Treatment sequencing and impact of number of treatment lines on survival in follicular lymphoma: A national population-based study.

Follicular lymphoma (FL) is a clinically heterogeneous disease. The need for treatment, treatment sequencing, number of treatment lines, and its association with survival have not been described in a population-based setting. We identified all patients diagnosed with FL in the Swedish Lymphoma register from 2007 to 2014, followed until 2020, with detailed data on progression/relapse, transformation, and 2nd and further lines of therapy. During a median follow-up of 6.8 years, 1226 patients (69%) received 1st systemic treatment, 358 patients (20%) were managed with watch-and-wait (WaW) only, and 188 (10%) patients were treated with radiotherapy and did not require additional therapy during the study period. Among patients starting systemic treatment, 496 (40%), 224 (18%), and 88 (7%) received 2nd-, 3rd-, or 4th-line therapy, respectively. The 10-year cause-specific cumulative incidence of transformation was 13%. Among patients managed with 1st line R-single, R-CHOP, or BR, 54%, 33%, and 29% required 2nd line, respectively. The cumulative probability of starting subsequent treatment within 2 years was 26% after 1st line and 35% after 2nd line treatment. Two-year OS following 1st, 2nd, 3rd, and 4th line systemic treatment was 84%, 70%, 52%, and 36%, respectively, and remained similar when excluding transformations. We conclude that a substantial proportion of FL patients can be managed with WaW for a long period of time, while patients who require multiple treatment lines constitute a group with a large clinical unmet need. These results constitute valuable real-world reference data for FL.

Incidence of adhesive small bowel obstruction after surgery for colorectal cancer in Sweden 2007-2016.

AIM: Population-based data on incidence and risk factors of adhesive small bowel obstruction (SBO) are limited. The aims of this study were to assess the risk of SBO and SBO surgery after bowel resection for colorectal cancer (CRC) and to assess whether this risk is modified by minimally invasive surgery (MIS) and radiotherapy in a retrospective national study. METHODS: CRCBaSe, a nationwide register linkage originating from the Swedish Colorectal Cancer Register, was used to identify Stage I-III CRC patients who underwent resection in 2007-2016, with follow-up throughout 2017. Matched CRC-free comparators (1:6) were included as a reference of SBO and SBO surgery incidence. The association between MIS and preoperative radiotherapy and the incidence rate of SBO was evaluated in adjusted multivariable Cox regression models. RESULTS: Among 33 632 CRC patients and 198 649 comparators, the 5-year cumulative incidence of SBO and SBO surgery was 7.6% and 2.2% among patients and 0.6% and 0.2% among comparators, with death as a competing risk. In all patients, MIS was associated with a reduced incidence of SBO (hazard ratio [HR] 0.7, 95% CI 0.6-0.8) and SBO surgery (HR 0.5, 95% CI 0.3-0.7). In rectal cancer patients, radiotherapy was associated with an increased incidence of SBO (HR 1.6, 95% CI 1.4-1.8) and SBO surgery (HR 1.7, 95% CI 1.3-2.3). DISCUSSION: Colorectal cancer surgery is associated with a marked increase in risk of SBO, compared with the general population. The incidence is further increased if open surgery or radiotherapy is performed.

Transcranial Doppler Ultrasound, Perfusion Computerized Tomography, and Cerebral Angiography Identify Different Pathological Entities and Supplement Each Other in the Diagnosis of Delayed Cerebral Ischemia.

INTRODUCTION: There is still controversial discussion of the value of transcranial Doppler (TCD) in predicting vasospasms in patients with aneurysmal SAH (aSAH). A newer method of predicting a delayed ischemic deficit (DCI) is CT perfusion (CTP), although it is not quite understood which kind of perfusion deficit is detected by this method since it seems to also identifying microcirculatory disturbances. We compared the TCD and CTP values with angiography and evaluated TCD and CTP changes before and after patients received intra-arterial spasmolytic therapy. MATERIAL AND METHODS: Retrospective analysis of TCD, CTP, and angiographies of N = 77 patients treated from 2013 to 2016. In 38 patients intra-arterial spasmolysis had been performed, and in these cases TCD and CTP data were compared before and after lysis. Thirty-nine patients had a pathological CTP but no angiographically seen vasospasm. RESULTS: There was no correlation between the known thresholds of mean transit time (MTT) in CTP and vasospasm or with mean velocities in TCD and vasospasm. After spasmolysis in patients with vasospasms, only the MTT showed significant improvement, whereas TCD velocities and Lindegaard index remained unaffected. CONCLUSION: TCD and CTP seem to identify different pathological entities of DCI and should be used supplementary in order to identify as many patients as possible with vasospasms after aSAH.

Leg Prosthesis With Somatosensory Feedback Reduces Phantom Limb Pain and Increases Functionality.

Phantom limb pain (PLP) develops in most patients with lower limb amputation. Changes in the peripheral and central nervous system (CNS) are hypothesized to contribute to PLP. Based on ideas to modify neural reorganization within the CNS, the aim of the study was to test, whether prostheses with somatosensory feedback might help to reduce PLP, and increase the functionality of movement with a prosthesis. We therefore equipped the prostheses of 14 lower leg amputees with a simple to use feedback system that provides electrocutaneous feedback to patients' thigh whenever the foot and toes of the prosthesis touch the ground. Two weeks of training with such a feedback prosthesis reduced PLP, increased the functional use of the prosthesis, and increased patients' satisfaction with prosthesis use. We found a significant overall reduction of PLP during the course of the training period. Most patients reported lower PLP intensities at the end of the day while before training they have usually experienced maximal PLP intensities. Furthermore, patients also reported larger walking distances and more stable walking and better posture control while walking on and across a bumpy or soft ground. After training, the majority of participants (9/14) preferred such a feedback system over no feedback. This study extends former observations of a similar training procedure with arm amputees who used a similar feedback training to improve the functionality of an arm prosthesis in manipulating and grasping objects.

Referred cramping phantom hand pain elicited in the face and eliminated by peripheral nerve block.

Phantom limb pain is a restricting condition for a substantial number of amputees with quite different characteristics of pain. Here, we report on a forearm amputee with constant phantom pain in the hand, in whom we could regularly elicit the rare phenomenon of referred cramping phantom pain by touching the face. To clarify the underlying mechanisms, we followed the cramp during the course of an axillary blockade of the brachial plexus. During the blockade, both phantom pain and the referred cramp were abolished, while a referred sensation of "being touched at the phantom" persisted. Furthermore, to identify the cortical substrate, we elicited the cramp during functional magnetic imaging. Imaging revealed that referred cramping phantom limb pain was associated with brain activation of the hand representation in the primary sensorimotor cortex. The results support the hypothesis that referred cramping phantom limb pain in this case is associated with a substantial brain activation in the hand area of the deafferented sensorimotor cortex. However, this alone is not sufficient to elicit referred cramping phantom limb pain. Peripheral inputs, both, from the arm nerves affected by the amputation and from the skin in the face at which the referred cramp is evoked, are a precondition for referred cramping phantom limb pain to occur, at least in this case.

Compromised Grid-Cell-like Representations in Old Age as a Key Mechanism to Explain Age-Related Navigational Deficits.

A progressive loss of navigational abilities in old age has been observed in numerous studies, but we have only limited understanding of the neural mechanisms underlying this decline [1]. A central component of the brain's navigation circuit are grid cells in entorhinal cortex [2], largely thought to support intrinsic self-motion-related computations, such as path integration (i.e., keeping track of one's position by integrating self-motion cues) [3-6]. Given that entorhinal cortex is particularly vulnerable to neurodegenerative processes during aging and Alzheimer's disease [7-14], deficits in grid cell function could be a key mechanism to explain age-related navigational decline. To test this hypothesis, we conducted two experiments in healthy young and older adults. First, in an fMRI experiment, we found significantly reduced grid-cell-like representations in entorhinal cortex of older adults. Second, in a behavioral path integration experiment, older adults showed deficits in computations of self-position during path integration based on body-based or visual self-motion cues. Most strikingly, we found that these path integration deficits in older adults could be explained by their individual magnitudes of grid-cell-like representations, as reduced grid-cell-like representations were associated with larger path integration errors. Together, these results show that grid-cell-like representations in entorhinal cortex are compromised in healthy aging. Furthermore, the association between grid-cell-like representations and path integration performance in old age supports the notion that grid cells underlie path integration processes. We therefore conclude that impaired grid cell function may play a key role in age-related decline of specific higher-order cognitive functions, such as spatial navigation.

Quantitative sensory testing after macroreplantation: evidence for a specific somatosensory profile.

A comprehensive functional recovery is one of the criteria for successful replantation of an amputated limb. Functionality of a replanted limb is strongly dependent on its regained sensibility. In previous studies concerning the sensibility of replanted limbs, only a few somatosensory submodalities were examined in small samples. The purpose of this study is to provide a full pattern of somatosensory symptoms after replantation. Quantitative sensory testing was performed according to a standardized protocol in a sample of 15 patients who underwent replantation of their upper limb proximal to the radiocarpal joint (macroreplantation). Results indicate that most of these patients showed a specific somatosensory profile characterized by thermal and mechanical hypoesthesia and hyperalgesia in response to pressure pain, whereas no single case of hyperalgesia to heat pain occurred. This distinct profile of impaired somatosensation shares some features of the somatosensory profile of neuropathic pain syndromes. Patients' limbs that were replanted many years before the present quantitative sensory testing showed more sensory deficits than patients with more recent replantations. This knowledge might be helpful in the development of more specific and more successful rehabilitation programs with replanted patients and improves the behavioral function of the replanted limb.

Preliminary Evidence for Training-Induced Changes of Morphology and Phantom Limb Pain.

The aim of this study was to investigate whether a special prosthetic training in phantom limb pain patients aimed at increasing the functional use of the prosthesis leads to neural morphological plasticity of brain structures and a reduction in phantom limb pain. For chronic pain disorders, it was shown that morphological alterations due to pain might become at least partially reversed by pain therapies. Phantom limb pain is a chronic pain disorder that is frequently followed by neural plasticity of anatomical brain structures. In our study, 10 patients with amputation of the upper limb participated in a two-week training with a myoelectric prosthesis with somatosensory feedback. Grip strength was fed back with electrocutaneous stimulus patterns applied to the stump. Phantom limb pain was assessed before and after the two-week training. Similarly, two T1 weighted MRI scans were conducted for longitudinal thickness analyses of cortical brain structures. As result of this treatment, patients experienced a reduction in phantom limb pain and a gain in prosthesis functionality. Furthermore, we found a change of cortical thickness in small brain areas in the visual stream and the post-central gyrus ipsilateral to the amputation indicating morphological alterations in brain areas involved in vision and pain processing.

Dermatomal Organization of SI Leg Representation in Humans: Revising the Somatosensory Homunculus.

Penfield and Rasmussen's homunculus is the valid map of the neural body representation of nearly each textbook of biology, physiology, and neuroscience. The somatosensory homunculus places the foot representation on the mesial surface of the postcentral gyrus followed by the representations of the lower leg and the thigh in superio-lateral direction. However, this strong homuncular organization contradicts the "dermatomal" organization of spinal nerves. We used somatosensory-evoked magnetic fields and source analysis to study the leg's neural representation in the primary somatosensory cortex (SI). We show that the representation of the back of the thigh is located inferior to the foot's representation in SI whereas the front of the thigh is located laterally to the foot's representation. This observation indicates that the localization of the leg in SI rather follows the dermatomal organization of spinal nerves than the typical map of neighboring body parts as depicted in Penfield and Rasmussen's illustration of the somatosensory homunculus.

Enhanced Brain Responses to Pain-Related Words in Chronic Back Pain Patients and Their Modulation by Current Pain.

Previous functional magnetic resonance imaging (fMRI) studies in healthy controls (HC) and pain-free migraine patients found activations to pain-related words in brain regions known to be activated while subjects experience pain. The aim of the present study was to identify neural activations induced by pain-related words in a sample of chronic back pain (CBP) patients experiencing current chronic pain compared to HC. In particular, we were interested in how current pain influences brain activations induced by pain-related adjectives. Subjects viewed pain-related, negative, positive, and neutral words; subjects were asked to generate mental images related to these words during fMRI scanning. Brain activation was compared between CBP patients and HC in response to the different word categories and examined in relation to current pain in CBP patients. Pain-related words vs. neutral words activated a network of brain regions including cingulate cortex and insula in subjects and patients. There was stronger activation in medial and dorsolateral prefrontal cortex (DLPFC) and anterior midcingulate cortex in CPB patients than in HC. The magnitude of activation for pain-related vs. negative words showed a negative linear relationship to CBP patients' current pain. Our findings confirm earlier observations showing that pain-related words activate brain networks similar to noxious stimulation. Importantly, CBP patients show even stronger activation of these structures while merely processing pain-related words. Current pain directly influences on this activation.

Cortical reorganization after macroreplantation at the upper extremity: a magnetoencephalographic study.

With the development of microsurgical techniques, replantation has become a feasible alternative to stump treatment after the amputation of an extremity. It is known that amputation often induces phantom limb pain and cortical reorganization within the corresponding somatosensory areas. However, whether replantation reduces the risk of comparable persisting pain phenomena as well as reorganization of the primary somatosensory cortex is still widely unknown. Therefore, the present study aimed to investigate the potential development of persistent pain and cortical reorganization of the hand and lip areas within the sensory cortex by means of magnetoencephalographic dipole analyses after replantation of a traumatically amputated upper limb proximal to the radiocarpal joint. Cortical reorganization was investigated in 13 patients with limb replantation using air puff stimulation of the phalanges of both thumbs and both corners of the lower lip. Displacement of the centre of gravity of lip and thumb representations and increased cortical activity were found in the limb and face areas of the primary somatosensory cortex contralateral to the replanted arm when compared to the ipsilateral hemisphere. Thus, cortical reorganization in the primary somatosensory cortex also occurs after replantation of the upper extremity. Patients' reports of pain in the replanted body part were negatively correlated with the amount of cortical reorganization, i.e. the more pain the patients reported, the less reorganization of the subjects' hand representation within the primary somatosensory cortex was observed. Longitudinal studies in patients after macroreplantation are necessary to assess whether the observed reorganization in the primary somatosensory cortex is a result of changes within the representation of the replanted arm and/or neighbouring representations and to assess the relationship between the development of persistent pain and reorganization.

Human brain stem structures respond differentially to noxious heat.

Concerning the physiological correlates of pain, the brain stem is considered to be one core region that is activated by noxious input. In animal studies, different slopes of skin heating (SSH) with noxious heat led to activation in different columns of the midbrain periaqueductal gray (PAG). The present study aimed at finding a method for differentiating structures in PAG and other brain stem structures, which are associated with different qualities of pain in humans according to the structures that were associated with different behavioral significances to noxious thermal stimulation in animals. Brain activity was studied by functional MRI in healthy subjects in response to steep and shallow SSH with noxious heat. We found differential activation to different SSH in the PAG and the rostral ventromedial medulla (RVM). In a second experiment, we demonstrate that the different SSH were associated with different pain qualities. Our experiments provide evidence that brainstem structures, i.e., the PAG and the RVM, become differentially activated by different SSH. Therefore, different SSH can be utilized when brain stem structures are investigated and when it is aimed to activate these structures differentially. Moreover, percepts of first pain were elicited by shallow SSH whereas percepts of second pain were elicited by steep SSH. The stronger activation of these brain stem structures to SSH, eliciting percepts of second vs. first pain, might be of relevance for activating different coping strategies in response to the noxious input with the two types of SSH.

Plasticity in the Visual System is Associated with Prosthesis Use in Phantom Limb Pain.

The experience of strong phantom limb pain (PLP) in arm amputees was previously shown to be associated with structural neural plasticity in parts of the cortex that belong to dorsal and ventral visual streams. It has been speculated that this plasticity results from the extensive use of a functional prosthesis which is associated with increased visual feedback to control the artificial hand. To test this hypothesis, we reanalyzed data of cortical volumes of 21 upper limb amputees and tested the association between the amount of use of the hand prosthesis and cortical volume plasticity. On the behavioral level, we found no relation between PLP and the amount of prosthesis use for the whole patient group. However, by subdividing the patient group into patients with strong PLP and those with low to medium PLP, stronger pain was significantly associated with less prosthesis use whereas the group with low PLP did not show such an association. Most plasticity of cortical volume was identified within the dorsal stream. The more the patients that suffered from strong PLP used their prosthesis, the smaller was the volume of their posterior parietal cortex. Our data indicate a relationship between prosthesis use and cortical plasticity of the visual stream. This plasticity might present a brain adaptation process to new movement and coordination patterns needed to guide an artificial hand.

Gray matter changes following limb amputation with high and low intensities of phantom limb pain.

Limb amputation and chronic phantom limb pain (PLP) are both associated with neural alterations at all levels of the neuraxis. We investigated gray matter volume of 21 upper limb amputees and 14 healthy control subjects. Results demonstrate that amputation is associated with reduced gray matter in areas in the motor cortex representing the amputated limb. Additionally, patients show an increase in gray matter in brain regions that belong to the dorsal and ventral visual stream. We subdivided the patient group into patients with medium to high PLP (HPLP; N = 11) and those with slight PLP (SPLP; N = 10). HPLP patients showed reduced gray matter in brain areas involved in pain processing. SPLP patients showed a significant gray matter increase in regions of the visual stream. Results indicate that all patients may have an enhanced need for visual control to compensate the lack of sensory feedback of the missing limb. As we found these alterations primarily in the SPLP patient group, successful compensation may have an impact on PLP development. Therefore, we hypothesize that visual adaptation mechanisms may compensate for the lack of sensorimotor feedback and may therefore function as a protection mechanism against high PLP development.

Sensory feedback prosthesis reduces phantom limb pain: proof of a principle.

BACKGROUND: Constrained functionality and phantom limb pain (PLP) are major concerns for forearm amputees. Neuroscientific investigations of PLP suggest that behaviorally relevant stimulation of the stump can decrease PLP. Furthermore the prosthesis user could use feedback information of the prosthesis hand for optimizing prosthesis motor control when handling soft and fragile objects. Somatosensory feedback information from a prosthetic hand may therefore help to improve prosthesis functionality and reduce phantom limb pain. OBJECTIVES: We wanted to find out whether a two weeks training on a hand prosthesis that provides somatosensory feedback may help to improve prosthesis functionality and reduce phantom limb pain. METHODS: Eight forearm amputees with phantom limb pain were trained for two weeks to use a hand prosthesis with somatosensory feedback on grip strength. RESULTS: The current study demonstrates a significant increase of functionality of the prosthesis in everyday tasks. Furthermore, the study shows that usage of a prosthesis that provides somatosensory feedback on the grip strength is effective to reduce phantom limb pain. CONCLUSIONS: A prosthesis with a feedback function appears to be a promising therapeutic tool to reduce phantom limb pain and to increase functionality in everyday tasks. Future studies should further investigate the scope of application of that principle.

Brachial plexus block in phantom limb pain: a case report.

OBJECTIVE: The purpose of this case report is twofold: first, to present evidence of long-lasting relief in a patient suffering from phantom limb pain after pharmacologically blocking his plexus brachialis and, second, to replicate results from a previous study focusing on cortical reorganization and phantom limb pain. SUBJECT: Before regional anesthesia, the patient suffered from a phantom hand that cramped and was immovable. SETTING: We performed a diagnostic axillary blockade of the brachial plexus to differentiate peripheral from more central contributions to phantom limb pain. RESULTS: During blockade of the brachial plexus, the patient reported a reduction of phantom limb pain for the first time following years of suffering and a complete loss of cramping together with muscle relaxation of the phantom hand. Additionally, we found cortical reorganization in the primary somatosensory cortex (re-reorganization). Strikingly, the relaxed phantom limb together with the reduction of phantom limb pain remained preserved even 6 months after blockade of the brachial plexus. CONCLUSIONS: A single temporary blockade of the brachial plexus may relieve phantom limb pain and unpleasant phantom feelings (cramping) for an extended period.

The volatility of the amygdala response to masked fearful eyes.

Recently, it has been suggested that backwardly masked, and thus subliminally presented, fearful eyes are processed by the amygdala. Here, we investigated in four functional magnetic resonance imaging experiments whether the amygdala responds to subliminally presented fearful eyes per se or whether an interaction of masked eyes with the masks or with parts of the masks used for backward masking might be responsible for the amygdala activation. In these experiments, we varied the mask as well as the position of the target eyes. The results show that the amygdala does not respond to masked fearful eyes per se but to an interaction between masked fearful eyes and the eyes of neutral faces used for masking. This finding questions the hypothesis that the amygdala processes context-free parts of the human face without awareness.