The GIST of it all: management of gastrointestinal stromal tumors (GIST) from the first steps to tailored therapy. A bibliometric analysis.

PURPOSE: Improvement of patient care is associated with increasing publication numbers in biomedical research. However, such increasing numbers of publications make it challenging for physicians and scientists to screen and process the literature of their respective fields. In this study, we present a comprehensive bibliometric analysis of the evolution of gastrointestinal stromal tumor (GIST) research, analyzing the current state of the field and identifying key open questions going beyond the recent advantages for future studies to assess. METHODS: Using the Web of Science Core Collection, 5040 GIST-associated publications in the years 1984-2022 were identified and analyzed regarding key bibliometric variables using the Bibliometrix R package and VOSviewer software. RESULTS: GIST-associated publication numbers substantially increased over time, accentuated from year 2000 onwards, and being characterized by multinational collaborations. The main topic clusters comprise surgical management, tyrosine kinase inhibitor (TKI) development/treatment, diagnostic workup, and molecular pathophysiology. Within all main topic clusters, a significant progress is reflected by the literature over the years. This progress ranges from conventional open surgical techniques over minimally invasive, including robotic and endoscopic, resection techniques to increasing identification of specific functional genetic aberrations sensitizing for newly developed TKIs being extensively investigated in clinical studies and implemented in GIST treatment guidelines. However, especially in locally advanced, recurrent, and metastatic disease stages, surgery-related questions and certain specific questions concerning (further-line) TKI treatment resistance were infrequently addressed. CONCLUSION: Increasing GIST-related publication numbers reflect a continuous progress in the major topic clusters of the GIST research field. Especially in advanced disease stages, questions related to the interplay between surgical approaches and TKI treatment sensitivity should be addressed in future studies.

Pharmacologic prevention and therapy of postoperative paralytic ileus after gastrointestinal cancer surgery: systematic review and meta-analysis.

BACKGROUND: Postoperative paralytic ileus (POI) is a significant concern following gastrointestinal tumor surgery. Effective preventive and therapeutic strategies are crucial but remain elusive. Current evidence from randomized-controlled trials on pharmacological interventions for prevention or treatment of POI are systematically reviewed to guide clinical practice and future research. MATERIALS AND METHODS: Literature was systematically searched for prospective randomized-controlled trials testing pharmacological interventions for prevention or treatment of POI after gastrointestinal tumor surgery. Meta-analysis was performed using a random effects model to determine risk ratios and mean differences with 95% CI. Risk of bias and evidence quality were assessed. RESULTS: Results from 55 studies, involving 5078 patients who received experimental interventions, indicate that approaches of opioid-sparing analgesia, peripheral opioid antagonism, reduction of sympathetic hyperreactivity, and early use of laxatives effectively prevent POI. Perioperative oral Alvimopan or intravenous administration of Lidocaine or Dexmedetomidine, while safe regarding cardio-pulmonary complications, demonstrated effectiveness concerning various aspects of postoperative bowel recovery [Lidocaine: -5.97 (-7.20 to -4.74)h, P <0.0001; Dexmedetomidine: -13.00 (-24.87 to -1.14)h, P =0.03 for time to first defecation; Alvimopan: -15.33 (-21.22 to -9.44)h, P <0.0001 for time to GI-2 ] and length of hospitalization [Lidocaine: -0.67 (-1.24 to -0.09)d, P =0.02; Dexmedetomidine: -1.28 (-1.96 to -0.60)d, P =0.0002; Alvimopan: -0.58 (-0.84 to -0.32)d, P <0.0001] across wide ranges of evidence quality. Perioperative nonopioid analgesic use showed efficacy concerning bowel recovery as well as length of hospitalization [-1.29 (-1.95 to -0.62)d, P =0.0001]. Laxatives showed efficacy regarding bowel movements, but not food tolerance and hospitalization. Evidence supporting pharmacological treatment for clinically evident POI is limited. Results from one single study suggest that Neostigmine reduces time to flatus and accelerates bowel movements [-37.06 (-40.26 to -33.87)h, P <0.0001 and -42.97 (-47.60 to -38.35)h, P <0.0001, respectively] with low evidence quality. CONCLUSION: Current evidence concerning pharmacological prevention and treatment of POI following gastrointestinal tumor surgery is limited. Opioid-sparing concepts, reduction of sympathetic hyperreactivity, and laxatives should be implemented into multimodal perioperative approaches.

Long-term quality of life after resection of retroperitoneal soft tissue sarcoma.

INTRODUCTION: Retroperitoneal soft tissue sarcoma (RPS) is characterized by high recurrence rates. Since complete tumor resection, often necessitating multivisceral resection, enables long-term survival in both primary and recurrent disease, health related quality of life (QoL) after RPS resection has attracted increasing interest. However, data regarding this topic is limited. Here, we multidimensionally assessed long-term QoL after RPS resection. METHODS: Five previously validated (1. EORTC QLQ-C30, 2. WEMWBS, 3. FoP-Q-SF, 4. PC-PTSD, 5. Pro-CTCAE) were sent to patients having undergone resection of primary, recurrent and metastasized RPS at Heidelberg University Hospital between 10/2001 and 12/2020. Multivariable linear regression models were used to test associations between clinical/demographic variables and patient reported outcomes (PROs). RESULTS: Questionnaires were answered by 127 patients (71% response rate). The median interval between RPS diagnosis and assessment of PROs was 80 months. The overall Global Health score was 64.1 and comparable to the general German population. RPS patients reported deficits regarding emotional and social functioning, whereas physical limitations were less pronounced. Besides diarrhea, abdominal symptoms were comparable to the overall population. Tumor recurrences, the number of surgeries, multivisceral resections or postoperative complications did not significantly affect long-term QoL ratings. CONCLUSION: RPS patients rate their QoL relatively high, even after multiple and multivisceral resections. Psychosocial well-being should be monitored in follow-up sessions to offer tailored support if necessary, thus improving postoperative care.

Preoperative Dose-Escalated Intensity-Modulated Radiotherapy (IMRT) and Intraoperative Radiation Therapy (IORT) in Patients with Retroperitoneal Soft-Tissue Sarcoma: Final Results of a Clinical Phase I/II Trial.

BACKGROUND: To report the final results of a prospective, one-armed, single-center phase I/II trial (NCT01566123). METHODS: Between 2007 and 2017, 37 patients with primary or recurrent (N = 6) retroperitoneal sarcomas were enrolled. Treatment included preoperative IMRT of 45-50 Gy with a simultaneous integrated boost of 50-56 Gy, surgery and IORT. The primary endpoint was local control (LC) at 5 years. The most common histology was dedifferentiated liposarcoma (51%), followed by leiomyosarcoma (24%) and well-differentiated liposarcoma (14%). The majority of lesions were high-grade (FNCLCC G1: 30%, G2: 38%, G3: 27%, two missing). Five patients were excluded from LC analysis per protocol. RESULTS: The minimum follow-up of the survivors was 62 months (median: 109; maximum 162). IORT was performed for 27 patients. Thirty-five patients underwent gross total resection; the pathological resection margin was mostly R+ (80%) and, less often, R0 (20%). We observed 10 local recurrences. The 5-year LC of the whole cohort was 59.6%. Eleven patients received a dose > 50 Gy plus IORT boost; LC was 64.8%; the difference, however, was not significant (p = 0.588). Of 37 patients, 15 were alive and 22 deceased at the time of final analysis. The 5-year OS was 59.5% (68.8% per protocol). CONCLUSIONS: The primary endpoint of a 5-year LC of 70% was not met. This might be explained by the inclusion of recurrent disease and the high rate of G3 lesions and leiomyosarcoma, which have been shown to profit less from radiotherapy. Stratification by grading and histology should be considered for future studies.

A century of retroperitoneal soft-tissue sarcoma research: From single center experience to precision oncology? A bibliometric analysis of past, present, and future perspectives.

BACKGROUND: Increasing publication numbers in the biomedical field led to an improvement of patient care in many aspects but are challenging for scientists when integratively processing data of their fields. Using bibliometric analyses, the present study assesses the productivity and predominant topics in retroperitoneal soft-tissue sarcoma (RPS) research across the past 122 years, thereby identifying crucial questions to address in future RPS research. METHODS: Using the Web of Science Core Collection, 1018 RPS-associated publications from 1900 to 2022 were identified and analyzed regarding key bibliometric variables using the Bibliometrix R package and the VOSviewer software. RESULTS: A continuous increase in RPS-associated publication numbers can be noticed over the time, which is strongly pronounced from 2005 onwards, and is characterized by a multinationally driven collaborative clinical research focus. The research primarily reflects progression regarding surgical techniques, histology-based therapy, radiotherapy regimens, and identification of prognostic clinicopathological factors. This progression is accompanied with improved overall survival of RPS patients. However, a paucity of RPS-specific basic/translational research indicates that such research might be additionally needed to better understand the pathophysiology of RPS and with that to enable the development of personalized therapies and to further improve patient outcome. CONCLUSION: Increasing publication numbers of multinationally driven clinical RPS research are accompanied with improved overall survival of RPS patients, highlighting the importance of international collaborations to facilitate future clinical trials. However, this bibliometric analysis reveals a lack of RPS-specific basic/translational research which is needed to further improve patient outcome in the context of precision oncology.

[Retroperitoneal soft tissue sarcoma: surgical management]. / Retroperitoneale Weichteilsarkome: Chirurgische Therapie.

BACKGROUND: Retroperitoneal soft tissue sarcomas are rare and heterogeneous tumors with high recurrence rates that require a multimodal treatment approach and a surgical resection strategy adapted to tumor localization and histological subtype. OBJECTIVE: Based on current scientific data this article intends to provide an overview on subtype-specific features, prognostic factors and operative techniques in the surgical management of retroperitoneal soft tissue sarcomas. MATERIAL AND METHODS: A review of the literature addressing surgical management of retroperitoneal soft tissue sarcomas was performed. Current evidence and recommendations were summarized. RESULTS AND CONCLUSION: Macroscopically complete tumor resection represents the sole curative treatment option for both primary and recurrent retroperitoneal soft tissue sarcomas. To minimize the probability of tumor-infiltrated resection margins, compartmental resection has become a standard treatment for retroperitoneal soft tissue sarcomas. This approach includes resection of all organs and structures adjacent to the tumor. Multivisceral resection is often associated with this approach and it is acceptable in terms of morbidity and mortality if performed at a center with experience in retroperitoneal sarcoma surgery. Histologic subtype, tumor grading, and quality of initial surgical treatment are major prognostic factors for oncologic overall survival.

Outcome after surgical resection of multiple recurrent retroperitoneal soft tissue sarcoma.

INTRODUCTION: Local recurrences (LR) and distant metastases (DM) are common in retroperitoneal soft tissue sarcoma (RPS). Longer time to recurrence and resection of the recurrent lesion have been identified as beneficial prognostic factors for overall survival (OS) upon first tumor relapse. However, prognostic factors concerning OS upon subsequent recurrences are scarcely defined. In this study, we aimed to identify prognostic factors for post-relapse outcome in multiple recurrent RPS. METHODS: Patients undergoing resection of primary and recurrent RPS at the University Hospital Heidelberg were retrospectively analyzed. Multivariable Cox regression analyses were performed to identify predictors of overall, LR- and DM-free survival. Subgroup analyses were performed for liposarcoma and leiomyosarcoma patients. RESULTS: 201 patients with primary disease, 101 patients with first, 66 patients with second and 43 patients with third LR as well as 75 patients with DM were analyzed. More than 12 months to recurrence and resection of recurrence were associated with improved OS after resection of first and second LR (5-year OS for first/second LR; resection: 64%/62%, no resection: 20%/46%). Gross macroscopic incomplete resection of first (p < 0.001), second (p = 0.001), and third recurrences (p < 0.001) was an independent prognostic factor for poor OS. CONCLUSION: Development of LR and DM is frequent in RPS. Once a tumor relapsed, patients benefit from tumor resection not only in case of first, but also in case of subsequent recurrences.

Significance of intraoperative radiation therapy and high cumulative radiation doses in retroperitoneal soft tissue sarcoma.

INTRODUCTION: In retroperitoneal soft tissue sarcoma (STS) local recurrence (LR) rates remain high despite more aggressive surgical approaches. Since wide resection margins cannot be achieved in all patients, application of intraoperative radiation therapy (IORT) has been frequently discussed. Still, the significance of IORT in multimodal treatment of retroperitoneal STS remains unclear. MATERIAL AND METHODS: Patients undergoing resection of primary or recurrent retroperitoneal STS at the University of Heidelberg Department of General, Visceral and Transplantation Surgery were retrospectively analyzed. Univariate Kaplan-Meyer and multivariate Cox regression analyses were performed to identify predictors of LR-free survival and to investigate the impact of IORT and high cumulative radiation doses. Analyses with propensity-score matched subgroups for IORT and cumulative radiation dose were performed to control for selection bias. Subgroup analyses for patients with retroperitoneal liposarcoma were likewise performed. RESULTS: 272 patients were identified. Recurrent tumors, histology of dedifferentiated liposarcoma or unclassified sarcoma and microscopically incomplete resection were associated with decreased LR-free survival. In liposarcoma, only recurrent and dedifferentiated tumors were confirmed as poor prognostic factors concerning LR. IORT and cumulative radiation doses exceeding 60 Gy did not influence LR rates (estimated 5-year LR-free survival: IORT: 39%, non-IORT: 46%; p = 0.79). CONCLUSION: In this retrospective evaluation, additional application of IORT does not significantly influence oncological outcome in retroperitoneal soft tissue sarcoma. Randomized trials are needed to clarify the benefit of IORT.

Differential perception of sharp pain in patients with borderline personality disorder.

BACKGROUND: Cutting is the most common method of non-suicidal self-injury (NSSI) to reduce inner tension in patients with Borderline Personality Disorder (BPD). Aim of this study was to compare pain perception induced by an incision and by application of a surrogate model for sharp mechanical pain (a non-invasive "blade") in BPD. METHODS: 22 female patients and 20 healthy controls (HC) received a small incision into the volar forearm, a 7s-blade application on the same side, and non-invasive phasic stimuli (pinprick, blade, laser, tactile). Pain intensity as well as affective versus sensory components were assessed. RESULTS: Incision was rated similarly by both groups (BPD: 28.6 ± 5.5 vs. HC: 33.9 ± 6.6; mean maximum pain ± SEM; p > 0.8), without significant difference for "7-s-blade" (BPD: 18.1 ± 3.8 vs. HC: 25.3 ± 3.6; mean maximum pain ± SEM; p > 0.17) or between "7-s-blade" and incision (BPD: p > 0.12; HC: p > 0.84). However, patients' intensity ratings returned significantly faster to baseline after incision (BPD: 38.9 ± 12.6 s vs. HC: 74.52 ± 11.5 s; p < 0.05), and patients evaluated "blade" and incision without any affective and with different sensory descriptors, indicating an altered evaluation of NSSI-like stimulation with qualitative in addition to quantitative differences-especially for the sharp pain component. CONCLUSIONS: The reduced perception of suprathreshold nociceptive stimuli is based on a missing affective component and specific loss of the perception of "sharpness" as part of the sensory component of pain. The results further demonstrate the usefulness of the "blade" for the perception of sharpness in patients. SIGNIFICANCE: Patients with Borderline Personality Disorder (BPD) who engage in non-suicidal self-injury (NSSI) report less pain in response to phasic nociceptive stimuli. In comparing an invasive pain stimulus to phasic nociceptive stimuli in BPD patients, the "blade" as non-invasive surrogate model for sharp mechanical pain in psychiatric patients is used. In contrast to healthy volunteers, BPD patients do not report significant affective ratings and specifically display a reduced sensory component for sharpness.

Effects of a Painful Stimulus on Stress Regulation in Male Patients With Borderline Personality Disorder: A Pilot Study.

Pain processing in relation to stress has so far not been investigated in male patients with borderline personality disorder (BPD). This experimental pilot study examined 17 male BPD patients and 20 male healthy controls (HCs) to assess the effects of a pain stimulus on arousal, aggression, pain (ratings), and heart rate. At baseline, BPD patients showed significantly higher arousal and aggression; however, there was no significant difference in heart rate compared to the HC group. Following stress induction, a noninvasive mechanical pain stimulus was applied. No significant differences in pain ratings or heart rates were found between the groups. For arousal, a significantly stronger decrease was revealed in the BPD group compared to the HC group (t = 2.16, p = .038). Concerning aggression, the BPD group showed a significantly greater decrease after the pain stimulus than the HC group (t = 3.25, p = .002). This data showed that nonsuicidal self-injury can reduce arousal and aggression in male BPD.

Stress reactivity and pain-mediated stress regulation in remitted patients with borderline personality disorder.

Objective: Patients with borderline personality disorder (BPD) use nonsuicidal self-injury (NSSI) to cope with states of elevated inner tension. It is unclear to what extent remitted BPD patients experience these states and whether the experience of pain still regulates emotion. The purpose of this study was the investigation of baseline stress levels, stress reactivity, and pain-mediated stress regulation in remitted BPD patients. Method: Subjective and objective stress parameters were assessed in 30 remitted BPD patients, 30 current BPD patients, and 30 healthy controls. After stress induction, a non-nociceptive tactile stimulus, a tissue-injuring, or a noninvasive pain stimulus was applied to the right volar forearm. Results: Baseline stress levels of remitted BPD patients lie in between the stress levels of current BPD patients and healthy controls. Urge for NSSI increased significantly more in current than remitted BPD patients. The experience of pain led to a greater decrease of arousal in current compared to remitted BPD patients and healthy controls. Conclusions: States of increased tension still seem to appear in remitted BPD patients. The role of pain-mediated stress regulation appears to be reduced in remitted patients.

The role of nociceptive input and tissue injury on stress regulation in borderline personality disorder.

Approximately 60% to 90% of patients with borderline personality disorder (BPD) show nonsuicidal self-injurious behavior (NSSI) with cutting being the most frequently applied method. One of NSSI's functions is to reduce aversive tension. Previous studies have found a tension-reducing effect of painful tissue injury by an incision. It is still unclear whether this effect is based on the effect of tissue injury or the effect of pain experience, or both. The aim of this study was to determine whether tissue injury leads to a stronger stress reduction than a sole pain stimulus in patients with BPD. After stress induction, 57 BPD patients and 60 healthy controls (HCs) received either an incision or a non-tissue-injuring mechanical nociceptive stimulus ("blade") typically perceived as painful or a non-nociceptive tactile sham stimulus (blunt end of scalpel). Participants were unaware of which procedure was applied. For stress assessment, subjective and objective parameters were measured. As immediate response to the stimulus application, we found greater stress reduction after both painful stimuli (incision and blade) in BPD patients but no difference in stress decrease between the tissue-injuring incision and the non-tissue-injuring pain stimulus (blade). Compared with HCs, incision and blade were followed by greater immediate decrease of arousal in BPD patients. Our findings confirm that among BPD patients, the nociceptive input leads to stress reduction. In contrast, the impact of tissue damage on stress reduction was relatively small. In addition, the results suggest that painful stimuli lead to a greater stress reduction in BPD patients compared with HCs.

The role of seeing blood in non-suicidal self-injury in female patients with borderline personality disorder.

Patients with Borderline Personality Disorder (BPD) often engage in non-suicidal self-injury (NSSI), to reduce arousal levels under stress. However, the importance of seeing blood for the effect of NSSI is yet unknown. The present pilot study examined 20 female BPD patients and 20 healthy controls (HC) to assess the role of seeing blood on arousal, pain, urge for NSSI (ratings) and heart rate (continuously measured). Participants completed two sessions consisting of stress induction (forced mental arithmetics with white noise), followed by a seven second non-invasive pain stimulus with a blade to the volar forearm. At one session, only the painful blade stimulus was applied, at the other, artificial blood was added. For arousal, a significantly stronger decrease was revealed in the BPD than in the HC group, however with no significant effects between blood and non-blood conditions. Concerning urge for NSSI, the BPD showed a significantly greater decrease in blood condition over time than the HC group. Interestingly, heart rate decreased stronger over time in the HC group during the blood condition than in BPD. For tension relief by non-damaging mechanical painful stimulus the addition of visible blood showed neither subjective (arousal, urge for NSSI), nor objective (heart rate) advantages.