Standard versus personalized schedule of regorafenib in metastatic gastrointestinal stromal tumors: a retrospective, multicenter, real-world study.

BACKGROUND: Despite its proven activity as third-line treatment in gastrointestinal stromal tumors (GIST), regorafenib can present a poor tolerability profile which often leads to treatment modifications and transient or permanent discontinuation; thus, in clinical practice physicians usually adopt various dosing and interval schedules to counteract regorafenib-related adverse events and avoid treatment interruption. The aim of this real-world study was to investigate the efficacy and safety of personalized schedules of regorafenib in patients with metastatic GIST, in comparison with the standard schedule (160 mg daily, 3-weeks-on, 1-week-off). PATIENTS AND METHODS: Institutional registries across seven Italian reference centers were retrospectively reviewed and data of interest retrieved to identify patients with GIST who had received regorafenib from February 2013 to January 2021. The Kaplan-Meier method was used to estimate survival and the log-rank test to make comparisons. RESULTS: Of a total of 152 patients with GIST, 49 were treated with standard dose, while 103 received personalized schedules. At a median follow-up of 36.5 months, median progression-free survival was 5.6 months [95% confidence interval (CI) 3.73-11.0 months] versus 9.7 months (95% CI 7.9-14.5 months) in the standard-dose and the personalized schedule groups, respectively [hazard ratio (HR) 0.51; 95% CI 0.34-0.75; P = 0.00052]. Median overall survival was 16.6 months (95% CI 14.1-21.8 months) versus 20.5 months (95% CI 15.0-25.4 months), respectively (HR 0.75; 95% CI 0.49-1.22; P = 0.16). CONCLUSIONS: Regorafenib-personalized schedules are commonly adopted in daily clinical practice of high-volume GIST expert centers and correlate with significant improvement of therapeutic outcomes. Therefore, regorafenib treatment optimization in patients with GIST may represent the best strategy to maximize long-term therapy.

Final analysis of the randomized trial on imatinib as an adjuvant in localized gastrointestinal stromal tumors (GIST) from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG), the Australasian Gastro-Intestinal Trials Group (AGITG), UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), and Spanish Group for Research on Sarcomas (GEIS)☆.

BACKGROUND: In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk gastrointestinal stromal tumors (GIST) patients. Interim analysis results were published in 2015 upon recommendation from an independent data review committee. We report the final outcome of the study. PATIENTS AND METHODS: This was a randomized, open-label, multicenter phase III trial carried out at 112 hospitals in 12 countries. Patients were randomized to 2 years of imatinib, 400 mg daily, or no further therapy after surgery. The primary endpoint was imatinib failure-free survival (IFFS), while relapse-free survival (RFS), relapse-free interval (RFI), overall survival (OS) and toxicity were secondary endpoints. Adjusting for the interim analyses, results on IFFS were assessed on a 4.3% significance level; for the other endpoints, 5% was used. RESULTS: Nine hundred and eight patients were randomized between January 2005 and October 2008: 454 to imatinib and 454 to observation; 835 patients were eligible. With a median follow-up of 9.1 years, 5 (10)-year IFFS was 87% (75%) in the imatinib arm versus 83% (74%) in the control arm [hazard ratio (HR) = 0.87, 95.7% confidence interval (CI) (0.65; 1.15), P = 0.31]; RFS was 70% versus 63% at 5 years and 63% versus 61% at 10 years, [HR = 0.71, 95% CI (0.57; 0.89), P = 0.002]; OS was 93% versus 92% at 5 years and 80% versus 78% at 10 years [HR = 0.88, 95% CI (0.65; 1.21), P = 0.43]. Among 526 patients with high-risk GIST by local pathology, 10-year IFFS and RFS were 69% versus 61%, and 48% versus 43%, respectively. CONCLUSIONS: With 9.1 years of follow-up, a trend toward better long-term IFFS in imatinib-treated patients was observed in the high-risk subgroup. Although the difference was not statistically significant and the surrogacy value of such an endpoint is not validated, this may be seen as supporting the results reported by the Scandinavian/German trial, showing a sustained small but significant long-term OS benefit in high-risk GIST patients treated with 3 years of adjuvant imatinib.

Preclinical and clinical evidence of activity of pazopanib in solitary fibrous tumour.

BACKGROUND: To explore the activity of pazopanib in solitary fibrous tumour (SFT). PATIENTS AND METHODS: In a preclinical study, we compared the activity of pazopanib, sorafenib, sunitinib, regorafenib, axitinib and bevacizumab in a dedifferentiated-SFT (DSFT) xenotransplanted into Severe Combined Immunodeficiency (SCID) mice. Antiangiogenics were administered at their reported optimal doses when mean tumour volume (TV) was 80 mm(3). Drug activity was assessed as TV inhibition percentage (TVI%). From May 2012, six consecutive patients with advanced SFT received pazopanib, on a national name-based programme. In one case sunitinib was administered after pazopanib failure. RESULTS: In the xenograft model, pazopanib showed the lowest antitumour activity (21%TVI), while regorafenib was the most active (95%TVI). Sorafenib, bevacizumab, sunitinib were markedly active (78/70/65%TVI). Axitinib was marginally active (51%TVI). In the retrospective case-series, three patients carried malignant-SFT (MSFT), three DSFT. Best Response Evaluation Criteria in Solid Tumour (RECIST) responses were: three stable disease (SD), all MSFT, three progressive disease (PD), all DSFT, corresponding to one partial response (PR), two SD, three PD by Choi criteria. Median-progression-free survival was 3 months (range 1-15). In one patient, sunitinib was started after pazopanib failure, with a response. CONCLUSIONS: In dedifferentiated-SFT xenograft pazopanib induced a marginal antitumour activity, while regorafenib appeared the most active and promising agent. When administered in patients, pazopanib showed a modest activity in terms of tumour growth stabilisation, observed only in non-dedifferentiated cases.

Long-term follow-up of patients with GIST undergoing metastasectomy in the era of imatinib -- analysis of prognostic factors (EORTC-STBSG collaborative study).

BACKGROUND: Long-term complete remissions remain a rare exception in patients with metastatic gastrointestinal stromal tumors (GIST) treated with IM (imatinib). To date the therapeutic relevance of surgical resection of metastatic disease remains unknown except for the use in palliative intent. PATIENTS AND METHODS: We analyzed overall survival (OS) and progression-free survival (PFS) in consecutive patients with metastatic GIST who underwent metastasectomy and received IM therapy (n = 239). RESULTS: Complete resection (R0+R1) was achieved in 177 patients. Median OS was 8.7 y for R0/R1 and 5.3 y in pts with R2 resection (p = 0.0001). In the group who were in remission at time of resection median OS was not reached in the R0/R1 surgery and 5.1 y in the R2-surgery (p = 0.0001). Median time to relapse/progression after resection of residual disease was not reached in the R0/R1 and 1.9 years in the R2 group of patients, who were resected in response. No difference in mPFS was seen in patients progressing at time of surgery. CONCLUSIONS: Our analysis implicates possible long-term survival in patients in whom surgical complete remission can be achieved. Incomplete resection, including debulking surgery does not seem to prolong survival. Despite the retrospective character and likely selection bias, this analysis may help in decision making for surgical approaches in metastatic GIST.

Obesity and socioeconomic status in developing countries: a systematic review.

We undertook a systematic review of studies assessing the association between socioeconomic status (SES) and measured obesity in low- and middle-income countries (defined by the World Bank as countries with per capita income up to US$12,275) among children, men and women. The evidence on the subject has grown significantly since an earlier influential review was published in 2004. We find that in low-income countries or in countries with low human development index (HDI), the association between SES and obesity appears to be positive for both men and women: the more affluent and/or those with higher educational attainment tend to be more likely to be obese. However, in middle-income countries or in countries with medium HDI, the association becomes largely mixed for men and mainly negative for women. This particular shift appears to occur at an even lower level of per capita income than suggested by an influential earlier review. By contrast, obesity in children appears to be predominantly a problem of the rich in low- and middle-income countries.

Friction anisotropy of the surface of organic crystals and its impact on scanning force microscopy.

The transverse component of the friction forces acting on the tip of an atomic force microscope scanning on the surface of an organic crystal was monitored as a function of the scan direction. The relation between friction and the crystallographic system is disclosed, revealing that the symmetry of the friction phenomenon is dictated by the direction of the prominent corrugations of the crystal surface. It is also illustrated that molecular-resolution images can be collected through the monitoring of the motion of the tip in a transverse direction with respect to the scan direction.

Oncogenic and ligand-dependent activation of KIT/PDGFRA in surgical samples of imatinib-treated gastrointestinal stromal tumours (GISTs).

As the range of receptor tyrosine kinase (RTK) inhibitors widens, a detailed understanding of the activating mechanisms of KIT/platelet-derived growth factor receptor (PDGFR)A and the related downstream pathways involved in the development and maintenance of GISTs is becoming increasingly important. We analysed areas with different histological response ratios in surgical specimens taken from imatinib-treated and untreated GIST patients in order to investigate KIT and PDGFRA expression/activation, the presence of their cognate ligands and the activation of downstream signalling, by means of biochemistry, immunohistochemistry and flow cytometry. All of the cases showed KIT and PDGFRA co-expression. In addition to the oncogenic activation of mutated receptors, activation of wild-type KIT and wild-type PDGFRA, sustained by heterodimerization and an autocrine-paracrine loop, was demonstrated by the presence of their specific ligands, stem cell factor (SCF) and PDGFA. To confirm RTK activation further, all of the samples (including those with the highest regression ratios) were investigated for downstream effectors, and all proved to have activated downstream signalling. The results show that after the mutated receptors are switched off, heterologous wild-type receptors become important in imatinib-treated GISTs as a means of maintaining signalling activation. Taken together, our findings suggest that drugs targeting wild-type receptors should be tested in imatinib-treated GIST patients.

Preoperative imatinib mesylate for unresectable or locally advanced primary gastrointestinal stromal tumors (GIST).

AIM: To explore the effect of preoperative imatinib mesylate (IM) in patients with unresectable or locally advanced primary gastrointestinal stromal tumor (GIST). METHODS: From January 2003 to January 2008, all patients affected by bulky localized GIST who presented at our institution were considered for preoperative IM with cytoreductive intent. Clinical, pathological and molecular characteristics were assessed and the rate of response recorded. Progression-free survival (PFS) was calculated according to Kaplan-Meier analysis. RESULTS: Fifteen patients (1 esophageal, 7 gastric, 3 duodenal, 4 rectal GISTs) received preoperative IM for a median of 9 months. All patients had tumor shrinkage, with a median size reduction of 34%. One patient had radiological complete response. In all cases an improvement of the originally planned surgical procedure was obtained: 3 patients initially considered unresectable underwent complete surgery; 7 patients with initial indication for extensive surgery were more conservatively operated on; 4 patients initially deemed at high perioperative risk underwent safe surgery. Due to the small sample size, no association between tumor shrinkage and tumor site, size, IM duration, mutational status and pathological response could be formally explored. PFS at 3 years from IM onset was 77%. CONCLUSIONS: In unresectable or locally advanced GISTs, preoperative IM is a useful tool both to improve resectability and reduce surgical morbidity. It should be therefore always be considered before embarking on a major surgical procedure. The long-term impact of IM on PFS and survival is presently under investigation in multicenter prospective randomized trials.

Some lessons learned from imatinib mesylate clinical development in gastrointestinal stromal tumors.

Imatinib mesylate is a molecular-targeted agent, shown to be effective in chronic myeloid leukemia and gastrointestinal stromal tumors (GIST). The latter may currently serve as a model on which speculating how the future of molecular-targeted therapy in solid tumors will be. So far, some lessons have been learnt. 1) Molecular-targeted therapy can be effective in the advanced disease setting, resulting in major tumor responses. 2) Patterns of tumor responses may be peculiar, radiologically and pathologically. 3) Anti-tumor activity may be highly predictable by assessing tumor molecular biology. 4) The methodology of clinical development of molecular-targeted agents may differ from standard chemotherapy in some respects, because, say, the preclinical rationale may be stronger, thus increasing the Bayesian prior probability of efficacy, or the optimal dose cannot be determined separately from the assessment of activity and efficacy. 5) Molecular-targeted agents will hardly remain "orphan drugs", if effective. 6) While an obvious impact on survival in the advanced disease setting has been clearly demonstrated, the biologic and clinical impact of molecular-targeted therapy still needs to be elucidated. Its eradicating capabilities, as well as the implications of secondary resistance, are to be understood. 7) Integrated, multimodality approaches, including surgery, may still be of value in the molecular-targeted therapy era.

Short-term effects of exercise on body water distribution of severely obese subjects as determined by bioelectrical impedance analysis.

We have previously shown that a short-term weight (Wt) reduction programme consisting of energy restriction, physical activity and psychological counselling, produces physiological changes of body water distribution (BWD) in obese subjects as detected by bioelectrical impedance analysis. The present study was aimed at testing the contribution of diet and physical activity to the observed changes in BWD. A number of 96 obese inpatients were consecutively enrolled in the study at our Obesity Clinic. During a 3-wk period, they underwent a body Wt reduction programme comprising the same dietary strategy and psychological counselling. The programme differed as far as physical activity is concerned, with 52 subjects randomized to a baseline exercise programme (BEP), 22 to a cardiovascular exercise programme (CEP) and 22 to a cardiovascular and strength programme (CSP). Absolute and percent Wt reduction was significantly higher in CSP than BEP subjects (p < 0.05) and the same hold for the changes in impedance (Z) at frequencies of 5, 50 and 100 kHz (p < 0.05). The change in the Z5/Z100 ratio did not show however any between-group difference (p = NS). The average values of Z changes were 1.5 to 2 times higher in CEP and 5.0 to 5.5 times higher in CSP than BEP subjects. We conclude that the type of exercise performed does influence the absolute changes of total body water and extracellular water but not BWD in severely obese subjects undergoing Wt loss.

Ten-year survival results in metastatic renal cell cancer patients treated with monoimmunotherapy with subcutaneous low-dose interleukin-2.

After more than ten years of clinical investigations, IL-2 immunotherapy appears to constitute the most effective treatment metastatic renal cell carcinoma (RCC),at least in terms of survival time. Moreover, it has been shown that comparable results may be achieved with different schedules of treatment, including intravenous high-dose or subcutaneous (SC) low-dose IL-2. Finally, it has been demonstrated that the association with interferon-alpha does not increase the efficacy of IL-2. Therefore, SC low-dose IL-2 alone may be considered as an adequate therapy for metastatic RCC. In fact, our previous studies with SC low-dose IL-2 alone have shown a 5-year survival time similar to that described with higher and more toxic doses of IL-2. This study was performed to analyze the 10-year survival results with SC low-dose IL-2 in metastatic RCC The study included 44 consecutive metastatic RCC patients, with a minimum follow-up of 120 months. One comlete immunotherapeutic cycle consisted of IL-2 at 3 million IU twice/day SC, 5 days/week for 6 consecutive weeks. In non-progressing patients, a second cycle was planned after a 21-day rest period. Complete response (CR) was achieved in only 2 out of 44 (4%) patients, while partial response (PR) was obtained in 8 out of /44 (18%) patients. Therefore, the response rate (CR + PR) was 10 out of 44 (22%), with a median response duration of 12 months. Stable disease (SD) occurred in 21 out of 44 (48%) patients,whereas the remaining 13 out of 44 (30%) patients had a progressive disease (PD). A 10-year survival was achieved in 2 out of 44 (5%) and the percent of survival at 10 years was significantly higher in patients with response or SD than in those with PD. This study confirms at 10 years the results previously referred to by other authors and by ourselves, in showing that the efficacy of IL-2 immunotherapy in terms of control of cancer growth is associated with a clear prolongation of the overall survival time in metastatic RCC.

A phase II study of chemoneuroimmunotherapy with platinum, subcutaneous low-dose interleukin-2 and the pineal neurohormone melatonin (P.I.M.) as a second-line therapy in metastatic melanoma patients progressing on dacarbazine plus interferon-alpha.

Immunochemotherapeutic combinations containing IL-2 theoretically represent the most effective therapies for metastatic melanoma, particularly in association with cisplatin (CDDP); however, both IL-2 and CDDP have been generally utilized at high doses, with the consequence of considerable toxicity. According to psychoneuroimmunological knowledge, the antitumor activity of IL-2 has been proven to be enhanced by the immunomodulating pineal neurohormone melatonin (MLT), which has also been shown to increase the cytotoxicity of cancer chemotherapy and reduce its toxicity. On this basis, a study was planned with low-dose IL-2 and CDDP in association with MLT as a second-line therapy for metastatic melanoma patients progressing on dacarbazine plus interferon-alpha. The study included 13 evaluable patients. CDDP was injected i.v. at 30 mg/m2/day for 3 days every 21 days. IL-2 was administered s.c. at 3 million IU/day from days 4 to 9 and from days 11 to 16 of the cycle. Finally, MLT was given orally at 20 mg/day in the evening, every day without interruption. One patient obtained a complete response (CR), while partial response (PR) was achieved in 3 other patients. Therefore, the objective tumor response-rate (CR + PR) was 4 out of 13 (31%). A stable disease occurred in 5 patients, whereas the remaining 4 patients had a progressive disease. The treatment was extremely well-tolerated in all patients and, in particular, no CDDP-related neurotoxicity was observed. The results of this preliminary study would suggest that low-dose CDDP and IL-2 in association with the pineal hormone MLT (P.I.M. schedule), given as a second line therapy, is an effective and well-tolerated treatment for metastatic melanoma, with a clinical efficacy at least comparable to that obtained with a first-line therapy of dacarbazine plus interferon-alpha.

Lower limb alactic anaerobic power output assessed with different techniques in morbid obesity.

Short-term alactic anaerobic performance in jumping (5 consecutive jumps with maximal effort), sprint running (8 m) and stair climbing (modified Margaria test) were measured in 75 obese subjects (BMI: 40.3+/-5.0 kg/m2) and in 36 lean control subjects (BMI: 22.4+/-3.2 kg/m2) of the same age and gender distribution. The results show that obese subjects attained a significantly lower specific (per unit body mass) power output both in jumping (W(spec,j); p<0.001) and stair climbing (W(spec,s); p<0.001) and run at a significantly lower average velocity (v; p<0.001) during sprinting. In spite of the different motor skillfulness required to accomplish the jumping and climbing tests, W(spec,s) (and hence the vertical velocity in climbing, v(v)) was closely correlated with W(spec,j) (R2=0.427, p<0.001). In jumping, although the average force during the positive work phase was significantly higher in obese subjects (p<0.001), no difference between the 2 groups was detected in absolute power. In stair climbing the absolute power output of obese resulted significantly higher (18%) than that of lean controls (p<0.001). In sprint running, the lower average horizontal velocity attained by obese subjects also entailed a different locomotion pattern with shorter step length (L(s); p<0.001), lower frequency (p<0.001) and longer foot contact time with ground (T(c,r); p<0.001). W(spec,j) seems to be a determinant of the poorer motor performance of obese, being significantly correlated with: I) the vertical displacement of the centre of gravity (R2=0.853, p<0.001) in jumping; II) with v(v) in stair climbing; and III) with T(c,r) (R2=0.492, p<0.001), L(s) (R2=0.266, p<0.001) and v (R2=0.454, p<0.001) in sprinting. The results suggest that obese individuals, although partially hampered in kinetic movements, largely rely on their effective specific power output to perform complex anaerobic tasks, and they suffer from the disproportionate excess of inert mass of fat. Furthermore, in view of the sedentary style of life and the consequent degree of muscle de-conditioning accompanying this condition, it may prove useful to implement rehabilitation programs for obesity with effective power training protocols.

Characterization of the 1H-cyclopentapyrimidine-2,4(1H,3H)-dione derivative (S)-CPW399 as a novel, potent, and subtype-selective AMPA receptor full agonist with partial desensitization properties.

(S)-CPW399 (2b) is a novel, potent, and subtype-selective AMPA receptor full agonist that, unlike (S)-willardiine and related compounds, in mouse cerebellar granule cells, stimulated an increase in [Ca(2+)](i), and induced neuronal cell death in a time- and concentration-dependent manner. Compound 2b appears to be a weakly desensitizing, full agonist at AMPA receptors and therefore represents a new pharmacological tool to investigate the role of AMPA receptors in excitotoxicity and their molecular mechanisms of desensitization.

Corneal toxicity of xylazine and clonidine, in combination with ketamine, in the rat.

PURPOSE: To compare the corneal toxicity of xylazine (XYL)/ketamine (KET) with that of clonidine (CLO)/KET in the rat, in the presence or not of the alpha(2)-adrenergic antagonist yohimbine (YOH). METHODS: XYL (10 mg/kg) and CLO (0.15 mg/kg) were administered subcutaneously in the rat in combination with KET (50 mg/kg), in the presence or not of YOH (2 mg/kg). RESULTS: The corneas immediately lost transparency and luster, but recovered within 120 min. By both light and electron microscopy, a marked stromal edema and alterations of all layers were observed. In addition, XYL/KET altered the permeability of the cornea as indicated by the augmented levels of (14)C-indomethacin, topically administered 30 min after the anesthetic combination. CONCLUSIONS: The mechanism of the corneal toxicity of XYL and CLO in the rat is unclear but we speculate that: (a) proptosis and inhibition of normal blinking did not play a major role because topical application of hyaluronic acid did not protect against it; corneal decompensation, edema and opacification could be due to (b) osmotic or (c) mechanical endothelial stress: the first resulting from the sudden increase of the glucose concentration in the aqueous humor due to the well-known inhibition of insulin release by alpha(2)-adrenergic agonists, and the second from the acute elevation of intraocular pressure caused by these alpha(2)-adrenergic mydriatics in the rat; (d) addition, XYL and CLO could act by directly interacting with local alpha(2)- or, possibly, alpha(1)-adrenergic receptors, whose function is still not clear but probably essential for corneal homeostasis.

Stimulation of IL-12 secretion by GM-CSF in advanced cancer patients.

In addition to its efficacy in the treatment of chemotherapy-induced neutropenia, recent evidence would suggest that GM-CSF may have immunomodulatory effects on anticancer immunity. In particular, GM-CSF has been proven to promote dendritic cell maturation, with following potential stimulation of the anticancer cytokine, IL-12. Unfortunately, at present there are only few and controversial results on GM-CSF effects on IL-12 secretion in cancer patients. This preliminary study was performed to evaluate IL-12 response to an acute injection of GM-CSF in human neoplasms. The study included 20 advanced cancer patients, who received GM-CSF for chemotherapy-induced neutropenia. GM-CSF was injected at 3 micrograms/kg at 8.00 A.M., and venous blood samples were drawn before GM-CSF, and at 4, 8, 12 and 24 hours after its injection. Serum levels of IL-12 were measured by an enzyme immunoassay. High basal levels of IL-12 were seen in 8/20 patients. In patients with abnormally high pretreatment levels of IL-12, no significant change occurred in IL-12 mean serum concentration after GM-CSF administration. In contrast, patients with normal baseline levels of IL-12 showed a significant increase in IL-12 mean concentrations in response to GM-CSF, with a peak after 12 hours. This preliminary study seems to show that GM-CSF may acutely stimulate IL-12 secretion in cancer patients. Further studies are required to evaluate the effects of chronic GM-CSF administration, and the impact of GM-CSF-induced secretion of IL-12 on the efficacy of the immunotherapies of cancer with cytokines, such as IL-2. In any case, this study would justify further research in the emerging oncological applications of GM-CSF as an immunomodulatory agent on host anticancer defenses.