Radiological complete response with regorafenib for multiple lung metastases of ascending colon cancer: a case report.

BACKGROUND: Regorafenib is an oral diphenylurea multikinase inhibitor and currently approved for use following third-line therapy for metastatic colorectal cancer (CRC) patients. Only one case has previously been reported of metastatic CRC showing a complete response (CR) to regorafenib. CASE PRESENTATION: A 68-year-old Japanese man underwent laparoscopy-assisted ileocecal resection and D3 lymphadenectomy due to his ascending colon cancer. Eighteen months after surgery, a laparoscopic hepatic left lateral segmentectomy was performed due to a liver tumor, and a pathological diagnosis of colorectal liver metastasis was made. Three months after the second surgery, contrast-enhanced computed tomography (CT) revealed multiple lung metastases. The patient had undergone 18 courses of the FOLFOX + bevacizumab chemotherapy regimen as their first-line therapy and 11 courses of the FOLFIRI + ramucirumab chemotherapy regimen as their second-line therapy. As their third-line therapy, the patient was administered the regorafenib chemotherapy regimen. We evaluated the chemotherapy treatment's effect on the lung tumors by CT after 3, 7, 11, and 17 courses of the regorafenib chemotherapy regimen, finding that the lung tumors had shrunk with time; thus, each tumor was considered a partial response (PR) based on the RECIST guidelines. After 21 courses of the regorafenib chemotherapy regimen, the chemotherapy was discontinued in response to the patient's wishes. Even at 1 and 3 months after the discontinuation of the chemotherapy, CT revealed that the lung tumors had shrunk, with each considered a PR. Furthermore, 9 months after the discontinuation of the chemotherapy, CT revealed scarring of the lung tumors. This was considered a CR, rather than a PR. The patient remains disease-free 18 months after the discontinuation of chemotherapy. CONCLUSIONS: In this paper, we present the second case of radiological CR with regorafenib for multiple lung metastases of ascending colon cancer. Currently, there is no consensus on a treatment strategy for patients with radiological CR.

Dopamine error signal to actively cope with lack of expected reward.

To obtain more of a particular uncertain reward, animals must learn to actively overcome the lack of reward and adjust behavior to obtain it again. The neural mechanisms underlying such coping with reward omission remain unclear. Here, we developed a task in rats to monitor active behavioral switch toward the next reward after no reward. We found that some dopamine neurons in the ventral tegmental area exhibited increased responses to unexpected reward omission and decreased responses to unexpected reward, following the opposite responses of the well-known dopamine neurons that signal reward prediction error (RPE). The dopamine increase reflected in the nucleus accumbens correlated with behavioral adjustment to actively overcome unexpected no reward. We propose that these responses signal error to actively cope with lack of expected reward. The dopamine error signal thus cooperates with the RPE signal, enabling adaptive and robust pursuit of uncertain reward to ultimately obtain more reward.

Analysis of the neuronal network of the medullary respiratory center in transgenic rats expressing archaerhodopsin-3 in Phox2b-expressing cells.

Preinspiratory (Pre-I) neurons in the parafacial respiratory group (pFRG) comprise one of the respiratory rhythm generators in the medulla of the neonatal rat. A subgroup of pFRG/Pre-I neurons expresses the transcription factor Phox2b. To further analyze detailed neuronal mechanisms of respiratory rhythm generation in the neonatal rat, we developed a transgenic (Tg) rat line in which Phox2b-positive cells expressed archaerhodopsin-3 (Arch). Brainstem-spinal cord preparations were isolated from 0-2-day-old Tg newborn rats and were superfused with artificial cerebrospinal fluid equilibrated with 95% O2 and 5% CO2, pH 7.4, at 25-26 °C. Inspiratory fourth cervical ventral root (C4) activity was monitored, and membrane potentials of neurons in the pFRG including Pre-I and inspiratory neurons were recorded. Phox2b-positive cells in the Tg rats were essentially positive for enhanced green fluorescent protein (EGFP) signals (reporter for Arch) in the pFRG. Continuous photo-stimulation of the rostral ventral medulla for up to 90 s by covering the pFRG with green laser light (532 nm) induced a decrease of respiratory rate measured at C4 accompanied by membrane hyperpolarization of Phox2b-positive pFRG/Pre-I neurons. In contrast, Phox2b-negative inspiratory neurons were not hyperpolarized during the photo-stimulation. Our findings showed that Phox2b-expressing pFRG/Pre-I neurons are involved in the maintenance of the basic respiratory rhythm in neonatal rat.

Monitoring and Updating of Action Selection for Goal-Directed Behavior through the Striatal Direct and Indirect Pathways.

The basal ganglia play key roles in adaptive behaviors guided by reward and punishment. However, despite accumulating knowledge, few studies have tested how heterogeneous signals in the basal ganglia are organized and coordinated for goal-directed behavior. In this study, we investigated neuronal signals of the direct and indirect pathways of the basal ganglia as rats performed a lever push/pull task for a probabilistic reward. In the dorsomedial striatum, we found that optogenetically and electrophysiologically identified direct pathway neurons encoded reward outcomes, whereas indirect pathway neurons encoded no-reward outcome and next-action selection. Outcome coding occurred in association with the chosen action. In support of pathway-specific neuronal coding, light activation induced a bias on repeat selection of the same action in the direct pathway, but on switch selection in the indirect pathway. Our data reveal the mechanisms underlying monitoring and updating of action selection for goal-directed behavior through basal ganglia circuits.

Phase I study of primary treatment with 5-FU, oxaliplatin, irinotecan, levofolinate, and panitumumab combination chemotherapy in patients with advanced/recurrent colorectal cancer involving the wild-type RAS gene: the JACCRO CC-14 study.

BACKGROUND: FOLFOXIRI is now regarded as the chemotherapy regimen that offers the best platform for the treatment of colorectal cancer. However, the safety and efficacy of FOLFOXIRI + panitumumab has not been demonstrated. We conducted a phase I study to determine the recommended dose of FOLFOXIRI + panitumumab as first-line treatment for RAS wild-type metastatic colorectal cancer (mCRC). METHODS: Patients received combination therapy consisting of panitumumab (6 mg/kg on day 1) + FOLFOXIRI [irinotecan (CPT-11), oxaliplatin (L-OHP) 85 mg/m2, and folinate (LV) 200 mg/m2] on day 1, followed by fluorouracil (5-FU) 3200 mg/m2 infused as a 46-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of RAS wild-type mCRC patients. A decrease in CPT-11 dose was planned (started at level 1: CPT-11 165 mg/m2). RESULTS: Seven patients were enrolled, and six were assessed for safety and efficacy. Maximum tolerated dose was not reached at level 1; all patients were treated at these levels. The common Grade 3 or 4 relevant toxicities were diarrhea (50%), hypokalemia (33%) and stomatitis (33%). No treatment-related deaths occurred. Of the six patients assessed four had partial response and the two others had stable disease; hence, the response rate was 66.7% (95% confidence interval 28.9-100%) and the disease control rate was 100%. Time to protocol treatment failure was 7.2 (1.4-7.3) months. CONCLUSION: The FOLFOXIRI + panitumumab chemotherapy regimen was well tolerated by our patients with mCRC and showed promising anti-tumor activity. The recommended phase II dose was determined to be the same as the standard doses of this regimen used worldwide.

[Neural Mechanisms That Facilitate Adaptive Behavior Based on Acquired Stimulus-Outcome Information].

In response to changing internal and external situations, we always need to adapt our behavior based on previous experiences, particularly, acquired stimulus-outcome information. The orbitofrontal cortex (OFC), a prefrontal cortical region, is critical for this type of decision-making. The current understanding of the fundamental functions of the OFC has been reviewed by introducing, as an example, how the OFC contributes to the processing of uncertain rewards. Furthermore, the importance of revealing context and temporally specific causal roles of neural circuits including the OFC in decision-making, as well as the techniques to achieve the goal, have been discussed.

Hippocampal-prefrontal theta phase synchrony in planning of multi-step actions based on memory retrieval.

Planning of multi-step actions based on the retrieval of acquired information is essential for efficient foraging. The hippocampus (HPC) and prefrontal cortex (PFC) may play critical roles in this process. However, in rodents, many studies investigating such roles utilized T-maze tasks that only require one-step actions (i.e., selection of one of two alternatives), in which memory retrieval and selection of an action based on the retrieval cannot be clearly differentiated. In monkeys, PFC has been suggested to be involved in planning of multi-step actions; however, the synchrony between HPC and PFC has not been evaluated. To address the combined role of the regions in planning of multi-step actions, we introduced a task in rats that required three successive nose-poke responses to three sequentially illuminated nose-poke holes. During the task, local field potentials (LFP) and spikes from hippocampal CA1 and medial PFC (mPFC) were simultaneously recorded. The position of the first hole indicated whether the following two holes would be presented in a predictable sequence or not. During the first nose-poke period, phase synchrony of LFPs in the theta range (4-10 Hz) between the regions was not different between predictable and unpredictable trials. However, only in trials of predictable sequences, the magnitude of theta phase synchrony during the first nose-poke period was negatively correlated with latency of the two-step ahead nose-poke response. Our findings point to the HPC-mPFC theta phase synchrony as a key mechanism underlying planning of multi-step actions based on memory retrieval rather than the retrieval itself.

High-throughput measurement of single-cell growth rates using serial microfluidic mass sensor arrays.

Methods to rapidly assess cell growth would be useful for many applications, including drug susceptibility testing, but current technologies have limited sensitivity or throughput. Here we present an approach to precisely and rapidly measure growth rates of many individual cells simultaneously. We flow cells in suspension through a microfluidic channel with 10-12 resonant mass sensors distributed along its length, weighing each cell repeatedly over the 4-20 min it spends in the channel. Because multiple cells traverse the channel at the same time, we obtain growth rates for >60 cells/h with a resolution of 0.2 pg/h for mammalian cells and 0.02 pg/h for bacteria. We measure the growth of single lymphocytic cells, mouse and human T cells, primary human leukemia cells, yeast, Escherichia coli and Enterococcus faecalis. Our system reveals subpopulations of cells with divergent growth kinetics and enables assessment of cellular responses to antibiotics and antimicrobial peptides within minutes.

Noninvasive optical inhibition with a red-shifted microbial rhodopsin.

Optogenetic inhibition of the electrical activity of neurons enables the causal assessment of their contributions to brain functions. Red light penetrates deeper into tissue than other visible wavelengths. We present a red-shifted cruxhalorhodopsin, Jaws, derived from Haloarcula (Halobacterium) salinarum (strain Shark) and engineered to result in red light-induced photocurrents three times those of earlier silencers. Jaws exhibits robust inhibition of sensory-evoked neural activity in the cortex and results in strong light responses when used in retinas of retinitis pigmentosa model mice. We also demonstrate that Jaws can noninvasively mediate transcranial optical inhibition of neurons deep in the brains of awake mice. The noninvasive optogenetic inhibition opened up by Jaws enables a variety of important neuroscience experiments and offers a powerful general-use chloride pump for basic and applied neuroscience.

Expression status of mRNA for sex hormone receptors in human dental pulp cells and the response to sex hormones in the cells.

OBJECTIVES: Sex hormone receptors are reported to be present in human dental pulp (HDP) cells. The purpose of this study was to examine the biological significance of oestrogen and androgen receptors (ER and AR, respectively) in HDP cells. DESIGN: We isolated HDP cells expressing ER- and AR-mRNAs and investigated the expression status of the receptors and the response to sex hormones in the cells. RESULTS: HDP cells expressing ER- and/or AR-mRNAs had the ability to form alizarin red S-positive nodules in which calcium and phosphorus were deposited in vitro and to differentiate into odontoblasts-like cells and dentine-like tissue in vivo. Individual clones isolated from HDP cells exhibited a different expression pattern of mRNA for ER and AR. Some clones expressed ERα- and/or ERß-mRNAs and the others coexpressed ER- and AR-mRNAs. Using the Ingenuity software, we found that 17ß-estradiol (E2) and dihydrotestosterone (DHT) could act directly on HDP cells through ER-or androgen signalling-mediated mechanisms. E2 or DHT stimulated the mRNA expression for genes related to odontogenesis of dentine-containing teeth and odontoblast differentiation, suggesting that ER and AR in HDP cells may be involved in dentinogenesis. CONCLUSIONS: Our findings provide new insights into the biological significance of sex hormone receptors in HDP cells.

Risk-responsive orbitofrontal neurons track acquired salience.

Decision making is impacted by uncertainty and risk (i.e., variance). Activity in the orbitofrontal cortex, an area implicated in decision making, covaries with these quantities. However, this activity could reflect the heightened salience of situations in which multiple outcomes-reward and reward omission-are expected. To resolve these accounts, rats were trained to respond to cues predicting 100%, 67%, 33%, or 0% reward. Consistent with prior reports, some orbitofrontal neurons fired differently in anticipation of uncertain (33% and 67%) versus certain (100% and 0%) reward. However, over 90% of these neurons also fired differently prior to 100% versus 0% reward (or baseline) or prior to 33% versus 67% reward. These responses are inconsistent with risk but fit well with the representation of acquired salience linked to the sum of cue-outcome and cue-no-outcome associative strengths. These results expand our understanding of how the orbitofrontal cortex might regulate learning and behavior.

Single-port versus multiport laparoscopic cholecystectomy: a prospective randomized clinical trial.

PURPOSE: We report the outcomes of a randomized clinical trial of single-port laparoscopic cholecystectomy (SPLC) and multiport laparoscopic cholecystectomy (MPLC). METHODS: Fifty-four patients (27 in each group) were randomized. A visual analog scale was used with a 10-point scale for an objective assessment of incisional pain and incisional cosmesis on postoperative days 1, 3, and 14. RESULTS: The mean operating time was significantly longer in the SPLC. The mean cosmesis scores on postoperative days 3 (9.7 vs. 8.9, P = 0.01) and 14 (9.9 vs. 9.2, P<0.01) were significantly greater in the SPLC group than in the MPLC group. The group's mean visual analog scale scores for incisional pain, and their requirements for analgesics, did not differ significantly. CONCLUSIONS: Although SPLC takes longer than MPLC, experienced laparoscopic surgeons can perform SPLC safely with results comparable with those for MPLC. SPLC is superior to MPLC in terms of short-term cosmetic outcomes.

Reward prediction error signaling in posterior dorsomedial striatum is action specific.

Neural correlates of reward prediction errors (RPEs) have been found in dorsal striatum. Such signals may be important for updating associative action representations within striatum. In order that the appropriate representations can be updated, it might be important for the RPE signal to be specific for the action that led to that error. However, RPEs signaled by midbrain dopamine neurons, which project heavily to striatum, are not action-specific. Here we tested whether RPE-like activity in dorsal striatum is action-specific; we recorded single-unit activity in posterior dorsomedial and dorsolateral striatum as rats performed a task in which the reward predictions associated with two different actions were repeatedly violated, thereby eliciting RPEs. We separately analyzed fast firing neurons (FFNs) and phasically firing neurons (total n = 1076). Only among FFNs recorded in posterior dorsomedial striatum did we find a population with RPE-like characteristics (19 of all 196 FFNs, 10%). This population showed a phasic increase in activity during unexpected rewards, a phasic decrease in activity during unexpected omission of rewards, and a phasic increase in activity during cues when they predicted high-value reward. However, unlike a classical RPE signal, this signal was linked to the action that elicited the prediction error, in that neurons tended to signal RPEs only after their anti-preferred action. This action-specific RPE-like signal could provide a mechanism for updating specific associative action representations in posterior dorsomedial striatum.

Neural correlates of stimulus-response and response-outcome associations in dorsolateral versus dorsomedial striatum.

Considerable evidence suggests that there is functional heterogeneity in the control of behavior by the dorsal striatum. Dorsomedial striatum may support goal-directed behavior by representing associations between responses and outcomes (R-O associations). The dorsolateral striatum, in contrast, may support motor habits by encoding associations between stimuli and responses (S-R associations). To test whether neural correlates in striatum in fact conform to this pattern, we recorded single-units in dorsomedial and dorsolateral striatum of rats performing a task in which R-O contingencies were manipulated independently of S-R contingencies. Among response-selective neurons in both regions, activity was significantly modulated by the initial stimulus, providing evidence of S-R encoding. Similarly, response selectivity was significantly modulated by the associated outcome in both regions, providing evidence of R-O encoding. In both regions, this outcome-modulation did not seem to reflect the relative value of the expected outcome, but rather its specific identity. Finally, in both regions we found correlates of the available action-outcome contingencies reflected in the baseline activity of many neurons. These results suggest that differences in information content in these two regions may not determine the differential roles they play in controlling behavior, demonstrated in previous studies.

Observation of calcium phosphate powder mixed with an adhesive monomer experimentally developed for direct pulp capping and as a bonding agent.

In this study, morphological shape, elemental distribution and elution properties of Ca, P, Mg in four types of calcium phosphate powder were investigated using SEM, EPMA and ICP-AES. Calcium phosphate powder: OHAp, DCPD, beta-TCP and OCP were observed in the white powder form and in the photopolymerized adhesive monomer they scattered like dispersed fillers in resin composite. In elemental analysis, CaKalpha showed a relatively high concentration in relation to PKalpha. In elution analysis, each calcium phosphate showed different elution of Ca and P. But Mg was almost equal to the detection limit of ICP-AES. Namely it was suggested that reparative dentin formation was effectively promoted under the following conditions: a calcification promoting effect by direct contact of the calcium phosphate powder, an ionic effect of Ca and P eluted from the powder located in the vicinity of the exposed pulp and environmental pH change of the surface in exposed pulp.

Energy output reduction and surface alteration of quartz and sapphire tips following Er:YAG laser contact irradiation for tooth enamel ablation.

BACKGROUND: Despite the recent increase in application of Er:YAG laser for various dental treatments, limited information is available regarding the contact tips. This study examined the changes in energy output and surface condition of quartz and sapphire contact tips after Er:YAG laser contact irradiation for tooth enamel ablation. MATERIALS AND METHODS: Ten sets of unused quartz or sapphire contact tips were employed for contact irradiation to sound enamel of extracted teeth. The teeth were irradiated with Er:YAG laser at approximately 75 J/cm(2)/pulse and 20 Hz under water spray for 60 minutes. The energy output was measured before and every 5 minutes after irradiation, and the changes in morphology and chemical composition of the contact surface were analyzed. RESULTS: The energy output significantly decreased with time in both tips. The energy output from the sapphire tips was generally higher on average than that of the quartz. The contact surfaces of all the used quartz tips were concave and irregular. Most of the sapphire tips also appeared rough with crater formation and fractures, except for a few tips in which a high energy output and the original smooth surface were maintained. Spots of melted tooth substances were seen attached to the surface of both tips. CONCLUSION: In contact enamel ablation, the sapphire tip appeared to be more resistant than the quartz tip. The quartz tips showed similar patterns of energy reduction and surface alteration, whereas the sapphire tips revealed a wider and more characteristic variation among tips. Lasers Surg. Med. 41:595-604, 2009. (c) 2009 Wiley-Liss, Inc.

Altered sensitivities to morphine and cocaine in scaffold protein tamalin knockout mice.

Tamalin is a scaffold protein that interacts with metabotropic glutamate receptors and the kinase-deficient neurotrophin TrkCT1 receptor and forms a protein complex with multiple protein-trafficking and intracellular signaling molecules. In culture, tamalin promotes intracellular trafficking of group 1 metabotropic glutamate receptors through its interaction with guanine nucleotide exchange factor cytohesins and causes actin reorganization and membrane ruffling via the TrkCT1/cytohesin-2 signaling mechanism. However, how tamalin serves its physiological function in vivo has remained elusive. In this study, we generated tamalin knockout (Tam(-/-) KO) mice and investigated behavioral alterations resulting from their deficiency in functional tamalin. Targeted deletion of functional tamalin altered neither the overall brain architecture nor the general behavior of the mice under ordinary conditions. However, Tam(-/-) KO mice showed a decrease in sensitivity to acute morphine-induced hyperlocomotion and morphine analgesic effects in the hot-plate test. Furthermore, tamalin deficiency impaired the ability of the animals to show conditioned place preference after repeated morphine administration and to display locomotor sensitization by chronic cocaine treatment. Upon in vivo microdialysis analysis of the nucleus accumbens, Tam(-/-) KO and wild-type mice showed no genotypic differences in their response patterns of extracellular dopamine and glutamate before or after morphine administration. These results demonstrate that the tamalin scaffold protein plays a unique role in both acute and adaptive behavioral responses to morphine and cocaine and could regulate common neural substrates implicated in drugs of abuse.

Group IIA-soluble phospholipase A2 levels in patients with infections after esophageal cancer surgery.

PURPOSE: To examine the changes in blood-soluble phospholipase A(2)-IIA levels caused by surgical stress and postoperative infections. METHODS: We retrospectively analyzed a prospective database of 40 patients who underwent esophagectomy for esophageal cancer. Nine of these patients had a postoperative infection (E Inf(+) group), and 31 did not have a postoperative infection (E Inf(-) group). The blood sPLA(2)-IIA level was measured using a radioimmunoassay, and whole blood was stimulated with lipopolysaccharide (LPS) to examine the sPLA(2)-IIA production. RESULTS: In the E Inf(-) group, the blood sPLA(2)-IIA levels peaked on postoperative day (POD) 3 then decreased gradually thereafter. Receiver-operator characteristic statistics based on the sPLA(2)-IIA values on POD 5, which are used to classify postoperative infectious complications, revealed an area under the curve of 0.789. However, stimulation of peripheral blood cells with LPS did not induce the production of sPLA(2)-IIA. CONCLUSION: During the early postoperative phase, blood sPLA(2)-IIA levels increase according to the surgical stress. Soluble PLA(2)-IIA may be produced at the site of infection or in the liver, but not in the circulating blood. Sustained elevation of the serum sPLA(2)-IIA level, observed even after POD 3, seems to represent a response to postoperative infection.

[Perioperative nutrition for gastrointestinal surgery].

In elective gastrointestinal (GI) surgery, the patients' nutritional status should be assessed and if protein-energy malnutrition exists, preoperative nutritional support should be scheduled 7 to 14 days before surgery. In malnourished patients in particular, preoperative nutrition with total parenteral nutrition (TPN) reduces postoperative complication rates of infection. Preoperative enteral nutrition (EN) is considered to be as effective as TPN in improving postoperative surgical outcome. Many prospective randomized trials or meta-analyses comparing postoperative EN and TPN have revealed that postoperative EN improves surgical outcomes and lowers postoperative complication rates of infection to a degree similar to TPN. Although two recent prospective multicenter randomized trials in malnourished patients undergoing elective GI cancer surgery are controversial, no evidence that EN was less effective than TPN was recognized. Thus postoperative EN, prior to TPN, is recommended in patients with malnutrition or insufficient oral intake for 7 days or more after surgery. When TPN is administered, hyperglycemia due to overfeeding should be carefully controlled. Patients who undergo distal gastrectomy or colectomy can start oral intake 3 to 4 days after surgery, with pertinent peripheral infusion. Immunonutrition containing immune-enhancing nutrients such as arginine, n-3 polyunsaturated fatty acid, glutamine, etc., especially administered preoperatively, is a promising nutritional therapy for reducing postoperative infectious complications.

Electron probe micro-analysis of a contact probe after Er:YAG laser tooth ablation.

The purpose of this study was to investigate the contact probes of Er:YAG laser before and after tooth ablation. Three kinds of contact probe were prepared. The first was an unused probe (NE). The second was used to prepare 10 cervical cavities (KP). The third was a probe that was judged for an exchange by three dentists who had expertise with Er:YAG laser (EX). The surface observation and mapping analysis were performed. The contact surface of NE was a flat and smooth surface, only Si was observed. KP demonstrated an uneven surface, Si was observed throughout, with scattered indications of Ca and P. EX displayed regions of fracture along the edge and a surface exhibiting dissolved adherents in parts. It was suggested that micro-explosions have effects on not only the tooth substance, but also the contact surface of the probe.