-deficient patients [25(OH)D] < 20 ng/mL, but not in vitamin D-non-deficient patients. The changes in VDR expression and CSA were in the same direction in 13 patients, but in the opposite direction in 5 patients. CONCLUSION: Vitamin D supplementation may increase muscle VDR expression and CSA in patients with a DRF, especially in vitamin D-deficient patients. The increase in CSA without an increase in VDR expression in some patients indicates that the effect of vitamin D supplementation on muscle mass could be mediated by indirect effect of serum vitamin D restoration and by VDR.

Two-dimensional analysis of head-shaking nystagmus in patients with Meniere's disease.

The HSN test is a simple examination that can be easily performed by clinicians, however only a few studies have analyzed the 2-dimensional characteristics of HSN in patients with MD. The objective of the study was to characterize different types of 2-dimensional head-shaking nystagmus (HSN) in patients with Meniere's disease (MD). Sixty-five patients with definite MD were enrolled. HSN was considered pathologic, if slow-phase velocity (SPV) was ≥ 4°/s and was classified as paretic or recovery according to the direction, and as monophasic or biphasic according to the presence of direction change. HSN was categorized as pure horizontal, mixed or pure vertical. When vertical SPV was larger than horizontal SPV, HSN was categorized as perverted. Forty-four patients (68%) had pathologic HSN and 28 patients (43%) had pathologic canal paresis. Monophasic-paretic HSN was the most common and followed by biphasic-paretic HSN, monophasic-recovery HSN and biphasic-recovery HSN. Delayed-peak monophasic-paretic HSN, which was not observed in vestibular neuritis, was found in 6 patients with MD. Thirty-three patients (51%) had a vertical component, which was monophasic and downbeat in 32 (97%). Every pathologic HSN in horizontal plane had higher SPV in horizontal plane than that of vertical plane. Perverted HSN was found in 4 patients, of whom 3 had pure vertical and one had mixed type HSN. Our data showed that HSN is a sensitive detector of vestibular dysfunction. HSN showed diverse types with a new type of delayed-peak HSN. Vertical components of HSN were observed in about half, but they were negligible compared to horizontal components. Weak perverted HSN (vertical SPV ≤ 4°/s) could be found in patients with MD.

Conduction Properties Of Decellularized Nerve Biomaterials.

The purpose of this study is to optimize poly(3,4,-ethylenedioxythiophene) (PEDOT) polymerization into decellular nerve scaffolding for interfacing to peripheral nerves. Our ultimate aim is to permanently implant highly conductive peripheral nerve interfaces between amputee, stump, nerve fascicles and prosthetic electronics. Decellular nerve (DN) scaffolds are an FDA approved biomaterial (Axogen ) with the flexible tensile properties needed for successful permanent coaptation to peripheral nerves. Biocompatible, electroconductive, PEDOT facilitates electrical conduction through PEDOT coated acellular muscle. New electrochemical methods were used to polymerize various PEDOT concentrations into DN scaffolds without the need for a final dehydration step. DN scaffolds were then tested for electrical impedance and charge density. PEDOT coated DN scaffold materials were also implanted as 15-20mm peripheral nerve grafts. Measurement of in-situ nerve conduction immediately followed grafting. DN showed significant improvements in impedance for dehydrated and hydrated, DN, polymerized with moderate and low PEDOT concentrations when they were compared with DN alone (a ≤ 0.05). These measurements were equivalent to those for DN with maximal PEDOT concentrations. In-situ, nerve conduction measurements demonstrated that DN alone is a poor electro-conductor while the addition of PEDOT allows DN scaffold grafts to compare favorably with the "gold standard", autograft (Table 1). Surgical handling characteristics for conductive hydrated PEDOT DN scaffolds were rated 3 (pliable) while the dehydrated models were rated 1 (very stiff) when compared with autograft ratings of 4 (normal). Low concentrations of PEDOT on DN scaffolds provided significant increases in electro active properties which were comparable to the densest PEDOT coatings. DN pliability was closely maintained by continued hydration during PEDOT electrochemical polymerization without compromising electroconductivity.

A multicenter phase II study of belotecan, new camptothecin analogue, in patients with previously untreated extensive stage disease small cell lung cancer.

Belotecan (Camtobell, CKD602) is a new camptothecin derivative antitumor agent that belongs to the topoisomerase inhibitors. The aim of this phase II study was to evaluate the efficacy and safety of single agent belotecan in patients with small cell lung cancer (SCLC). Patients with previously untreated extensive stage disease (ED) SCLC were entered into the study. Belotecan was given by daily intravenous infusion at 0.5mg/m(2)/day for 5 consecutive days, every 3 weeks. 62 patients were enrolled in this study. The overall response rate to chemotherapy on an intention-to-treat basis was 53.2%. The median overall survival was 10.4 months, the median time to progression 4.6 months, and the 1-year survival rate 49.9%. The most common toxicity was hematologic. Grade 3/4 neutropenia occurred in 71.0% of patients and grade 3/4 thrombocytopenia 12.9%. Non-hematologic toxicity of grade 3 or 4 was low. The results suggest that belotecan is relatively active and well tolerable as single agent in patients with ED SCLC. Further investigations with platinum or other active agents are needed.

Enhanced harmonic generation from expanding clusters.

We report controlled enhancement of optical third harmonic generation (THG) from hydrodynamically expanding clusters of approximately 6x10(5) noble-gas atoms several hundred femtoseconds following ionization and heating by ultrashort pump pulses. This resonant enhancement is more pronounced for orthogonal than for parallel pump-probe polarizations, a consequence of faster cluster expansion along the pump polarization. Simulations show that the nonlinear susceptibility chi(3) of the individual clusters and the coherence length of the clustered plasma medium are optimized nearly simultaneously as the clusters expand, and both contribute to the observed THG enhancement. This dual enhancement mechanism may be scalable to relativistic probe intensity and to generation of high-order harmonics in the soft-x-ray regime.

Botulinum toxin A for the management of vulvodynia.

Clinically, botulinum toxin A blocks the cholinergic innervation of the target tissue. Recently, it has been proved effective not only at a neuromuscular junction but also within parasympathetic or sympathetic neural synapses. Seven women with pain on genitalia that could not be controlled with conventional pain managements were enrolled in this study. Twenty to 40 U of botulinum toxin A were used in each injection. Injection sites were the vestibule, levator ani muscle or the perineal body. Repeat injections were administered every 2 weeks if the patient's symptoms had not fully subsided. In all patients, pain had disappeared with botulinum toxin A injections. Five patients needed to be injected twice; the other two patients needed only one injection. We did not observe complications related to botulinum toxin A injections, such as pain, hemorrhage, infection, muscle paralysis or other complications. The subjective pain score improved from 8.3 to 1.4, and no one has experienced a recurrence (the follow-up period was four to 24 months, with a mean follow-up of 11.6 months). Botulinum toxin A is effective in blocking nociception. Even though further investigation and well-controlled study will be necessary, we suggest that the botulinum toxin therapy would be useful and safe in managing vulvodynia of muscular or neuroinflammatory origins.

Mechanical and heat sensitization of cutaneous nociceptors in rats with experimental peripheral neuropathy.

This study examined whether or not the properties of cutaneous nociceptive fibers are altered in the neuropathic state by comparing lumbars 5 and 6 spinal nerve ligation (SNL) rats with sham-operated controls. The rats with the unilateral SNL developed mechanical allodynia in the ipsilateral hind limb, whereas the sham group did not. Two to 5 weeks after the neuropathic or sham surgery, rats were subjected to single fiber-recording experiments to examine the properties of afferent fibers in the sural and plantar nerves. A total of 224 afferents in the C- and Adelta-ranges were characterized in the neuropathic and sham groups. Spontaneous activity was observed in 16 of 155 fibers in the neuropathic group and one of 69 fibers in the sham group. The response threshold of both the C- and Adelta-fibers to mechanical stimuli was lower in the neuropathic group than the sham group. The afferent fibers responsive to heat stimuli were all C-fibers, and none were Adelta-fibers. The response threshold of the C-fibers to the heat stimuli was lower in the neuropathic group than the sham group. The magnitude of the responses of both C- and Adelta-fibers to the suprathreshold intensity of the mechanical stimulus was greater in the neuropathic group than the sham group. However, the magnitude of the responses of C-fibers to the suprathreshold intensity of the heat stimulus in the neuropathic group was not different from that in the sham group. These results suggest that after a partial peripheral nerve injury, the nociceptors on the skin supplied by an uninjured nerve become sensitized to both mechanical and heat stimuli. This nociceptor sensitization can contribute to neuropathic pain.

Effects of estrogen on nitric oxide synthase and histological composition in the rabbit clitoris and vagina.

We investigated the functional and histological changes after oophorectomy in the rabbit clitoris and vagina to determine the mechanism responsible for the development of arousal disorder in postmenopausal women. Twenty mature female New Zealand white rabbits were randomly divided into three groups: control; oophorectomy; and estrogen replacement after oophorectomy. We compared the nitric oxide synthase (NOS) activity and the degree of expression of neuronal (nNOS) and endothelial NOS (eNOS) using biochemical and Western blot analysis in clitoral and vaginal tissues. Histological change of smooth muscle and collagen contents in those tissues were also compared using Masson's trichrome staining. NOS activity and the expression of nNOS and eNOS were significantly increased in the oophorectomized group while there was a decrease to the level of the control group in the estrogen replacement group. Histological examination showed that oophorectomy induced a significant increase in collagen and decrease in muscle content in both clitoris and vagina, while the ratio of smooth muscle content was increased significantly after the estrogen replacement. Our results clearly demonstrate that estrogen deficiency induces compensatory NOS production which may be related to decreases in muscle to collagen ratio in female rabbit genital organs.

Intramedullary tuberculosis manifested as Brown-Sequard syndrome in a patient with systemic lupus erythematosus.

A 25-year-old girl presented with progressive deterioration of right side weakness with decreased sensation on the left trunk. She had been treated with high dose steroid due to autoimmune thrombocytopenia for 2 months. Clinical, laboratory and immunologic studies revealed that she had systemic lupus erythematosus (SLE), MRI of spinal cord showed marginal contrast enhancing and fluid containing mass in the cord of the C5-6 level, suggesting intramedullary abscess. She underwent surgery of mass removal with biopsy. The pathologic findings from cord tissues revealed numerous acid fast bacilli (AFB) in necrotic tissues. After surgery and anti-tuberculous treatment, her neurologic symptoms were markedly improved with restoration of right side motor weakness. To our knowledge, this is the first case report of intramedullary tuberculosis in a patient with SLE. Since intramedullary tuberculosis may sometimes mimic neurologic complication of SLE itself, it may pose diagnostic and therapeutic confusion for clinicians. We report a case of spinal cord tuberculosis affecting C5, 6 level which was manifested as Brown-Sequard syndrome in a patient with SLE.

Hemodynamic insult by vascular risk factors and pharmacologic erection in men with erectile dysfunction: Doppler sonography study.

To evaluate the penodynamic impact of known vascular risk factors in men with erectile dysfunction, we obtained thorough medical histories covering diabetes, hypertension, heart disease and hypercholesterolemia, alcohol ingestion, and smoking in 265 consecutive patients. We also measured their penile hemodynamic parameters by color duplex ultrasonography after intracavernous prostaglandin E1 injection. In patients with vascular risk factors there was a statistically significant decrease in the peak systolic velocity and increase in the end-diastolic velocity of the cavernosal artery (P < 0.01). Those men who had diabetes had higher average end-diastolic velocities and lower resistance indices (P < 0.01). Smoking and alcohol use also affected penile hemodynamics (P < 0.05). These data confirm that vascular risk factors do increase the likelihood of vasculogenic impotence and that diabetes plays a major role in veno-occlusive dysfunction in the penis.

A novel function of haptoglobin: haptoglobin-haemoglobin complex induces apoptosis of hepatocarcinomatous Hep 3B cells.

Haptoglobin-haemoglobin complex (Cx) showed a cytotoxic effect on the growth of Hep 3B (human hepatocellular carcinoma) cells, dose dependently. The antiproliferative effect of Cx on the multiplication of Hep 3B cells was augmented by the presence of prostaglandin (PG) D2. Antihuman Hb IgG abolished the effect of Cx, dose-dependently, which indicates that the antiproliferative effect of Cx really is exerted by Cx. Hep 3B cells treated with Cx showed the characteristic biochemical changes of apoptosis, such as DNA fragmentation which was blocked by pretreatment with cycloheximide, and the increase of transglutaminase expression. Thus, the antiproliferative effect of Cx against Hep 3B cells occurs via the typical apoptotic pathway.

The effect of Theiler's murine encephalomyelitis virus (TMEV) VP1 carboxyl region on the virus-induced central nervous system disease.

Members of the Theiler's murine encephalomyelitis virus GDVII subgroup, which includes GDVII strain, are highly neurovirulent and induce a rapidly fatal polioencephalomyelitis. By contrast, Theiler's original subgroup members, which includes DA strain, are not as neurovirulent, and produce a chronic, demyelinating disease with virus persistence. We investigated the importance of the carboxyl region of the capsid protein VP1 in TMEV-induced disease since a trypsin-cleavable immunodominant neutralization epitope is situated in the VP1 carboxyl region, and since this region is believed to lie adjacent to the putative receptor binding site. The present studies support the role of DA VP1 residue 268 (and the aligned GDVII VP1 270) in Theiler's murine encephalomyelitis virus-induced CNS disease; however, the effect of this residue varies depending on its context: mutation of DA VP1 268 attenuates demyelination; mutation of GDVII VP1 270 in a GDVII/DA recombinant virus has no effect on demyelination but reduces early deaths (neurovirulence); mutation of GDVII VP1 270 in GDVII virus has no effect on neurovirulence. These data suggest that DA VP1 268/GDVII VP1 270 are not functionally equivalent and that a residue in recombinant viruses can differ in function from the same residue situated in a parental strain. Additional mutagenesis studies suggest that: the trypsin cleavage site of TMEV, which affects virus viability, is located at the lysine at DA VP1 261 (GDVII VP1 263); GDVII VP1 276, the predicted carboxyl terminus of VP1, affects VP1/2A processing and virus infectivity.

Chimeric cDNA studies of Theiler's murine encephalomyelitis virus neurovirulence.

Strain GDVII and other members of the GDVII subgroup of Theiler's murine encephalomyelitis virus are highly neurovirulent and rapidly fatal, while strain DA and other members of the TO subgroup produce a chronic, demyelinating disease. GDVII/DA chimeric cDNA studies suggest that a major neurovirulence determinant is within the GDVII 1B through 1D capsid protein coding region, although the additional presence of upstream GDVII sequences, including the 5' untranslated region, contributes to full neurovirulence. Our studies indicate that there are limitations in precisely delineating neurovirulence determinants with chimeric cDNAs between evolutionarily diverged viruses, such as GDVII and DA.

Expression and amplification of cellular oncogenes in human developing placenta and neoplastic trophoblastic tissue.

To confirm the expression of cellular oncogenes during normal development, their differential RNA levels in developing human placenta have been studied using radioactive probes such as v-abl, v-erbA, v-fms, v-mos, v-myc, N-ras and v-src. The c-mos and N-ras genes are expressed and amplified at high levels especially in term placenta, while c-abl, and c-erbA are expressed constantly during development. These findings indicate that c-mos and N-ras genes may be closely linked to normal differentiation, although c-abl and c-erbA may participate in overall developmental processes. In contrast, transcripts of c-myc and c-src are enhanced at first trimester and decreased sequentially thereafter, showing that these genes may play a role in early proliferation. Expression patterns of c-fms gene are same as that of c-myc and c-src except reelevation at term. In addition, to characterize the effect of cellular oncogene expression has been also examined in hydatidiform mole and tumor cells such as BeWo and choriocarcinoma. All cellular oncogenes examined in this study were significantly overexpressed. Thus, our results suggest that cellular oncogene activation may be strongly associated with neoplastic change of trophoblast.

Simple spectrophotometric determination of haptoglobin-haemoglobin complex in haemolysed samples.

The concentration of haptoglobin-haemoglobin complex in haemolysed serum was measured by reducing the sample with sodium hydrosulphite. The absorption spectra of serum before and after sodium hydrosulphite treatment were compared, and the absorbance change was used to determine the amount of haemoglobin in the sample. By analysing the difference absorption spectra of various types of haemoglobin-containing samples, it was also possible to determine the haptoglobin level in samples haemolysed severely beyond their haemoglobin-binding capacities. When the present methods are used, along with the spectrophotometric method for free haptoglobin, one can measure separately the amounts of free haptoglobin, haptoglobin-haemoglobin complex, and free haemoglobin in samples with varying degrees of haemolysis.

Simple spectrophotometric determination of haptoglobin level in serum.

Haptoglobin concentration was determined from the change caused in the absorption spectrum of hemoglobin due to binding with haptoglobin. Absorbance changed markedly near the Soret band, and a linear correlation could be observed between the extent of the absorbance change and the amount of free haptoglobin. The levels of serum haptoglobin measured by the present method correlated well with those determined by an electrophoretic or a peroxidase method. High concentrations (more than 10 mg/100 ml) of hematin gave positive interference in the measured haptoglobin level, whereas bilirubin and chylomicron showed low levels of interference. The proposed method could be used as a simple and reliable method for the determination of haptoglobin level in various types of sample.

Inhibition of prostaglandin synthase activity of sheep seminal vesicular gland by human serum haptoglobin.

Serum haptoglobin was added to the reaction mixture of prostaglandin synthase (EC 1.14.99.1) and its inhibitory effect was studied [1-14C]Arachidonic acid was used as substrate and the enzyme activity was estimated by monitoring the radioactivity of the products after thin layer chromatography. With or without addition of hemoglobin to the reaction mixture, both the purified haptoglobin 1-1 and 2-2 showed inhibitory activity. In the presence of 5 microM hematin, however, inhibitory activity haptoglobin was not observed. Inhibition of prostaglandin synthesis in the system depended on the molar ratio of haptoglobin to hemoglobin in the reaction mixture. These results demonstrate that haptoglobin inhibits prostaglandin synthase by restricting available heme group for the enzyme activity through complexing with hemoglobin. However, haptoglobin did not inhibit completely the stimulatory effect of free hemoglobin. Relevant significant of this effect was discussed.