Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer.

BACKGROUND: Initial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/ tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/ tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches. METHODS: FIRE-8 ( NCT05007132 ) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m2 body surface area (BSA), orally twice daily on days 1-5 and 8-12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled. DISCUSSION: To the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy. TRIAL REGISTRATION: EU Clinical Trials Register (EudraCT) 2019-004223-20 . Registered October 22, 2019, ClinicalTrials.gov NCT05007132 . Registered on August 12, 2021.

[Collected data on freehand technique instrumentation and literature comparison on fluoroscopic and CT-assisted navigation]. / Erhobene Daten zur Instrumentierung in Freihandtechnik und Literaturvergleich zu fluoroskopisch- und CT-gestützter Navigation.

BACKGROUND: A proven and frequently used surgical procedure in patients with idiopathic scoliosis (IS) is posterior transpedicular corrective spondylodesis using the freehand technique. Novel procedures with fluoroscopically and computed tomography (CT)-assisted navigation are presumed to be less risky and more accurate. OBJECTIVE: Is the freehand technique for IS safe with respect to screw-associated complications and intraoperative radiation exposure? MATERIAL AND METHODS: Prospectively collected data (2017-2018) from 39 consecutive patients (average age 18.7 years) with thoracic single curvature IS (61.7°â€¯± 13.9°) from a specialized scoliosis center were evaluated for the following parameters (mean ± standard deviation): total radiation product, fluoroscopy time, fused segments, operative time, blood loss and screw-associated complications. A comparison with data from the literature on intraoperative radiation exposure using navigation procedures was carried out. RESULTS: The total radiation product per patient was 71.7 ± 44.0 cGy*cm2, fluoroscopy time 17.4 ± 8.6 s. (7.8 segments), operative time 183.5 ± 54.2 min and blood loss 379.5 ± 183 ml. There were no screw-associated complications in the entire collective. Correction of the main curvature was 75.7%. Comparison of the data with index data from the literature showed a 1.25-12.5-fold higher radiation exposure for patients with fluoroscopically assisted navigation and 9.25-12.3-fold higher radiation exposure with CT-assisted procedures compared to the present results. CONCLUSION: The results of this study showed that with appropriate experience freehand positioning of pedicle screws is associated with comparable accuracy and less radiation exposure for patients than navigation procedures. With respect to the young age of patients, a radiation-induced long-term risk for malignant diseases should be taken into consideration.

Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus.

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon-γ cytokine production and promote interleukin-10 production in old CD4+ T cells. In addition, TAC administration decreased interleukin-2 secretion in old CD4+ T cells more effectively while inhibiting the proliferation of CD4+ T cells in old mice. Both TAC-treated murine and human CD4+ T cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8+ T cells did not alter allograft survival outcome in old TAC-treated mice, suggesting that TAC age-specific effects were mainly CD4+ T cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4+ T cell mediated. The suppression of calcineurin levels and Ca2+ influx in both old murine and human T cells emphasizes the clinical relevance of age-specific effects when using TAC.

The effect of incidental dural lesions on outcome after decompression surgery for lumbar spinal stenosis: results of a multi-center study with 800 patients.

PURPOSE: Incidental durotomy is one of the most common complications in lumbar spine surgery. There are conflicting reports whether a dural lesion is associated with an inferior outcome after lumbar decompression. This study analyzed the effect of incidental durotomy in this specific group of patients (Dura+) and compared the results with the remaining cohort without dural laceration (Dura-). METHODS: This prospective multi-center study included 800 patients with lumbar spinal stenosis who underwent exclusive decompression surgery. All procedures were performed as part of a multi-center investigation at three highly specialized spine clinics. Outcome measures (ODI, EQ5D, VASback pain and VASleg pain) were obtained preoperatively as well as 3 and 12 months after surgery. The effect of an incidental durotomy on the clinical outcomes was analyzed statistically between the two cohorts. RESULTS: An intraoperative dura lesion was recorded in 6.5 % (n = 52/800) of all cases. Both cohorts (Dura+ and Dura-) did not reveal any differences regarding patient demographics, risk factors, or co-morbidities at baseline. The length of the hospital stay was significantly longer for the Dura+ cohort (8.0 vs. 6.4 days; p < 0.01). After 12 months, the Dura- cohort demonstrated a significantly greater improvement in VASback pain in comparison to the Dura+ cohort (Δ21.4 vs. Δ7.2 points; p < 0.05). The differences for the remaining outcome measures were not statistically significant (p > 0.05). CONCLUSIONS: The results of this study reveal that an incidental durotomy was associated with a significant increase in the patient's length of stay, and risk for re-intervention for the treatment of persisting CSF leakage. In contrast to previous reports which have investigated the effects of incidental durotomies on the clinical outcome after lumbar decompression surgery, our data further suggest a possible inferior outcome in terms of low back pain improvement in the Dura+ cohort, which became clinically apparent at the 12-month follow-up period. Future studies should investigate whether a more pronounced decompression required for adequate exposure and repair of a dural laceration may, ultimately, result in increased segmental instability and in clinically undesirable low back pain.

A case of cutaneous Rhodotorula infection mimicking cryptococcosis.

Rhodotorula is a ubiquitous environmental and commensal yeast, and an emerging opportunistic pathogen, particularly in immunocompromised individuals. Clinical infections with Rhodotorula have been increasingly recognized over the past 30 years; however, infections in solid-organ transplant recipients are uncommon, and cutaneous manifestations have rarely been reported. We describe a 59-year-old male renal transplant recipient, who developed cutaneous infection with Rhodotorula upon failure of his graft and commencement of haemodialysis.

Obesity-related immune responses and their impact on surgical outcomes.

The obesity epidemic represents a critical disease burden with broad clinical consequences. At the same time, obesity has been linked to inferior surgical outcomes and considered a contraindication for some elective surgical procedures. A growing body of mechanistic evidence has accumulated linking obesity to changes of metabolism and immune responses. This concept provides an integrated inflammatory network based on the perception of obesity as a state of chronic low-grade inflammation. With a more detailed understanding of this dynamic network and mechanistic insights, novel treatment and management strategies may be developed with the goal to optimize surgical outcomes in obese patients.

[Thromboprophylaxis and platelet aggregation inhibitors in spinal surgery: perioperative management]. / Thromboseprophylaxe und Aggregationshemmer in der Wirbelsäulenchirurgie: perioperative Management.

BACKGROUND: The perioperative use of anticoagulants (AC) and platelet aggregation inhibitors (PAI) in the field of spinal surgery suggests an increased rate of epidural bleeding. However, evidence is lacking and these medications are most often indispensable in the prevention of thromboembolic complications. Comprehensive recommendations for the correct use of AC and PAI are lacking. OBJECTIVE: The aim of this study was an analysis of the current situation with regards to the use of AC and PAI in spinal surgery and development of new recommendations. MATERIAL AND METHODS: Two independent surveys on the perioperative use of AC and PAI were obtained from centers for spinal surgery in Germany. The study obtained information on the perioperative use of AC and PAI, risk assessment of thromboembolic and hemorrhagic events as well as on the type and extent of the substance groups used. RESULTS: Almost the entire patient collective (98%) received perioperative low molecular weight heparin. In 64% the medical prophylaxis was started before surgery and in 36% after surgery. The period of prophylaxis was determined arbitrarily. Approximately 40% of interviewees employed paravertebral infiltration and 19% injected into the epidural space in patients on PAI medication. Open spinal canal surgery was performed in 30% of PAI medicated patients and closed spinal canal surgery was executed in 40%. The risk assessment of PAI differed significantly between aspirin and receptor blocker medication as well as dual administration of PAI. DISCUSSION: The use of AC and PAI in spinal surgery in Germany is very heterogeneous and large deviations from the guidelines frequently occurred. Therefore, there is a strong need for further studies to accurately assess the perioperative use of AC and PAI and to formulate precise recommendations.

[The impact of sleep endoscopy for obstructive sleep-disordered breathing in children and adolescents]. / Bedeutung der Schlafendoskopie bei obstruktiv-schlafbezogener Atmungsstörung im Kindes- und Jugendalter.

OBJECTIVE: Studies on the surgical treatment of OSAS in adults have shown an improved outcome after targeted therapy by drug-induced sleep endoscopy (DISE). So far, only a few studies have focused on this method in children. The aim of this study is to evaluate the impact of DISE for children with obstructive sleep-disordered breathing and to determine the influence of DISE on treatment recommendations. SUBJECTS AND METHODS: The medical records of children (n=25) who underwent polysomnography and DISE between 05/2012 and 12/2013 were retrospectively reviewed. The subjects were divided into an UARS (upper airway resistance syndrome)/mild OSAS group (AHI<5; n=10) and a moderate/severe OSAS group (AHI≥5; n=15). RESULTS: The oropharynx was the most common site of obstruction. Prevalence of complete obstruction at the oropharynx was significantly higher in moderate or severe OSAS (p=0.02). The obstruction pattern of the velopharynx was significantly associated with the size of the adenoids (p=0.02), but tonsil and adenoid size were not related to the severity of OSAS. 71% of children with grade IV tonsils showed complete obstruction of the oropharynx. After DISE, the initial management plan changed in 5 patients (20%). CONCLUSION: DISE is a promising technique to identify sites of obstruction in children with OSAS and to guide treatment decisions. Further studies are needed to predict persistent OSAS based on this tool.

[Transforaminal lumbar interbody fusion for the treatment of degenerative spondylolisthesis]. / Transforaminale lumbale interkorporelle Fusion zur Versorgung der degenerativen Spondylolisthese.

INTRODUCTION: Degenerative spondylolisthesis (DS) is a common cause of lumbal and lumbosacral pain as well as radicular pain. Retention and fusion is a good treatment option. Some patients have a symptomatic adjacent degenerative disc disease (DDD) in addition to DS. In these cases the adjacent segments should be fused as well. There are different techniques of fusion available, such as posterior with instrumentation or additional anterior support. This study evaluated results of transforaminal lumbar interbody fusion (TLIF) in patients with monosegmental DS and adjacent DDD. MATERIAL AND METHODS: A total of 28 patients with monosegmental DS and adjacent DDD were included into the study (all patients with bisegmental posterior instrumentation and fusion, 14 patients 1 level TLIF, 14 patients 2 level TLIF). Before surgery and 12 months after surgery the following measurements were made: pain (visual analog scale VAS), Oswestry disability index (ODI) and plain radiographs with radiometric analysis. In a sub-analysis patients with 1 and 2 level TLIF were compared. RESULTS: Pain reduction (average VAS from 8.7-3.1) and ODI (63% to 28%) showed significant improvements. Radiometric analysis showed a significant disc height reconstruction and a significant reduction of spondylolisthesis (TLIF level with spondylolisthesis). Bisegmental anterior support showed a significantly better relordosation compared to monosegmental anterior support. The complication rate was 21.4% including hemorrhages, dura leakage, wound infection and adjacent segment degeneration. There were no fatal complications. DISCUSSION: The TLIF procedure is a safe and effective treatment for monosegmental DS with adjacent symptomatic DDD. Clinical results (pain, function) show no difference between both kinds of fusion (dorsal fusion and instrumentation versus dorsal fusion with instrumentation and TLIF) for the adjacent DDD. However, additional anterior support is more effective for relordosation of the segment. This could have impact on the mid-term and long-term outcome or in cases of adjacent segment fusion.

A rare case of perivascular epithelioid cell tumor (PEComa) of the pancreas diagnosed by endoscopic ultrasound.

A 49-year-old woman consulted her general practitioner (GP) regarding epigastric pain that she had experienced for 2 months. Physical examination and laboratory results were unremarkable. An abdominal ultrasound indicated a solid pancreatic tumor, which was confirmed on subsequent CT and MRI. Endoscopic ultrasound (EUS) showed a well-defined heterogeneous, predominantly hypoechoic mass in the pancreatic body, so a neuroendocrine tumor (NET) was suspected. However, EUS-guided fine-needle aspiration (EUS-FNA) was performed and based on (immuno-)histochemical findings, the extremely rare diagnosis of a perivascular epithelioid cell tumor (PEComa) of the pancreas was made. Due to the malignant potential of pancreatic PEComas, laparoscopic left-sided pancreatectomy was performed. We present a case diagnosed by preoperative EUS-FNA highlighting the clinical and endosonographic features which help to distinguish it from its most important differential diagnosis, neuroendocrine tumors (NETs) of the pancreas.

[Surgical management of adult scoliosis. The challenge of osteoporosis and adjacent level degeneration]. / Die operative Behandlung der adulten Skoliose. Osteoporose und Versagen des Anschlusssegments als besondere Herausforderung bei der operativen Versorgung.

Adult scoliosis is defined as a spinal deformity with a Cobb angle of more than 10 degrees in the coronal plain in a skeletally mature patient. Patients predominantly suffer from back pain symptoms, often accompanied by signs of spinal stenosis (central as well as lateral). Asymmetric degeneration leads to asymmetric load and therefore to a progression of the degeneration and deformity as either scoliosis (0.5-1 degree per year), kyphosis, or both. The diagnostic evaluation includes static and dynamic imaging, magnetic resonance imaging, and myelo-computed tomography, as well as invasive diagnostic procedures such as discograms, facet blocks, and epidural and root blocks. The treatment, either conservative or surgical, is then tailored to the patient's specific symptomatology. Surgical management is usually complex and must take into account an array of specific problems, including the patient's age and general medical condition, the length of the fusion, the condition of the adjacent segments, the condition of the lumbosacral junction, osteoporosis, and any previous scoliosis surgery. The main goal of corrective surgery is a balancing of the coronal and sagittal planes.This review focuses on the special indications for vertebral body cement augmentation in patients with osteoporosis and the problem of adjacent level degeneration and its surgical management.

[Anterior scoliosis surgery. State of the art and a comparison with posterior techniques]. / Ventrale Skolioseoperationen. Stand der Technik und Vergleich mit dorsalen Verfahren.

For more than 2 decades ventral derotation spondylodesis (Zielke VDS) as a major improvement over Dwyer instrumentation (DI) was the gold standard of instrumented curve correction and stabilization from the anterior approach. As the first available system it enables a true three-dimensional curve correction. A disadvantage is the low internal stabilization capability with a need for long-term external stabilization by means of cast and brace treatment postoperatively. Meanwhile with the development of modern single and dual solid rod systems these disadvantages can be avoided completely. Video-assisted (thoracoscopic) anterior scoliosis surgery accounts for less than 2% of anteriorly treated scoliosis cases, mainly due to a long operating time and significant learning curve.From the posterior approach the Cotrel-Dubousset instrumentation (CDI) as a polysegmentally attached posterior hook threaded dual rod system used to be state of the art for a long time, since it eliminated the disadvantages of Harrington instrumentation (HI) in terms of only one-dimensional correction and low stabilization capabilities. However even with CDI effective derotation was impossible. In posterior scoliosis surgery there is a strong trend away from hook systems towards transpedicular segmentally fixed dual rod systems not only in the lumbar spine but also in the thoracic area. Advantages of these newer techniques are shorter fusion, improved correction, and less loss of correction over time.Advantages of modern anterior instrumentation systems in comparison to posterior transpedicular instrumented dual rod systems are less blood loss, better derotation, slightly shorter fusion levels, and a better influence on sagittal plane control or improvement especially for hypokyphotic thoracic scoliosis cases. Our data also document a superior spontaneous correction of the lumbar curve after selective anterior instrumented correction (Lenke 1B+C), although other studies could not find significant differences. In our experience the neurological risk of anterior instrumented correction is also lower than that of posterior scoliosis surgery, although the morbidity and mortality data of the Scoliosis Research Society could not prove that anymore in recent years. A negative effect of anterior transthoracic scoliosis surgery in comparison to posterior surgery is a more negative effect on lung function, which improves slower after surgery and does not quite reach the levels of posterior surgery at follow-up. But new data on posterior segmental transpedicular correction and fusion also prove a lordosating effect with negative effect on lung function.

[Modern scoliosis surgery under the conditions of the German DRG-system]. / Finanzierbarkeit der modernen Skoliosechirurgie unter den Bedingungen des DRG-Systems.

In the German health system the payment of a hospital stay is standardised. The common basis is the G-DRG System (German diagnosis-related groups) in which every stay is paid by a lump sum. Scoliosis correction in our times means pedicle screw-based multilevel double rod instrumentation or anterior plate-rod instrumentation with primary stability. The outcome of those methods has improved the results of correction and decreased the complication rate but also means high costs due to the implants. Scoliosis correction is covered by DRG I06. Due to constant efforts a general improvement took place in the assessment of DRG I06. That is the reason why the losses incurred in DRG I06C could be lowered to 38% and in I06D to 22% in 2008. For an appropriate assessment further improvements are required.

Whole-heart coronary magnetic resonance angiography: value for the detection of coronary artery stenoses in comparison to multislice computed tomography angiography.

BACKGROUND: Coronary magnetic resonance imaging and computed tomography are being discussed as alternatives to catheter angiography in the detection of coronary artery disease. Yet, only few comparative validations have been performed. PURPOSE: To compare steady-state free precession whole heart coronary magnetic resonance imaging (MRI) with multidetector coronary computed tomography angiography (CTA) for the detection of coronary artery disease using catheter angiography as the standard of reference. MATERIAL AND METHODS: Twenty patients with known CAD were examined with navigator (NAV) gated and corrected free-breathing 3D balanced gradient echo whole heart coronary MRI and coronary CTA. Subjective overall image quality (4 point scale, 1 = excellent), visibility of vessel segments and accuracy for the detection of significant coronary stenoses (>50%) were compared to coronary x-ray angiography by two blinded readers. RESULTS: Median of subjective image quality was 3 for coronary MRI and 2 for coronary CTA. Of a total of 209 segments, 67 segments (32%) had to be excluded from the evaluation by coronary MRI (61 due to insufficient image quality and 6 due to stent artifacts). For coronary CTA, 31 segments (15%) had to be excluded from the evaluation (12 due to insufficient image quality, 15 due to severe calcifications superimposing the vessel lumen and 4 due to stent artifacts. Segment based values for the detection of >/=50% diameter coronary x-ray angiographic stenoses were: specificity: MRI 88%, CTA 95%; sensitivity: MRI 82%, CTA 84%; diagnostic accuracy: MRI 87%, CTA 93%; positive predictive value: MRI 68%, CTA 77% and negative predictive value: MRI 94%, CTA 95%. CONCLUSION: Coronary WH-MRI was inferior to coronary CTA regarding image quality and number of evaluable segments but both had similar diagnostic value for the detection and exclusion of CAD when only evaluable segments were included.

[Whole-heart coronary MR angiography -- initial results]. / Whole-Heart-MR-Koronarangiographie -- erste Ergebnisse.

PURPOSE: To evaluate a new coronary MR angiography technique covering the whole coronary artery tree in one data set acquisition. MATERIALS AND METHODS: Six healthy volunteers and 15 patients with known CAD were examined with a navigator gated and corrected (NAV) free-breathing 3D steady-state free precession sequence covering the whole heart (WH-MRA) (TR = 5.4, TE = 2.7, SENSE factor = 2, 160 slices, 0.75 mm reconstructed slice thickness, in-plane resolution = 0.99 x 0.99 mm(2), scan time 14 min [50 % NAV efficiency]) and a vessel targeted 3D SSFP MRA sequence (t-MRA) (TR = 5.6 ms, TE = 2.8 ms, 20 slices of 1.5 mm reconstructed slice thickness, in-plane resolution = 0.99 x 0.99 mm(2), scan time = 7 min [50 % NAV efficiency]). Subjective image quality (4-point scale) and objective image quality parameters including vessel sharpness, vessel diameter and CNR were calculated for WH-MRA and t-MRA. In patients, the accuracy for detection of stenosis larger than 50 % was compared to the accuracy of X-ray coronary angiography (XA), which was considered the standard. RESULTS: WH-MRA demonstrated good vessel visibility in healthy subjects (100 %) whereas vessel visibility in patients was limited (78 % in an 8 segment evaluation). Vessel sharpness was inferior to that of t-MRA in patients (37 vs. 42 %) but equal in healthy subjects (42 %). Vessel diameter did not differ significantly between WH-MRA and t-MRA. CNR was significantly reduced for WH-MRA (CNR 7.4 vs. 11.5). The diagnostic accuracy for the detection of CAD was comparable for both MRA approaches (85.5 vs. 86.2 %). CONCLUSION: WH-MRA allows good coronary artery visualization in healthy subjects and patients and provides a simplified scanning procedure and advantages in 3D post-processing. Regarding image parameters and the detection of CAD, the results are comparable to those acquired with t-MRA. The major disadvantage remains the high number of diagnostically insufficient images.

Bilateral parotid gland metastases from carcinoma of the breast that presented 25 years after initial treatment.

We report a case of a 76-year-old woman with metastases to both parotid glands almost 25 years after mastectomy and chemotherapy for primary carcinoma of the breast. Immunohistochemical staining is invaluable in establishing the origin of metastatic deposits, in this case, expression of oestrogen receptors in a previously resected adenocarcinoma of the breast. The information can be used to target treatment accurately in selected cases of advanced malignancy.

Subcortical structures involved in pain processing: evidence from single-trial fMRI.

Pain is processed in multiple cortical and subcortical brain areas. Subcortical structures are substantially involved in different processes that are closely linked to pain processing, e.g. motor preparation, autonomic responses, affective components and learning. However, it is unclear to which extent nociceptive information is relayed to and processed in subcortical structures. We used single-trial functional magnetic resonance imaging (fMRI) to identify subcortical regions displaying hemodynamic responses to painful stimulation. Thulium-YAG (yttrium-aluminum-granate) laser evoked pain stimuli, which have no concomitant tactile component, were applied to either hand of healthy volunteers in a randomized order. This procedure allowed identification of areas displaying differential fMRI responses to right- and left-sided stimuli. Hippocampal complex, amygdala, red nucleus, brainstem and cerebellum were activated in response to painful stimuli. Structures related to the affective processing of pain showed bilateral activation, whereas structures involved in the generation of withdrawal behavior, namely red nucleus, putamen and cerebellum displayed differential (i.e. asymmetric) responses according to the side of stimulation. This suggests that spatial information about the nociceptive stimulus is made available in these structures for the guidance of defensive and withdrawal behavior.