Clinical and pathologic features correlated with rare favorable survival in patients with BRAFV600E mutated colorectal cancer

BackgroundBRAF^V600E mutations occur in fewer than 10% of all patients with metastatic colorectal cancer (CRC) and arise from sessile serrated adenomas. Despite efficacy with targeted therapies against MAPK signaling and with immunotherapies in this population, survival outcomes for patients with BRAF^V600E mutated metastatic CRC in general are poor. Characteristics distinguishing patients with BRAF^V600E mutated metastatic CRC with favorable versus unfavorable outcomes have not been well annotated.MethodsRecords of 187 patients with BRAF^V600E mutated metastatic CRC evaluated at MD Anderson Cancer Center between 2005–2020 were reviewed. Patients with the shortest and longest metastatic survival (N=25 for each group) were compared. Associations between prognostic group and clinical/pathologic features were measured by odds ratio and for median survival by log-rank testing.ResultsMedian metastatic survival differed between the 2 BRAF^V600E mutated metastatic CRC populations (8.6 vs. 83.9 months, hazard ratio 32; P<0.0001). Patients with poor survival more commonly had hepatic involvement [75% vs. 28%, odds ratio (OR) 8.1, 95% confidence interval (CI): 2.3–29; P=0.001]. Patients with favorable survival were more likely to develop metachronous metastases (52% vs. 16%, OR 5.7, 95% CI: 1.5–21; P=0.01) and undergo definitive locoregional therapy to metastatic disease (40% vs. 0%, OR 34.5, 95% CI: 1.9–630; P=0.01). Microsatellite instability (36% vs. 4%, OR 19.8, 95% CI: 2.2–180; P=0.008) and prior tobacco exposure (44% vs. 16%, OR 4.1, 95% CI: 1.1–15.6, P=0.04) were associated with a favorable prognosis. Durable responses to MAPK-targeted therapies and immunotherapy were noted in the favorable group.ConclusionsA small fraction of patients with BRAF^V600E mutated metastatic CRC can achieve excellent long-term survival which belies conventional context and is driven by either surgical metastectomy or by systemic treatment options. While poor overall prognosis remains the recognized outcome for most patients with BRAF^V600E mutated metastatic CRC, it is possible that few may achieve exceptionally favorable survival.     

High Hb A2 β-Thalassemia Due to a 468 bp Deletion in a Patient with Hb S/β-Thalassemia

We describe a case of Hb S/β-thalassemia (thal) involving a 468 bp deletion that removes the β-globin gene promoter but leaves the coding regions intact. This is the second report of this deletion, and our family study establishes that this deletion causes β⁰-thal with unusually high levels of Hb A₂ and Hb F. As with other genotypes involving deletions of the 5′ region of the β-globin gene, our patient had a mild form of Hb S/β-thal.     

Extraction and immunochemical characterization of cholecystokinin-like peptides from pig and rat brain

Two major classes of immunoreactive cholecystokinin peptides (iCCK) have been identified in rat and pig brains: (i) large basic peptides (big iCCK) resembling the 33-amino acid porcine cholecystokinin (pCCK33) in size and charge; (ii) small acidic peptides (small iCCK) resembling the COOH-terminal fragments of CCK. Boiling 0.1 M HCl maximally extracts big iCCK; boiling 0.1 M NaOH maximally extracts small iCCK. The differences in hormonal forms removed by these extractants are not likely to be due to enzymatic conversion during the extraction procedures. Fractionation on Sephadex G-50 and starch gel electrophoresis combined with radioimmunoassay using three antisera of different specificities--(i) directed towards the NH2 terminus of pCCK33, (ii) produced by immunization with COOH-terminal fragment CCK8, (iii) produced by immunization with COOH-terminal fragment CCK4--are consistent with the hypothesis that a major fraction of big iCCK may represent intact cholecystokinin with a COOH-terminal extension, as has recently been suggested for gastrin, a molecule having a COOH-terminal pentapeptide identical with that of cholecystokinin.     

The Effects of Intravenous Levofloxacin on the QT Interval and QT Dispersion

The QT dispersion (QT_d) is a non-invasive means of identifying those patients at an increased risk of developing sudden cardiac death (SCD). Although levofloxacin has a minimal effect on the QT_c interval, isolated reports of QT prolongation, polymorphic ventricular tachycardia with a normal QT interval and TdP have been reported. The purpose of this study was to examine the effect of intravenous levofloxacin on the QT interval and QT_d. Of the 50 patients who were deemed candidates to receive intravenous levofloxacin, 29 met the eligibility criteria and were enrolled in this study. A 12-lead ECG was performed before the initiation of levofloxacin (baseline), and on days 3 and 5. The QT^c _min, QT^c _max and the QT_d were calculated. Measurements where made by two independent observers blinded to the patients’ clinical status. The QT_d increased significantly on days 3 and 5 following the initiation of therapy [QT_d (baseline) 33.3 ± 20 ms, QT_d (day 3) 64.4 ± 31.3 ms (p = 0.023), QT_d (day 5) 66.8 ± 20.3 ms, (p = 0.008)]. The increase in the QT_d was significantly longer in men than women. Although women had a shorter baseline QT_d compared to men, this did not achieve statistical significance. Intravenous levofloxacin was found to significantly increase the QT_d, which was more pronounced in men compared to women. Its effect on the QT_d may increase the risk of developing a potentially fatal ventricular arrhythmia. Therefore, care must be taken when prescribing this medication to patients with a pre-existing risk of developing SCD.     

Drug-Induced Esophagitis

Drug-induced esophagitis is being recognized increasingly in the past few years. We have reviewed 175 cases with a view to classifying this disease based on pathology. Drug-induced esophageal injury tends to occur at the anatomical site of narrowing, with the middle third behind the left atrium predominating. The disease is classified broadly into two groups. The first group is transient and self-limiting, as exemplified by tetracycline- and emepronium-induced injury (57.3%). The second is the persistent esophagitis group, often with stricture with two distinct entities: 1) patients on nonsteroidal antiinflammatory agents whose injury is aggravated by gastroesophageal reflux (26.2%) (reflux aggravated), and 2) patients with potassium chloride and quinidine sulfate-induced injury (16.2%) (persisting drug injury). We report a case that highlights the pathophysiology (delayed transit, persisting potassium within the stricture) of this type of injury which is not reflux aggravated.     

Glucocorticoid and mineralocorticoid cross-talk with progesterone receptor to induce focal adhesion and growth inhibition in breast cancer cells

Progesterone receptor (PR), glucocorticoid receptor, and mineralocorticoid receptor belong to a subfamily of nuclear receptor superfamily with similar sequence and structural characteristics. Many reports have documented glucocorticoid-like effects of progesterone in various tissues. This study addresses the issue of cross-talk between corticosteroids and PR using PR-transfected MDA-MB-231 cells ABC28 and vector-transfected control cells CTC15. At physiological concentrations, dexamethasone, cortisol, and aldosterone mimic the effects of progesterone by inducing significant growth inhibition, cell spreading, and focal adhesions in PR-positive ABC28 cells. These hormones also induce progesterone-like effects in increasing the expression of p21(CIP1/WAF1) protein and decreasing the level of phospho-p42/p44 mAPK. Two lines of evidence suggest that these effects are mediated by cross-talk with PR. First, these compounds do not exhibit the same progesterone-like effects in PR-negative CTC15 cells. Second, PR blocker ZK98299 abolishes their effect on cell spreading and focal adhesion in ABC28 cells. The cross-talk is corticosteroid specific because estradiol and thyroid hormone triiodothyronine have no effect on PR-transfected cells ABC28. It is also interesting to note that dexamethasone induces a small but detectable increase of focal adhesions and limited growth stimulation in vector-transfected cells CTC15. In contrast, progesterone exhibits no detectable effect on CTC15 cells. This study provides evidence that glucocorticoid and mineralocorticoid cross-talk with PR to produce progesterone-like effects in breast cancer cells. Glucocorticoid receptor and PR share some overlapping activity in mediating focal adhesion but not in regulating cell proliferation.     

Abdominosacral resection for midrectal cancer.

Abdominosacral resection is the most reliable radical sphincter-saving operation for midrectal cancers which are too low for anterior resection. The posterior incision provides maximum exposure for wide resection of the tumor, a measured distal margin, and an accurate anastomosis. The procedure can be carried out consistently to the pelvic floor without disrupting the anal sphincters and their innervation. Sphincter function is consistently preserved. Mortality rate is no higher than for other radical rectal resections. Morbidity can be limited by the selective use of protective colostomy. The use of mechanical retractors and the end-to-end stapler facilitates the operation and should encourage its wider application. The transsacral approach allows mobilization of the rectum to the levators in every case, and resection is limited only by the distance of the tumor from the sphincter, and not by poor exposure due to obesity or a narrow pelvis. In the treatment of 926 consecutive patients with rectal cancer, sphincter-saving resection was possible in 79%. In our experience, abdominosacral resection extends the range of sphincter-saving resection beyond that which is possible by the abdominal approach alone, with no compromise in safety and no increased risk of local recurrence or death from cancer.     

Effect of autologous blood donation on the central venous pressure, blood loss and blood transfusion during living donor left hepatectomy

AIM: Autologous blood donation (ABD) is mainly used to reduce the use of banked blood. In fact, ABD can be regarded as acute blood loss. Would ABD 2-3 d before operation affect the CVP level and subsequently result in less blood loss during liver resection was to be determined. METHODS: Eighty-four patients undergoing living donor left hepatectomy were retrospectively divided as group Ⅰ (GI) and group Ⅱ (Gil) according to have donated 250-300 mL blood 2-3 d before living donor hepatectomy or not. The changes of the intraoperative CVP, surgical blood loss, blood products used and the changes of perioperative hemoglobin (Hb) between groups were analyzed and compared by using Mann-Whitney U test. RESULTS: The results show that the intraoperative CVP changes between GI (n = 35) and GII (n = 49) up to graft procurement were the same, subsequently the blood loss, but ABD resulted in significantly lower perioperative Hb levels in GI. CONCLUSION: Since none of the patients required any blood products perioperatively, all the predonated bloods were discarded after the patients were discharged from the hospital. It indicates that ABD in current series had no any beneficial effects, in term of cost, lowering the CVP, blood loss and reduce the use of banked blood products, but resulted in significant lower Hb in perioperative period.     

Myocardial micronecrosis produced by microsphere embolization. Role of an alpha-adrenergic tonic influence on the coronary microcirculation

Microspheres approximately 25 or 50 micrometers in diameter were systemically embolized from the left ventricular cavity. The number of microspheres given was empirically chosen to minimize the possibility of more than one microsphere lodging in an arteriole (3 mg/kg), yet was sufficient to allow for adequate histological assessment. The dogs were sacrificed after 24 hours, and focal areas of myocytolytic necrosis were noted in the myocardium. Groups of dogs were given pretreatment with drugs 10 minutes before embolization. Dogs pretreated with phentolamine (n = 8) and prazosin (n = 2) did not reveal any areas of myocardial necrosis after embolization with 25-micrometers microspheres. Cardiac lesions were also prevented in four of five dogs pretreated with verapamil. In contrast, cardiac lesions were not prevented by pretreatment with yohimbine (n = 2), dipyridamole (n = 3), propranolol (n = 2), or atropine (n = 2). Drug pretreatment with phentolamine or verapamil was not able to prevent cardiac lesions after embolization with 50-micrometers microspheres. Furthermore, despite a greater number of microspheres physically present in the subendocardial layer, the necrotic lesions were more frequent in the mid-wall and epicardial layers. Lesions produced by 25- or 50-micrometers emboli were also significantly smaller in the endocardium. Systemic embolization with microspheres excluding the coronary circulation did not produce cardiac lesions. We conclude that mechanical interruption of the coronary circulation with a 25-micrometers microsphere may be a necessary but not sufficient condition to produce cardiac necrosis. An alpha 1-adrenergic mechanism is also involved in the production of these lesions.(ABSTRACT TRUNCATED AT 250 WORDS)