Tumor budding is an independent prognostic factor in stage III colon cancer patients: a post-hoc analysis of the IDEA-France phase III trial (PRODIGE-GERCOR).

BACKGROUND: Histological characteristics at the invasive front may reflect tumor aggressiveness; specifically, tumor budding (Bd) is an emerging prognostic biomarker in colon cancer (CC). We explored further the significance of Bd for risk stratification by evaluating survival of stage III CC patients included in the IDEA-France phase III trial. PATIENTS AND METHODS: This post-hoc study was conducted on tissue slides from 1048 stage III CC patients. Bd was scored by central review by the Bd criteria of the 2016 International Tumor Budding Consensus Conference (ITBCC 2016) and classified as Bd1 (0-4 buds/0.785 mm2), Bd2 (5-9 buds), and Bd3 (≥10 buds) categories. Disease-free survival (DFS) and overall survival (OS) were analyzed by the log-rank test. Clinicopathological features and Immunoscore® were correlated with Bd. RESULTS: Overall, Bd1, Bd2, and Bd3 were observed in 39%, 28%, and 33% of CC, respectively. Bd2 and Bd3 were associated with vascular (P = 0.002) and perineural invasions (P = 0.0009). The 3-year DFS and the 5-year OS rates for Bd (1 versus 2-3) were 79.4% versus 67.2% (P = 0.001) and 89.2% versus 80.8% (P = 0.001), respectively. This was confirmed after adjustment for relevant clinicopathological features for DFS [hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.12-1.77, P = 0.003] and OS (HR 1.65, 95% CI 1.22-2.22, P = 0.001). When combined with pTN stage and Immunoscore® subgroups, Bd significantly improved disease prognostication. CONCLUSIONS: Bd demonstrated its independent prognostic value for DFS and OS. Given these findings, Bd as per the ITBCC 2016 should be mandatory in every pathology report in stage III CC patients. Bd and Immunoscore® could play a complementary role in personalized health care in this setting.

Efficacy and safety of the combination of encorafenib/cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: an AGEO real-world multicenter study.

BACKGROUND: The combination of encorafenib with cetuximab has become the standard of care in patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC) after a prior systemic therapy. This study aims to describe the efficacy and safety of encorafenib/cetuximab +/- binimetinib in patients with BRAF V600E-mutated mCRC in a real-world setting. PATIENTS AND METHODS: This retrospective study included patients with BRAF V600E-mutated mCRC who received this combination from January 2020 to June 2022 in 30 centers. RESULTS: A total of 201 patients were included, with 55% of women, a median age of 62 years, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) >1 in 20% of cases. The main tumor characteristics were 60% of right-sided primary tumor, 11% of microsatellite instability/mismatch repair deficient phenotype, and liver and peritoneum being the two main metastatic sites (57% and 51%). Encorafenib/cetuximab +/- binimetinib was prescribed in the first, second, third, and beyond third line in 4%, 56%, 29%, and 11%, respectively, of cases, with the encorafenib/cetuximab/binimetinib combination for 21 patients (10%). With encorafenib/cetuximab treatment, 21% of patients experienced grade ≥3 adverse events (AEs), with each type of grade ≥3 AE observed in <5% of patients. The objective response rate was 32.2% and the disease control rate (DCR) was 71.2%. The median progression-free survival (PFS) was 4.5 months [95% confidence interval (CI) 3.9-5.4 months] and the median overall survival (OS) was 9.2 months (95% CI 7.8-10.8 months). In multivariable analysis, factors associated with a shorter PFS were synchronous metastases [hazard ratio (HR) 1.66, P = 0.04] and ECOG-PS >1 (HR 1.88, P = 0.007), and those associated with a shorter OS were the same factors (HR 1.71, P = 0.03 and HR 2.36, P < 0.001, respectively) in addition to treatment beyond the second line (HR 1.74, P = 0.003) and high carcinoembryonic antigen level (HR 1.72, P = 0.003). CONCLUSION: This real-world study showed that in patients with BRAF V600E-mutated mCRC treated with encorafenib/cetuximab +/- binimetinib, efficacy and safety data confirm those reported in the BEACON registration trial. The main poor prognostic factors for this treatment are synchronous metastases and ECOG-PS >1.

Second-line treatment strategies for RAS wild-type colorectal cancer: A systematic review and Network Meta-analysis (NMA).

BACKGROUND: The optimal strategy for second-line (IIL) treatment in KRAS wt metastatic colorectal cancer (mCRC) is not determined yet. METHODS: A random-effect NMA of phase II/III RCTs was conducted to evaluate IIL treatment for all-RAS wt mCRC, comparing anti-EGFR or anti-VEGF, and chemotherapy (CT). RESULTS: Overall, 11 RCTs (3613 patients) were included. In KRAS wt patients, PFS was improved with anti-VEGF (HR 0.43) and anti-EGFR (HR 0.63) vs CT. However, anti-VEGF based therapy had the highest likelihood of being ranked as the best treatment in terms of PFS (SUCRA 99.3%) and OS (SUCRA 99.4%). Bevacizumab-based treatment is most likely to be the best treatment in terms of PFS (SUCRA 89.1%) and OS (SUCRA 86.7%). CONCLUSIONS: Second line treatment with anti-VEGF and anti-EGFR improved PFS in mCRC patients, however, anti-VEGF based therapy, particularly CT plus bevacizumab, is the best treatment according to SUCRA in terms of PFS and OS.

How I treat stage II colon cancer patients.

Stage II colon cancer (CC) is probably one of the best prognosis gastrointestinal tumors seen in our consultations, but often takes a lot of time for physicians to determine appropriate treatment because of the limited benefit of adjuvant chemotherapy (CT) in these patients, together with the limited evidence in this situation. How to choose the best treatment for each individual patient is thus dependent on molecular (microsatellite instability/microsatellite stability status) and clinico-pathological features relevant enough to classify these tumors into low-, intermediate- and high-risk stage II disease and to choose an appropriate attitude for each of these subgroups. In practice, the first step in treatment decision making must be to assess the patient's status and comorbidities to see if the patient is eligible for an adjuvant treatment. Then, as fluoropyrimidines (FPs) are the corner stone of CC adjuvant treatment, screening for dihydropyrimidine dehydrogenase deficiency is mandatory in western countries. Finally, depending on the patient's characteristics and tumor risk stage, the strategy may be surveillance, adjuvant FP alone or oxaliplatin-based adjuvant CT. In the near future, new tools such as Immunoscore® (HalioDx; Luminy Biotech Enterprises, Marseille Cedex, France) and circulating tumor DNA may help to identify more precisely patients with minimal residual disease for more personalized adjuvant treatment approaches.

Recurrence of cryptogenic stroke or TIA in patients with patent foramen ovale successfully treated by using different kind of percutaneous occluder devices: five-year follow-up.

AIM: Cryptogenic stroke remains the final diagnosis in 40% of ischemic acute cerebrovascular events. Until now there are no clinical evidences that the percutaneous closure of PFO is able to prevent the recurrence of stroke or transient ischemic attack (TIA). The aim of this study was to evaluate the incidence of recurrence in patients successfully treated by percutaneous closure of PFO with different occluder devices by using TCD, TTE and clinical evaluation. METHODS: From February 2004 to November 2009, 72 pts, (40 females and 32 males; average age 46 yrs, range 14-66), admitted with diagnosis of recurrent ischemic neurologic events (58 stroke and 14 TIA) underwent percutaneous closure of PFO. Thirty-one (43%) of the 72 patients had a concomitant history of migraine, 16 (52%) of whom with aura. Five different occluder devices were used, with a total amount of 74 implants. All pts were studied during the follow-up by clinical evaluation (Rankin modified scale), TCD and TTE. RESULTS: Successful device deployment is achieved in 100% of pts without any periprocedural major complication. Only in two pts atrial arrhythmia have occurred. All pts was discharged within 3 days in good overall conditions. In all pts a double antiplatelet regimen was adopted. The follow-up was complete in 100% of the cases (median 30, range 3-58 months ). At five years, there was no recurrent stroke or TIA, and no new cerebral lesions developed by MRI in those patients with residual shunt. Moreover, in 65 (90%) of them the Rankin scale significantly (P<0.0001) reduced to 0 whereas only in 2 pts score 1 was reached. In 19 (61%) of the 31pts with concomitant migraine, the intensity and the frequency of the attacks significantly (P<0.0001) decreased over time. At the TCD, 5 pts (7%) resulted positive for microembolic signals but, only 1 of them, was successfully treated for an associate defect. The TTE evaluation showed however an optimal sealing of all the devices without signs of erosion, incomplete closure and thrombus formation around the device. CONCLUSION: Our experience suggests that percutaneous treatment of PFO is safe and beneficial at the medium term follow-up for secondary prevention since able to prevent the clinical recurrence of acute cerebrovascular events irrespective of the device used.

Hydroxy-L-proline- and 2,2'-Dipyridyl-Induced Phenovariations in the Liverwort Nowellia curvifolia.

Two antagonists of "normal" proline-hydroxyproline-protein synthesis, 2,2'-dipyridyl and hydroxy-L-proline, induced the same kind of phenovariation in Nowellia curvifolia (Dicks) Mitt. (Cephaloziaceae) as they do in Scapania nemorosa (Scapaniaceae). This finding supports a hypothesized cardinal role for proline-hydroxyproline-protein in modulating aspects of morphogenesis and phylogeny in the leafy liverworts.

Desuppression of Leaf Primordia of Plagiochila arctica (Hepaticae) by Ethylene Antagonists.

Silver nitrate, alpha-aminooxyacetic acid, and aminoethoxyvinylglycine, three potent inhibitors of ethylene synthesis and action, induced the same kind of phenovariation in the liverwort Plagiochila arctica Bryhn and Kaal (Hepaticae) as do antagonists of the synthesis of hydroxyproline-containing protein. This finding (i) supports the hypothesis that hydroxyproline-protein has a role in ethylene-mediated suppression, (ii) provides evidence that the role of ethylene in the correlative development of leafy liverwort gametophytes may be similar to its role in flowering plants, and (iii) contributes to the characterization of a morphoregulatory system that mediates cellular suppression in leafy liverworts and possibly all land plants.

Spontaneous chronic subdural hematoma in a young adult.

Chronic subdural hematoma (CSDH) is a common pathology in the elderly but very rare in young adults. When CSDH occurs in this age group, severe head injury or some promotive factors are usually present. This article reports the case of a 29-year-old female presented at our Emergency Department with a few days' history of progressive frontal headache. Computed tomography scan of the head showed a right frontal CSDH. Only a decreased level of consciousness without focal deficits was present at clinical examination and her medical history was negative for trauma or promotive factors. Blood count showed a mild sideropenic anemia while coagulation tests were normal. No vascular malformations were shown at digital subtraction angiography. The patient underwent craniotomic evacuation. After surgery, the patient showed a full neurological recovery. Spontaneous CSDH in young adults is very rare. In the worldwide literature, many cases of non-traumatic CSDH are reported, but a promotive factor is generally present. We described a case of spontaneous CSDH, whose etiology remains unknown.

Endothelial colony-forming cells and pro-angiogenic cells: clarifying definitions and their potential role in mitigating acute kidney injury.

Acute kidney injury (AKI) represents a significant clinical concern that is associated with high mortality rates and also represents a significant risk factor for the development of chronic kidney disease (CKD). This article will consider alterations in renal endothelial function in the setting of AKI that may underlie impairment in renal perfusion and how inefficient vascular repair may manifest post-AKI and contribute to the potential transition to CKD. We provide updated terminology for cells previously classified as 'endothelial progenitor' that may mediate vascular repair such as pro-angiogenic cells and endothelial colony-forming cells. We consider how endothelial repair may be mediated by these different cell types following vascular injury, particularly in models of AKI. We further summarize the potential ability of these different cells to mitigate the severity of AKI, improve perfusion and maintain vascular structure in pre-clinical studies.

Androgen receptor in triple negative breast cancer: A potential target for the targetless subtype.

Triple negative breast cancer (TNBC) represents the 15-20% of all breast cancers (BC) and is characterized by a very aggressive behavior. Recent data suggest that TNBC is not a single disease, but it is rather an umbrella for different ontology-profiles such as basal like 1 and 2, mesenchymal, and the luminal androgen receptor (LAR). The LAR subtype is characterized by the expression of the Androgen Receptor (AR) and its downstream effects. Notwithstanding the role of the AR in several signaling pathways, its impact on a biological and clinical standpoint is still controversial. The LAR subtype has been associated with better prognosis, less chemotherapy responsiveness and lower pathologic complete response after neoadjuvant treatment. Clinical evidence suggests a role for anti-androgen therapies such as bicalutamide, enzalutamide and abiraterone, offering an interesting chemo-free alternative for chemo-unresponsive patients, and therefore potentially shifting current treatment strategies.

Basic fibroblast growth factor receptor in the rat adrenal cortex: effects of suramin and unilateral adrenalectomy on receptor numbers.

Previous studies have suggested that basic fibroblast growth factor (bFGF) is involved in the mediation of the compensatory adrenal growth response. These studies were undertaken to identify the bFGF receptor in the rat adrenal cortex and determine bFGF receptor levels in vivo. Initial studies using primary cultures of rat glomerulosa cells demonstrated a high affinity binding site with a Kd of 10 pM, consistent with reported values for the bFGF receptor; however, these results could not be demonstrated in capsule-glomerulosa tissue. Using autoradiography to verify the existence of bFGF receptors in vivo, heparin-insensitive [125I]bFGF-binding sites were concentrated primarily in the capsule and glomerulosa of the adrenal cortex, suggesting the presence of FGF receptors. The presence of bFGF receptors was further verified by demonstration of internalization of [125I]bFGF into cells of capsule-glomerulosa preps. This approach was used to demonstrate that suramin (a bFGF antagonist) pretreatment of rats results in bFGF receptor up-regulation in the adrenal cortex. In addition, we demonstrated a decrease in bFGF internalization in the remaining adrenal 24 h after unilateral adrenalectomy, suggesting the utilization of bFGF during the compensatory adrenal growth response. Together, these data support a role for bFGF in autocrine stimulation of the adrenal cortex and in the compensatory adrenal growth response.

Iron deficiency suppresses ileal nitric oxide synthase activity.

Intestinal motility disorders are more common in women of childbearing age who are prone to iron deficiency anemia. The neurotransmitters nitric oxide (NO) and acetylcholine (ACh) play a key role in ileal smooth muscle relaxation and contraction, respectively. Iron-containing heme is known to be a cofactor for nitric oxide synthase (NOS), the enzyme responsible for NO production. Therefore we tested the hypothesis that iron deficiency would downregulate ileal NOS activity without affecting the ileum's response to ACh. Twelve adult female prairie dogs were fed either an iron-supplemented (Fe+) (200 ppm) (n = 6) or an iron-deficient (Fe-) (8 ppm) (n = 6) diet for 8 weeks. Ileal circular muscle strips were harvested to measure responses to ACh and electrical field stimulation. Under nonadrenergic noncholinergic (NANC) conditions, Nomega-nitro-L-arginine (L-NNA), an NOS inhibitor, and VIP(10-28), a vasoactive intestinal peptide (VIP) inhibitor, were added prior to electrical field stimulation. NANC inhibitory responses are expressed as a percentage of optimal relaxation from EDTA. The excitatory response to ACh was similar in both groups (1.1 +/- 0.3 N/cm(2) vs. 1.5 +/- 0.3 N/cm(2), P = 0.45). The inhibitory response to electrical field stimulation under NANC conditions was greater in the Fe+ group (34.7 +/- 2.9%) compared to the Fe- group (23.9 +/- 3.2%; P<0.01). L-NNA eliminated the inhibitory response in the Fe+ group (0.02 +/- 0.02%) but not in the Fe- group (8.38 +/- 2.15%; P <0.01). VIP(10-28) led to greater relaxation in the Fe+ animals (45.8 +/- 6.6%) than in the Fe- animals (23.4 +/- 5.8%; P <0.05). Both L-NNA and VIP(10-28) had no inhibitory response (0.02 +/- 0.02%) in the Fe+ animals, whereas the Fe- animals had some residual inhibition (2.54 +/- 1.04%; P <0.05). These data suggest that ileal NANC relaxation is due to NOS and that iron deficiency results in (1) decreased NANC relaxation, (2) a compensatory relaxation due to a non-NOS, non-VIP mechanism, and (3) a normal excitatory response. We conclude that iron deficiency suppresses ileal NOS activity.

Vitamin A status modulates intestinal adaptation after partial small bowel resection.

BACKGROUND: Intestinal adaptation after loss of functional small bowel surface area is characterized by cellular hyperplasia and increased absorptive function. Interventions to enhance the adaptive response are needed to decrease the morbidity and mortality associated with short bowel syndrome. Retinoic acid was shown to stimulate crypt cell proliferation in the adapting remnant rat ileum by 6 hours after resection. Thus, vitamin A, which is required for normal epithelial cell proliferation and differentiation and which can modulate programmed cell death, may play an important role in the adapting intestine. On the basis of these observations, the effects of vitamin A deficiency on intestinal morphology, epithelial cell proliferation, and apoptosis in the adapting intestine after resection were investigated. METHODS: Weanling male Sprague-Dawley rats fed either a vitamin A-deficient or -sufficient diet for 58 days underwent 70% proximal small bowel resection. The deficient rats were divided into cohorts that were either maintained on the experimental diet after surgery or replenished with vitamin A 20 hours before surgery and switched to the control diet after surgery. RESULTS: Ten days after resection, vitamin A-deficient rats exhibited a markedly blunted adaptive response. The adaptive increase in villus height and crypt depth was absent in the deficient rats. However, adaptive increases in crypt cell proliferation were not attenuated by vitamin A deficiency, and there were no differences in apoptotic indices. CONCLUSIONS: Vitamin A deficiency inhibits the adaptive response to partial small bowel resection, supporting a role for vitamin A in the adaptive process. Changes in cellular proliferation or programmed cell death are not sufficient to account for this inhibition. This model system will be useful for examining the role of other mechanisms, such as changes in cell-cell and cell-extracellular matrix interactions, and rates of epithelial cell migration and cell extrusion.

Endoscopic surgery for monoventricular hydrocephalus.

BACKGROUND: Monoventricular hydrocephalus is usually treated with extrathecal shunting. However, today endoscopic fenestration of the septum pellucidum seems to be a very useful and less invasive technique. METHODS: Five patients with monoventricular hydrocephalus have been treated with neuroendoscopic techniques. In three cases with an excluded lateral ventricle due to contralateral shunt overdrainage, the normal-sized ventricle was first cannulated and fenestration of the septum pellucidum from the normal to the enlarged lateral ventricle was performed. RESULTS: Complete remission of intracranial hypertension symptoms and decrease in size of the enlarged ventricle were observed in all five patients. CONCLUSIONS: Endoscopic fenestration of the septum pellucidum is the technique of choice for treating monoventricular hydrocephalus. We advise first cannulating the normal lateral ventricle and then performing a septostomy from it to the enlarged ventricle. This approach allows one to easily recognize the protruding septum pellucidum and perform fenestration without difficulty using a direct trajectory. In exceptional cases of choroid plexus cyst obstructing one foramen of Monro, fenestration of the cyst wall is sufficient.

[National epidemiologic study on hydatidosis]. / Indagine epidemiologica nazionale sull'idatidosi.

The results of an epidemiological survey on surgical cases of human hydatidosis in 9 italian regions (Central, Southern and Insular Italy) with the highest incidence of disease and a population of 27,054,000 inhabitants are reported. The period considered was from 1980 through 1984. 2,592 cases have been collected and related to sex, age, occupation, residence of surgically treated patients and cyst localization. Comparison of results from the present and a previous survey was carried out.

Analysis of the morphology and distribution of argentaffin, argyrophil and insulin-immunoreactive endocrine cells in the small intestine of the adult opossum Didelphis aurita (Wied-Neuwied, 1826).

The aim of this study was to identify and quantify the argyrophil, argentaffin and insulin-immunoreactive cells (IIC) in the small intestine of the opossum Didelphis aurita. Seven adult male specimens of opossums were investigated. The animals were captured, and their blood insulin levels were determined. After euthanasia, fragments of the small intestine were processed for light microscopy and transmission electron microscopy, and submitted to histochemistry and immunohistochemistry for identification of argyrophil and argentaffin endocrine cells, and IIC. Argyrophil and argentaffin cells were identified in the intestinal villi and Liberkühn crypts, whereas IIC were present exclusively in the crypts. Ultrastructure of the IIC revealed cytoplasmic granules of different sizes and electron densities. The numbers of IIC per mm(2) in the duodenum and jejunum were higher than in the ileum (p<0.05). The animals had low levels of blood insulin (2.8 ± 0.78 µIU/ml). There was no correlation between insulin levels and the number of IIC in the small intestine. The IIC presented secretory granules, elongated and variable morphology. It is believed that insulin secretion by the IIC may influence the proliferation of cells in the Liberkühn crypts, and local glucose homeostasis, primarily in animals with low serum insulin levels, such as the opossum.

Vasodilatation in the rat dorsal hindpaw induced by activation of sensory neurons is reduced by paclitaxel.

Peripheral neuropathy is a major side effect following treatment with the cancer chemotherapeutic drug paclitaxel. Whether paclitaxel-induced peripheral neuropathy is secondary to altered function of small diameter sensory neurons remains controversial. To ascertain whether the function of the small diameter sensory neurons was altered following systemic administration of paclitaxel, we injected male Sprague Dawley rats with 1mg/kg paclitaxel every other day for a total of four doses and examined vasodilatation in the hindpaw at day 14 as an indirect measure of calcitonin gene related peptide (CGRP) release. In paclitaxel-treated rats, the vasodilatation induced by either intradermal injection of capsaicin into the hindpaw or electrical stimulation of the sciatic nerve was significantly attenuated in comparison to vehicle-injected animals. Paclitaxel treatment, however, did not affect direct vasodilatation induced by intradermal injection of methacholine or CGRP, demonstrating that the blood vessels' ability to dilate was intact. Paclitaxel treatment did not alter the compound action potentials or conduction velocity of C-fibers. The stimulated release of CGRP from the central terminals in the spinal cord was not altered in paclitaxel-injected animals. These results suggest that paclitaxel affects the peripheral endings of sensory neurons to alter transmitter release, and this may contribute to the symptoms seen in neuropathy.

[A pilot study on adolescents of both sexes. Correlation between phenotype, athletic performances and family history to type 2 diabetes]. / Uno studio pilota su adolescenti di entrambi i sessi: correlazione tra fenotipo, prestazioni fisiche e familiarità al diabete di tipo 2.

The authors have studied the influence of family history of type 2 diabetes on the physical phenotype of 47 health adolescents. In both sexes groups with positive family history (FH+) had the highest values of stature and body weight (P<0.05 for males, not significant for females), waist circumference (P<0.05 for males, not significant for females), and wrist circumference (P=0.05 for males, not significant for females). Considering athletic performance, FH+ males showed a significant higher performance in power exercises than FH- males; no significant differences were found between FH+ and FH- female groups. The study confirms that family history of type 2 diabetes can induce in both sexes precocious phenotype and athletic performances linked-related variations; larger studies are necessary to confirm these data and to verify preventive interventions promoting significant life-style changes.