Comparing advanced platforms for local excision of rectal lesions.

BACKGROUND: Transanal surgery facilitates organ preservation in select patients with benign and early malignant rectal lesions to avoid the functional consequences of radical surgery. The transanal endoscopic microsurgery (TEM) platform created a standard for local excision with lower margin positivity and recurrence rates than traditional transanal excision. The single-port robot (SP r) presents a promising alternative transanal platform. The goal of this study was to compare perioperative and pathologic outcomes of TEM and SP r for excision of rectal lesions. METHODS: A review of consecutive patients who underwent local excision of rectal lesions at a tertiary referral center from 1/2001 to 5/2022 was performed. Cases were stratified into TEM or SP rTAMIS in a 1:1 propensity score-matched cohort, adjusting for all baseline characteristics. Clinical, tumor-specific, and perioperative outcomes were compared using χ2, and Mann-Whitney U-tests. The main outcomes were oncologic quality measures, complications, and operative time. RESULTS: Matching resulted 50 patients in each cohort. Groups had similar age, gender, body mass index, comorbidity, diagnosis, lesion characteristics, and neoadjuvant chemoradiation rates. There were no intraoperative complications in either cohort. Three SP rTAMIS cases were converted intraoperatively; there were no conversions in TEM. SP rTAMIS had significantly shorter operative times than TEM (mean 104 vs. 245, p = 0.027). The rates of positive distal margins (2% TEM, 0% SP rTAMIS) and piecemeal resection (4% TEM, 0% SP rTAMIS) were similar. SP rTAMIS had significantly lower postoperative morbidity rates than TEM (9% vs. 20%, p = 0.031). There was no mortality in either cohort. CONCLUSIONS: SP robotics provided high-quality outcomes similar to TEM for local excision of rectal lesions. SP robotics had faster operative time with comparable clinical and oncologic outcomes to TEM. These early data are promising for expanding use of SP robotic platforms.

Longitudinal Analysis of Local Recurrence and Survival After Transanal Abdominal Transanal Radical Proctosigmoidectomy for Low Rectal Cancer Treated With Neoadjuvant Chemoradiation Therapy.

BACKGROUND: The transanal abdominal transanal radical proctosigmoidectomy was developed in 1984 as a sphincter preservation surgery in patients with low rectal cancers after preoperative radiation therapy. While serving as a catalyst for disruptive sphincter preservation surgery, it continues to be used and evolve. With the controversy over safety and local recurrence in other sphincter-preserving surgery, review of transanal abdominal transanal radical proctosigmoidectomy long-term oncologic outcomes is warranted. OBJECTIVE: To assess local recurrence and survival after transanal abdominal transanal radical proctosigmoidectomy after neoadjuvant chemoradiation therapy. DESIGN: Retrospective cohort study of a prospectively maintained database. SETTINGS: Tertiary rectal cancer referral center. PATIENTS: Patients with low adenocarcinoma (≤5 cm anorectal ring) receiving neoadjuvant chemoradiation therapy and then transanal abdominal transanal radical proctosigmoidectomy for curative resection between 1998 and 2021. MAIN OUTCOME MEASURES: Local recurrence rates and overall survival rates. RESULTS: Of 255 included patients, 67.8% were men (n = 173); the mean age was 58.7 years (SD 11.5) and the mean BMI was 27.1 (SD 5.4), with 50.2% (n = 128) having ASA class II and 49.8% (n = 127) having ASA class III/IV. The mean tumor size was 4.8 cm (SD 1.9), the majority of patients had clinical T3 disease (81.8%; n = 184), and 52.1% had nodal disease (n = 100). The median radiation dose was 5400 cGy, with 73.7% (n = 149) achieving good response and 90.2% (n = 230) receiving minimally invasive surgery. The complete total mesorectal excision rate was 94.3%, and 100% of patients (n = 255) had negative distal margins. The mean number of examined lymph nodes were 13.9 (SD 10.7). After a median follow-up of 55.4 months, 5.1% of patients (n = 13) developed local recurrence at a median time of 29.6 months. The 5-year overall survival was 84.1% (95% CI, 78.8-89.4). LIMITATIONS: Retrospective review with risk of bias and lack of generalizability. CONCLUSIONS: In this longitudinal study, the transanal abdominal transanal radical proctosigmoidectomy demonstrated excellent long-term locoregional control and survival in very low rectal cancers. The superior transanal abdominal transanal radical proctosigmoidectomy outcomes are durable over time, warranting expansion of the sphincter-preserving surgery technique. See Video Abstract . ANLISIS LONGITUDINAL DE LA RECURRENCIA LOCAL Y LA SUPERVIVENCIA DESPUS DE LA PROCTOSIGMOIDECTOMA RADICAL TRANSANAL ABDOMINAL TATA PARA EL CNCER DE RECTO BAJO TRATADO CON QUIMIORRADIACIN NEOADYUVANTE: ANTECEDENTES:La proctosigmoidectomía radical transanal abdominal se desarrolló en 1984 como una cirugía de preservación del esfínter en cánceres de recto bajo después de la radiación preoperatoria. Si bien sirve como catalizador para la cirugía disruptiva de preservación del esfínter, continúa utilizándose y evolucionando. Con la controversia sobre la seguridad y la recurrencia local en otras cirugías que preservan el esfínter, se justifica la revisión de los resultados oncológicos a largo plazo de la proctosigmoidectomía radical transanal abdominal.OBJETIVO:Evaluar localmente después de Proctosigmoidectomía Radical Transanal Abdominal Transanal después de quimiorradiación neoadyuvante.DISEÑO:Estudio de cohorte retrospectivo de una base de datos mantenida de forma prospectiva.AJUSTES:Centro terciario de referencia para el cáncer de recto.PACIENTES:Adenocarcinoma bajo (=/

Howard P. Roffwarg: sleep pioneer, legend, and ontogenetic hypothesis author.

Narrated in this article are accounts of the many contributions Howard P. Roffwarg, MD, made to the field of sleep research and sleep medicine across his entire professional career as a student, a mentor, a leader in the Sleep Research Society, a sleep medicine clinician, and a scientist who performed experimental investigations in humans and animals. Dr Roffwarg was the originator of what is known as the "Ontogenetic Hypothesis" of sleep. His research over many years on physiology has contributed greatly to much of the experimental support substantiating a role for rapid eye-movement sleep (REMS) in the early development of the brain. Though much is still unknown, the Ontogenetic Hypothesis, still to this day, inspires many neuroscientists in their investigations. These studies have demonstrated roles for both REMS and NREMS in development as well as on brain function throughout his life span. Dr Howard P. Roffwarg, is one of the legends in the field of sleep research.

Long-term outcomes by a transanal approach to total mesorectal excision for rectal cancer.

BACKGROUND: The challenge of performing a good total mesorectal excision (TME) dissection, particularly in the distal 1/3 of the rectum, has spurred interest in new techniques. Robotic surgery is advocated by some, and more recently, a "new" approach, the transanal total mesorectal excision, has been popularized to address this problem. While great interest in this technique exists, little long-term outcome data are available. We have been utilizing a transanal abdominal transanal approach to TME in order to facilitate the distal dissection, and here, we provide our long-term outcomes using this approach in the management of rectal cancer. METHODS: From a prospectively maintained rectal cancer database, we identified 373 consecutive rectal cancers treated with sphincter preservation surgery through a combined transanal and abdominal approach to TME. Perioperative, pathological, and oncologic outcomes were analyzed. RESULTS: Three hundred and seventy-three patients with rectal cancer underwent a transanally initiated TME with mean follow-up of 5.5 years. 91% of cancers were in the distal rectum. 68.9% were men and 53.2% of cancers were tethered or fixed on presentation. 97.7% received neoadjuvant radiotherapy (mean 5405 cGy, 5-fluorouracil based); average time from completion of neoadjuvant therapy to surgery was 11 weeks. 180 and 193 patients underwent completion of their operation through open and laparoscopic abdominal approaches. 96% of TME specimens were complete/near complete, 94% had a negative circumferential resection margin, and 98.6% had a negative distal margin. Perioperative morbidity and mortality rates were 13.4 and 0.3%. Overall local recurrence (LR), DM, and Kaplan-Meier 5-year actuarial survival were 7.4, 19.5, and 90%, respectively. CONCLUSION: This is the first report of long-term data using a transanal approach to TME supporting this approach for rectal cancer. Our data with 5-year follow-up show that adequate distal and circumferential margins with very good-quality TME specimens, and a low risk for LR with excellent overall survival can be achieved using this technique. Our long-term results support the promising reports of early experiences in the literature.

Quality of Life and Functional Outcome After Transanal Abdominal Transanal Proctectomy for Low Rectal Cancer.

BACKGROUND: Transanal abdominal transanal proctectomy is a sphincter-preserving procedure designed to avoid colostomy in patients with cancer in the distal third of the rectum. Oncologic outcomes of this procedure have been established. However, data regarding patient satisfaction and quality of life are scant. OBJECTIVE: The purpose of this study was to evaluate the quality of life and functional outcomes of patients after transanal abdominal transanal proctectomy. DESIGN: This is a cross-sectional study. SETTINGS: The study was conducted at a tertiary referral colorectal center. PATIENTS: Patients who underwent transanal abdominal transanal proctectomy were included and surveyed using the Fecal Incontinence Quality of Life Scale, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, the Quality of Life Questionnaire CR38 module, and a questionnaire designed by the authors to assess satisfaction with quality of life. MAIN OUTCOME MEASURES: Quality of life, functional outcomes, and patient satisfaction were measured and compared by age, tumor level, and stage of the disease. RESULTS: A total of 133 surveys were mailed, and 90 patients responded and were included in the study. Patient quality of life was not significantly different after surgery. Patients with more proximal tumors had better lifestyle, physical, and emotional scores. Older patients performed better on multiple levels, including coping, emotional, body image, future perspective, and digestive. Stage of disease had no impact on quality of life. Compared with reference values, patients who underwent transanal abdominal transanal proctectomy performed better on most of the components. All of patients preferred transanal abdominal transanal proctectomy over having a stoma based on their current anal sphincter function, and >97% of patients preferred transanal abdominal transanal proctectomy based on their current quality of life, sexual function, and level of activities. LIMITATIONS: This study is limited by the lack of a comparison group and a potential selection bias. CONCLUSIONS: Satisfaction with quality of life and functional outcomes is high after transanal abdominal transanal proctectomy. Older patients and those with more proximal tumors performed better. This patient population clearly preferred a sphincter-preserving option for treatment of their rectal cancer.

True NOTES TME resection with splenic flexure release, high ligation of IMA, and side-to-end hand-sewn coloanal anastomosis.

INTRODUCTION: Natural orifice transluminal endoscopic surgery (NOTES) represents the ultimate expression of minimally invasive surgery. We have developed and present here an initial feasibility and safety study of transanal total mesorectal excision (TME) with splenic flexure release, high ligation of the IMA and IMV, and side-to-end coloanal anastomosis with temporary diverting ileostomy for rectal cancer. METHODS: A program of full NOTES TME resection with release of the splenic flexure, high ligation of the IMA/IMV, with side-to-end coloanal anastomosis was performed transanally from December 2013 to July 2014. Demographics, preoperative, perioperative, and postoperative data were prospectively obtained. Operative components were broken into TME, colonic mobilization, splenic flexure release, IMA/IMV transection, transanal extraction of specimen, and coloanal anastomosis for analysis of performance completion. RESULTS: There were 3 women and 1 man on whom we operated. Mean age was 56 (46-65). Mean BMI was 26 (23.8-30.2). The operation was completed entirely transanally in 2 patients. Transanal component completion of the operation was as follows: TME in 3/4; colonic mobilization in 4/4; splenic flexure release in 3/4; IMA/IMV transection in 3/4; transanal specimen extraction in 4/4; coloanal anastomosis in 4/4. Abdominal time for completion of component parts was: splenic flexure release 4:53 (min:s), IMA/IMV 19:43, completion of TME 13:41. Mean EBL was 194 cc (25-500). Aside from stoma site, there were no abdominal incisions. There were no mortalities. Mesorectum was intact in all 4 patients and with negative circumferential and distal margins. CONCLUSION: This experience supports the feasibility and safety of a true NOTES TME. The critical anatomic views demonstrated on video affirm the potential of this approach for distal rectal cancer. Colorectal surgery represents the most logical application for NOTES. While highly promising, a great deal of work remains to develop the technique and applicability of NOTES colorectal surgery.

Single-port laparoscopic colorectal surgery shows equivalent or better outcomes to standard laparoscopic surgery: results of a 190-patient, 7-criterion case-match study.

INTRODUCTION: Single-port (SP) surgery has been characterized as having limited applicability regarding procedure, disease, and patient characteristics. There is a question if SP procedures offer disadvantages or advantages to multiport (MP) colorectal surgery. We hypothesize that SP is equivalent to MP and is a safe alternative in the full spectrum of colorectal disease and procedures. METHODS: A case-matched analysis of a prospectively maintained database to compare perioperative outcomes in SP versus MP was performed. Criteria included age, gender, BMI, previous abdominal surgery, previous XRT, disease process, and procedure. 95 exact matches for all 7 criteria were found between 159 SP and 1,617 MP cases. Perioperative outcomes, surgical technique, morbidity, mortality, local recurrence, and 5-year survival were analyzed. RESULTS: There was lower mean EBL in SP but no difference in transfusion requirement. OR time for SP left colectomy was shorter, with a trend to shorter OR times found in all procedures. 99 % SP and 98 % MP had no intra-operative complications. Conversion to open was equivalent (0/1). Mean largest incision was smaller for SP. There were no differences in return of bowel function or length of hospital stay. There were no mortalities. There were no differences in perioperative morbidity, local recurrence, distant metastasis, or overall 5-year survival. CONCLUSIONS: SP is a safe alternative to MP colorectal surgery across the full array of procedures in equivalent patients. This study demonstrates SP has less blood loss, smaller incisions, is quicker in left colectomy, and tends to be quicker across all procedures. Conversion and morbidity rates are equivalent to MP, without compromise in quality of surgical technique. While proper training is essential, concerns regarding the inability to use SP laparoscopic colorectal surgery safely are unfounded in nearly exactly matched patients. These issues will require further study as SP laparoscopic colorectal surgery is practiced more widely.

Inhibitory and excitatory amino acid neurotransmitters are utilized by the projection from the dorsal deep mesencephalic nucleus to the sublaterodorsal nucleus REM sleep induction zone.

The sublaterodorsal nucleus (SLD) in the pons of the rat is a locus supporting short-latency induction of a REM sleep-like state following local application of a GABAA receptor antagonist or kainate, glutamate receptor agonist. One putatively relevant source of these neurotransmitters is from the region of the deep mesencephalic nucleus (DpMe) just ventrolateral to the periaquiductal gray, termed the dorsal DpMe (dDpMe). Here, the amino acid neurotransmitter innervation of SLD from dDpMe was studied utilizing anterograde tract-tracing with biotinylated dextranamine (BDA) and fluorescence immunohistochemistry visualized with laser scanning confocal microscopy. Both markers for inhibitory and excitatory amino acid neurotransmitters were found in varicose axon fibers in SLD originating from dDpMe. Vesicular glutamate transporter2 (VGLUT2) represented the largest number of anterogradely labeled varicosities followed by vesicular GABA transporter (VGAT). Numerous VGAT and VGLUT2 labeled varicosities were observed apposed to dDpMe-labeled axon fibers indicating both excitatory and inhibitory presynaptic, local modulation within the SLD. Some double-labeled BDA/VGAT varicosities were seen apposed to small somata labeled for glutamate consistent with being presynaptic to the phenotype of REM sleep-active SLD neurons. Results found support the current theoretical framework of the interaction of dDpMe and SLD in control of REM sleep, while also indicating operation of mechanisms with a greater level of complexity.

Quality of life and fecal incontinence after transanal endoscopic microsurgery for benign and malignant rectal lesions.

BACKGROUND: Transanal endoscopic microsurgery (TEM) is a minimally invasive treatment used to excise a variety of rectal lesions. Potential overstretching of the sphincter's musculature due to dilation of the anal canal to allow placement of a 40-mm-wide scope combined with partial resection of the rectum and subsequent loss of rectal volume creates a concern regarding anorectal function postoperatively. Data regarding patient satisfaction with anorectal function and quality of life after TEM are scant. This report presents data on patient satisfaction gathered during a period of 10 years. METHODS: A prospectively maintained database of patients undergoing TEM from 1997 to 2007 was queried to identify patients to survey using the Fecal Incontinence Quality of Life Scale questionnaire, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) questionnaire version 3, and a questionnaire designed by the authors to assess satisfaction with quality of life. From a group of 86 patients, 57 (66 %) responded to the questionnaires. Patient satisfaction outcomes were determined by age, preoperative diagnosis, tumor level in the rectum, excision method, and radiation treatment. RESULTS: Most of the patients (94.7 %) preferred TEM to having a stoma. Age (p = 0.03) and nature of the lesion (p = 0.03) were the only factors that affected coping. Depression was affected only by the presence of malignancy (p = 0.001). Excision method was the only factor that significantly influenced overall lifestyle (p = 0.002). Neither tumor level (p = 0.8) nor radiation therapy (p = 0.9) affected patient satisfaction with lifestyle after TEM. The presence of malignancy (p = 0.004) and full-thickness excision (p = 0.02) were related to more problems with fecal incontinence. CONCLUSION: Satisfaction with fecal continence generally is high after TEM. Tumor level, size of tumor, and radiation therapy do not affect the level of satisfaction after TEM. Younger age and benign nature of the lesion help patients to cope better with lifestyle changes and reduce depression. Patients with submucosal excision have a significantly higher level of satisfaction.

GABAA receptors are located in cholinergic terminals in the nucleus pontis oralis of the rat: implications for REM sleep control.

The oral pontine reticular formation (PnO) of rat is one region identified in the brainstem as a rapid eye movement (REM) sleep induction zone. Microinjection of GABA(A) receptor antagonists into PnO induces a long lasting increase in REM sleep, which is similar to that produced by cholinergic agonists. We previously showed that this REM sleep-induction can be completely blocked by a muscarinic antagonist, indicating that the REM sleep-inducing effect of GABA(A) receptor antagonism is dependent upon the local cholinergic system. Consistent with these findings, it has been reported that GABA(A) receptor antagonists microdialyzed into PnO resulted in increased levels of acetylcholine. We hypothesize that GABA(A) receptors located on cholinergic boutons in the PnO are responsible for the REM sleep induction by GABA(A) receptor antagonists through blocking GABA inhibition of acetylcholine release. Cholinergic, varicose axon fibers were studied in the PnO by immunofluorescence and confocal, laser scanning microscopy. Immunoreactive cholinergic boutons were found to be colocalized with GABA(A) receptor subunit protein γ2. This finding implicates a specific subtype and location of GABA(A) receptors in PnO of rat in the control of REM sleep.

Sphincter-sparing surgery for adenocarcinoma of the distal 3 cm of the true rectum: results after neoadjuvant therapy and minimally invasive radical surgery or local excision.

BACKGROUND: Ideal treatment of rectal cancer includes controlling the cancer; minimizing trauma, morbidity, and mortality; and avoiding a colostomy with preservation of adequate function. These goals become more challenging the further distal in the rectum the cancer is located. We sought to determine whether minimally invasive sphincter-preservation surgery (SPS) can accomplish good cancer control, maintaining sphincter function with minimal morbidity and mortality in rectal cancers of the distal 3 cm after receiving neoadjuvant chemoradiotherapy. METHODS: We retrospectively reviewed a prospectively maintained rectal cancer database of a single colorectal surgeon to identify all patients with cancers of the distal 3 cm undergoing SPS via a laparoscopic total mesorectal excision or transanal endoscopic microsurgery (TEM). All patients received neoadjuvant chemoradiotherapy. Patient data, including demographics, initial tumor characteristics, staging, radiation dose, perioperative morbidity and mortality, and local recurrence (LR) and survival, were analyzed. RESULTS: A total of 161 patients (108 men) underwent SPS via 3 techniques: transanal abdominal transanal proctosigmoidectomy (TATA, n = 106), TEM (n = 49), or ultralow anterior resection (LAR, n = 6). Average age was 62 years (range 22-90 years). The mean levels in rectum from the anorectal ring were as follows: TATA, 1.3 cm (range -1.0 to 3.0 cm), TEM, 1.5 cm (range -0.5 to -3.0 cm), and LAR, 2.9 cm (range 2.5-3.0 cm) (p > 0.05). Preoperative T stage was as follows: T3, n = 108 (TATA 83, TEM 20, LAR 5), T2, n = 48 (TATA 22, TEM 25, LAR 1), T1, n = 3 (TATA 1, TEM 2), and T4, n = 2 (both TEM). All patients received concomitant 5-fluorouracil-based chemotherapy and radiotherapy (mean, 5300 cGy; range 3,000-7,295 cGy). The mean estimated blood loss was 376 ml (range 10-3,600 ml). There were no mortalities. Morbidity rates were as follows: LAR, 0; TATA, 13.2%; and TEM, 32 % (wound disruption: major, 10%; minor, 16%). Pathologic staging was as follows: ypCR: uT2, 34%, and uT3, 19%. Overall LR was 3.7%. By procedure, the follow-up, LR, and KM5YAS, respectively, were: TATA, 37.9 months, 3 and 95%; TEM, 36.3 months, 6 and 88%; and LAR, 63.1 months, 0 and 75% (p > 0.05). CONCLUSIONS: This study demonstrates positive oncologic outcomes, low LR rates, and high KM5YS after minimally invasive SPS. A colostomy-free lifestyle and cancer control make the minimally invasive surgical approach an excellent treatment option for complex distal rectal cancers.

GABA(A) receptors implicated in REM sleep control express a benzodiazepine binding site.

It has been reported that non-subtype-selective GABAA receptor antagonists injected into the nucleus pontis oralis (PnO) of rats induced long-lasting increases in REM sleep. Characteristics of these REM sleep increases were identical to those resulting from injection of muscarinic cholinergic agonists. Both actions were blocked by the muscarinic antagonist, atropine. Microdialysis of GABAA receptor antagonists into the PnO resulted in increased acetylcholine levels. These findings were consistent with GABAA receptor antagonists disinhibiting acetylcholine release in the PnO to result in an acetylcholine-mediated REM sleep induction. Direct evidence has been lacking for localization in the PnO of the specific GABAA receptor-subtypes mediating the REM sleep effects. Here, we demonstrated a dose-related, long-lasting increase in REM sleep following injection (60 nl) in the PnO of the inverse benzodiazepine agonist, methyl-6,7-dimethoxy-4-ethyl-ß-carboline (DMCM, 10(-2)M). REM sleep increases were greater and more consistently produced than with the non-selective antagonist gabazine, and both were blocked by atropine. Fluorescence immunohistochemistry and laser scanning confocal microscopy, colocalized in PnO vesicular acetylcholine transporter, a presynaptic marker of cholinergic boutons, with the γ2 subunit of the GABAA receptor. These data provide support for the direct action of GABA on mechanisms of acetylcholine release in the PnO. The presence of the γ2 subunit at this locus and the REM sleep induction by DMCM are consistent with binding of benzodiazepines by a GABAA receptor-subtype in control of REM sleep.

A novel GABAergic afferent input to the pontine reticular formation: the mesopontine GABAergic column.

Pharmacological manipulations of gamma-aminobutyric acid (GABA) neurotransmission in the nucleus pontis oralis (PnO) of the rat brainstem produce alterations in sleep/wake behavior. Local applications of GABA(A) receptor antagonists and agonists increase REM sleep and wake, respectively. These findings support a role for GABAergic mechanisms of the PnO in the control of arousal state. We have been investigating sources of GABA innervation of the PnO that may interact with local GABA(A) receptors in the control of state. Utilizing a retrograde tracer, cholera toxin-B subunit (CTb), injected into the PnO and dual-label immunohistochemistry with an antibody against glutamic acid decarboxalase-67 (GAD67), we report on a previously unidentified GABAergic neuronal population projecting to the contralateral PnO appearing as a column of cells, with long-axis in the sagittal plane, extending through the midbrain and pons. We refer to these neurons as the mesopontine GABAergic column (MPGC). The contiguous, columnar, anatomical distribution suggests operation as a functional neural system, which may influence expression of REM sleep, wake and other behaviors subserved by the PnO.

Future directions in neoadjuvant therapy of rectal cancer: maximizing pathological complete response rates.

Neoadjuvant therapy is widely accepted as the current standard of care for localized rectal cancer. Downstaging of disease has been significantly improved and pathological complete response rates (pCR) which were historically below 10% with preoperative radiation alone, now range from 15% to 30% with preoperative chemo-radiation. While the availability of new chemotherapeutic drugs (Irinotecan, Oxaliplatin, etc.) and molecular targeted agents (Bevacizamab, Cetuximab, etc.) hold a great deal of promise, results of recent studies indicate that the pCR rate with neoadjuvant therapy appears to have plateaued at 20-30%. The use of more intensive multidrug combinations has, however, significantly increased the toxicity of treatment. New paradigms in neoadjuvant therapy are therefore needed to further improve results of treatment. This review presents strategies for neoadjuvant therapy, with the potential to improve pCR rates and also survival of patients.

Management of rectal cancer: short- vs. long-course preoperative radiation.

There is considerable debate on the optimum approach to neoadjuvant therapy in rectal cancer. This review of major published studies of short-course preoperative radiation and the more conventional approach of long-course neoadjuvant chemoradiation was undertaken in an effort to understand the potential advantages and disadvantages of each of these approaches. Studies were evaluated with regard to patient selection, clinical outcomes, and toxicities. Short-course preoperative radiation has shown a clear advantage over surgery alone in reducing local recurrence rates and improving survival of patients with rectal cancer. However, studies using short-course preoperative treatment have included a significant number of early (30%; Stage I/II) and more proximal cancers yet appear to have higher positive margin rates, higher abdominoperineal resection rates, and lower aggregate survival than patients treated with long-course neoadjuvant chemoradiation. Although long-course preoperative chemoradiation is associated with higher rates of reversible acute toxicity, there appears to be more significant and a higher rate of late gastrointestinal toxicity observed in short-course preoperative radiation studies. Patient convenience and lower cost of treatment, however, can be a significant advantage in using a short-course treatment schedule. Selective utilization of either of these approaches should be based on extent of disease and goals of treatment. Patients with distal cancers or more advanced disease (T3/T4) appear to have better outcomes with neoadjuvant chemoradiation, especially where downstaging of disease is critical for more complete surgical resection and sphincter preservation.

Ablation of Kv3.1 and Kv3.3 potassium channels disrupts thalamocortical oscillations in vitro and in vivo.

The genes Kcnc1 and Kcnc3 encode the subunits for the fast-activating/fast-deactivating, voltage-gated potassium channels Kv3.1 and Kv3.3, which are expressed in several brain regions known to be involved in the regulation of the sleep-wake cycle. When these genes are genetically eliminated, Kv3.1/Kv3.3-deficient mice display severe sleep loss as a result of unstable slow-wave sleep. Within the thalamocortical circuitry, Kv3.1 and Kv3.3 subunits are highly expressed in the thalamic reticular nucleus (TRN), which is thought to act as a pacemaker at sleep onset and to be involved in slow oscillatory activity (spindle waves) during slow-wave sleep. We showed that in cortical electroencephalographic recordings of freely moving Kv3.1/Kv3.3-deficient mice, spectral power is reduced up to 70% at frequencies <15 Hz. In addition, the number of sleep spindles in vivo as well as rhythmic rebound firing of TRN neurons in vitro is diminished in mutant mice. Kv3.1/Kv3.3-deficient TRN neurons studied in vitro show approximately 60% increase in action potential duration and a reduction in high-frequency firing after depolarizing current injections and during rebound burst firing. The results support the hypothesis that altered electrophysiological properties of TRN neurons contribute to the reduced EEG power at slow frequencies in the thalamocortical network of Kv3-deficient mice.

Redefining contraindications to laparoscopic colorectal resection for high-risk patients.

BACKGROUND: Patients with major comorbidities often are denied laparoscopic colorectal resections because they are thought to be at too "high risk." Paradoxically, these patients generally have the most to gain from a minimally invasive surgical approach. This study aimed to examine the feasibility and safety of laparoscopic colorectal resection to determine whether it is contraindicated for "high-risk" patients. METHODS: From August 1996 to February 2004, 368 consecutive patients (95 men) undergoing a laparoscopic colorectal procedure by a single surgeon were prospectively studied with regard to pre-, peri-, and postoperative events. High-risk patients (n = 190) were defined as elderly (age, >80 years; n = 28), morbidly obese (body mass index [BMI], >30 kg/m(2); n = 55), American Society of Anesthesiology (ASA) 3 or 4 (n = 130), and recipients of preoperative radiotherapy (n = 54). Multiple risk factors were found for 67 patients, 7 of whom had three risk factors. The median age of the patients was 66 years (range, 19-92 years). The diagnoses included rectal cancer (n = 48), diverticulitis (n = 43), colon cancer (n = 34), benign polyp (n = 26), and other (n = 39). The following procedures were performed: colon resection (n = 114; left, 63; right, 41; total abdominal colectomy, 10), rectal resection (low anterior resection or pouch) (n = 49), coloanal anastomosis (n = 23), and other (n = 4). Data regarding intent to treat, operative events, morbidity, mortality, and outcomes were analyzed and form the basis of this report. RESULTS: No mortalities occurred. The major morbidity rate was 2%. There were no anastomotic leaks. The cases were laparoscopically performed (94%) or laparoscopically assisted, or were converted to open procedure (3%). The median estimated blood loss was 200 ml, and only 5% required perioperative transfusion. The perioperative course involved the following median periods: 2 days until flatus, 3 days until bowel movement, 1 day until clear liquid diet, 3 days until a regular diet, and 5 days until hospital discharge. CONCLUSION: In experienced hands, laparoscopic colorectal resection can be performed safely for "high-risk" surgical patients. The better than expected outcomes in this patient population reinforce the benefits of minimally invasive surgery for this patient group and argues against using parameters of increased age, morbid obesity, high ASA class, or preoperative radiation alone as contraindications to even complex laparoscopic colorectal procedures.

Carbachol induction of REM sleep in the rat is more effective at lights-out than lights-on.

Long-lasting increases in REM sleep are induced in the rat following injection of small amounts of muscarinic receptor agonists into the caudal oral pontine reticular formation. By injecting carbachol at the beginning of the light period or beginning of the dark period, we sought to determine whether the muscarinic, REM sleep induction is influenced by the time of day it is initiated. We found that carbachol is more effective at increasing REM sleep when administered at the beginning of the dark in 87% of the cases. Of these cases, 43% showed evidence of a decreased potency of carbachol by a shift in the dose-response curve to the right. The lack of agreement in efficacy and potency to increase REM sleep supports a conclusion that alterations in local muscarinic receptors are not mediating the effect of time of day. REM sleep control mechanisms down stream of the muscarinic receptors may be the responsible factors.

Kv3 potassium channels control the duration of different arousal states by distinct stochastic and clock-like mechanisms.

Sleep-wake behavior is tightly controlled in many animal species, suggesting genetically encoded, homeostatic control mechanisms that determine arousal-state dynamics. We reported that two voltage-gated potassium channels, Kv3.1 and Kv3.3, control sleep in wild-type and Kv3-mutant mice. Compared with wild-type (WT), homozygous double mutants (DKO) that lack these channels sleep 40% less in the light and 22% less in the dark. To understand how the lack of these channels affects sleep, we analysed arousal-state changes during the light period where the differences are greatest between WT and DKO. We determined the kinetic complexity of each arousal state from the episode durations of wakefulness, slow-wave sleep and rapid eye movement sleep (REMS). Based on the number of exponential components in episode-duration histograms, WT and DKO mice have several kinetically distinct states of wakefulness, and these states are longer in duration in DKO. For slow-wave sleep, WT mice have a single slow-wave sleep (SWS) state in contrast to DKO mice, which show two distinct SWS states, one that is 60% shorter than that in WT and a second that is similar in duration. Both WT and DKO mice have two kinetically distinct REMS states. DKO mice show an 84% reduction in the frequency of short REMS episodes (<45 s) without any change in the occurrence of long REMS episodes (>60 s). In contrast to the stochastic control of episode durations of wakefulness and SWS, the durations of both REMS states are normally distributed, indicating that the underlying control processes are fundamentally different.

Adenosine A1 receptors mediate inhibition of cAMP formation in vitro in the pontine, REM sleep induction zone.

Microinjection of adenosine A1 receptor agonist or an inhibitor of adenylyl cyclase into the caudal, oral pontine reticular formation (PnOc) of the rat induces a long-lasting increase in REM sleep. Here, we report significant inhibition of forskolin-stimulated cAMP in dissected pontine tissue slices containing the PnOc incubated with the A1 receptor agonist, cyclohexaladenosine (10(-8) M). These data are consistent with adenosine A1 receptor agonist actions on REM sleep mediated through inhibition of cAMP.