Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice

PEG-rHuMGDF injected daily in normal mice causes a rapid dose-dependent increase in megakaryocytes and platelets. At the same time that platelet numbers are increased, the mean platelet volume (MPV) and platelet distribution width (PDW) can be either decreased, normal, or increased depending on the dose and time after administration. Thus, PEG-rHuMGDF at a low dose causes decreases in MPV and PDW, MGDF at an intermediate dose causes an initial increase followed by a decrease in MPV and PDW, and PEG-rHuMGDF at higher doses causes an increase in MPV and PDW followed by a gradual normalization of these platelet indices. In addition to the expected thrombocytosis after 7 to 10 days of daily injection of high doses of PEG-rHuMGDF, a transient decrease in peripheral red blood cell numbers and hemoglobin is noted accompanied in the bone marrow by megakaryocytic hyperplasia, myeloid hyperplasia, erythroid and lymphoid hypoplasia, and deposition of a fine network of reticulin fibers. Splenomegaly, an increase in splenic megakaryocytes, and extramedullary hematopoiesis accompany the hematologic changes in the peripheral blood and marrow to complete a spectrum of pathologic features similar to those reported in patients with myelofibrosis and megakaryocyte hyperplasia. However, all the PEG-rHuMGDF-initiated hematopathology including the increase in marrow reticulin is completely and rapidly reversible upon the cessation of administration of PEG-rHuMGDF. Thus, transient hyperplastic proliferation of megakaryocytes does not cause irreversible tissue injury. Furthermore, PEG-rHuMGDF completely ameliorates carboplatin-induced thrombocytopenia at a low-dose that does not cause the hematopathology associated with myelofibrosis.     

Different Recurrence Pattern After Neoadjuvant Chemoradiotherapy Compared to Surgery Alone in Esophageal Cancer Patients

Purpose

To evaluate the rate and pattern of recurrences after neoadjuvant chemoradiotherapy (CRT) in esophageal cancer patients.

Methods

We described survival and differences in recurrences from a single center between neoadjuvant CRT (carboplatin/paclitaxel and 41.4 Gy) and surgery alone for the period 2000–2011. To reduce bias, we performed a propensity score matched analysis.

Results

A total of 204 patients were analyzed, 75 treated with neoadjuvant CRT and 129 with surgery alone. The pathologic response to neoadjuvant CRT was 69 % with a complete response rate of 25 %. After matching, baseline characteristics between the groups (both n = 75) were equally distributed. The 3- and 5-year disease-free survival was 53 and 42 % in the neoadjuvant CRT group compared with 24 and 18 % in the surgery-alone group (P = 0.011). After 3 and 5 years’ CRT, patients had an estimated locoregional recurrence-free survival of 83 and 73 % compared with 52 and 49 % in the surgery-alone group (P = 0.015). The distant recurrence-free survival was comparable in both groups. Locoregional recurrences were located less in the paraesophageal lymph nodes in the CRT group than in the surgery-alone group, 9 versus 21 %, respectively (P = 0.041). With respect to differences in distant recurrences, we observed more skeletal recurrences in the surgery-alone group compared to CRT, 12 versus 1 % (P = 0.009).

Conclusions

The neoadjuvant CRT regimen we used offers a significant improvement in outcome, with a different recurrence pattern compared with surgery alone. This effect is probably due to both the pathologic complete response and eradication of micrometastases in CRT group.     

Mortality, reinfarction, left ventricular ejection fraction and costs following reperfusion therapies for acute mvocardial infarction

The comparative efficacy of thrombolytic drugs and primary angioplastyfor acute myocardial infarction have recently been studied,but long-term follow-up data have not yet been reported. Weconducted a randomized trial involving 301 patients with acutemyocardial infarction; 152 patients were randomized to primaryangioplasty and 149 to intravenous streptokinase. Left ventricularfunction was assessed with a radionuclide technique both athospital discharge and at the end of the follow-up period. Follow-updata were collected after a mean (± SD) of 31 ±9 months. Total medical costs were calculated. At the end ofthe follow-up period, 5% of the angioplasty patients had diedfrom a cardiac cause compared to 11% of the patients randomizedto intravenous streptokinase, P=0·031. Cardiac deathor a non-fatal reinfarction occurred in 7% of angioplasty patientscompared to 28% of streptokinase patients, P0·001. Therewas a sustained benefit of angioplasty compared to streptokinaseon left ventricular function. The total medical costs in thetwo groups were similar. Coronary anatomy (patency and singleor multivessel disease), infarct location and previous myocardialinfarction were important determinants of clinical outcome andcosts. After 31±9 months of follow-up, primary angioplasty comparedto intravenous streptokinase results in a lower rate of cardiacdeath and reinfarction, a better left ventricular ejection fraction,and no increase in total medical costs. (Eur Heart J 1996; 17: 382–387)     

Colorectal cancer extracellular acidosis decreases immune cell killing and is partially ameliorated by pH-modulating agents that modify tumor cell cytokine profiles

Tumor cells upregulate myriad proteins that are important for pH regulation, resulting in the acidification of the extracellular tumor microenvironment (TME). Abnormal pH is known to dampen immune function, resulting in a worsened anti-tumor immune response. Understanding how extrinsic alterations in pH modulate the interactions between immune cells and tumors cells will help elucidate opportunities for new therapeutic approaches. We observed that pH impacts the function of immune cells, both natural killer (NK) and T cells, which is relevant in the context of a highly acidic TME. Decreased NK and T cell activity was correlated with decreasing pH in a co-culture immune cell-mediated tumor cell-killing assay. The addition of pH-modulating drugs cariporide, lansoprazole, and acetazolamide to the co-culture assay was able to partially mitigate this dampened immune cell function. Treatment of colorectal cancer (CRC) cells with NHE1 inhibitor cariporide increased CRC cell-secreted cytokines involved in immune cell recruitment and activation and decreased cytokines involved in epithelial-mesenchymal transition (EMT). Cariporide treatment also decreased CRC cell shed TRAIL-R2, TRAIL-R3, and PD-L1 which is relevant in the context of immunotherapy. These experiments can help inform future investigations into how the pH of the tumor microenvironment may be extrinsically modulated to improve anti-tumor immune response in solid tumors such as colorectal cancer.     

Long-term results of irrigated radiofrequency modified maze procedure in 200 patients with concomitant cardiac surgery: six years experience

BACKGROUND: The Cox maze procedure is considered an effective surgical treatment of atrial fibrillation in patients with and without organic heart disease. Radiofrequency energy offers an alternative to the complex surgical maze procedure. We used the radiofrequency modified maze III procedure in patients with atrial fibrillation undergoing elective concomitant cardiac surgery. This study evaluated the long-term results of the irrigated radiofrequency ablation to create linear lines of conduction block endocardially. METHODS: Between November 1995 and June 2001, 200 patients with mainly structural heart disease and chronic atrial fibrillation underwent intraoperative radiofrequency linear ablation in both atria with concomitant cardiac surgery. RESULTS: The in-hospital mortality rate was 3.5% (7 patients) and during the mean follow-up of 40 months (range, 12 to 80) 27 patients (13.5%) died. Eight patients (4%) were lost from follow-up and complete data were available in 158 survivors. Sinus or atrial rhythm was present in 116 patients (73.4%) and an atrial driven rhythm in 10 patients (6.3%) with an atrioventricular pacemaker. Atrial fibrillation or flutter was documented in 32 patients (20.3%). Antiarrhythmic drugs were used in 49% of survivors who were free of atrial fibrillation or flutter. CONCLUSIONS: Intraoperative radiofrequency endocardial ablation is an effective technique to eliminate atrial fibrillation with promising long-term results.     

Simultaneous measurement of gallbladder emptying with cholescintigraphy and US during infusion of physiologic doses of cholecystokinin: a comparison

Both ultrasonography (US) and cholescintigraphy are used to study gallbladder dynamics. The present study was undertaken to determine whether the two methods provide the same or different information relating to gallbladder emptying. Emptying was simultaneously studied with both methods during infusion of graded physiologic doses of cholecystokinin (CCK) in six healthy subjects. Infusion of stepwise increasing doses of CCK, ranging from 0.03 to 0.5 Ivy dog units per kilogram of body weight per hour (IDU/kg.h), induced significant dose-related increases in plasma CCK, decreases in gallbladder volume assessed with US, and gallbladder emptying assessed with cholescintigraphy. The threshold dose for inducing significant gallbladder emptying was 0.13 IDU/kg.h, as determined with both techniques, indicating similar detection limits. There was a highly significant correlation between decreases in gallbladder volume and decreases in radioactive counts over the gallbladder region, with a tendency toward greater gallbladder responses at sonography during the early phase of gallbladder contraction and toward greater responses at cholescintigraphy during the later phase of gallbladder contraction. It is concluded that these methods can be used interchangeably for the quantitation of gallbladder emptying.     

Major motor atrophic patterns in the face and neck: CT evaluation

Cranial nerve deficits from various pathologic processes of the head and neck may result in characteristic patterns of denervation muscular atrophy. Such atrophic patterns may be clues to the location and extent of the lesion, particularly when cranial nerves are involved early in the course of the disease process. Thirty-six patients with computed tomographic (CT) evidence of muscular atrophy secondary to pathologic conditions involving the motor division of cranial nerves were examined. Five characteristic denervation muscular atrophy patterns seen on CT scans were identified. In several patients, identification of the muscular atrophy pattern was the only clue to the presence of a pathologic condition. Recognition of these atrophic patterns can prevent misinterpretation of their CT appearance and direct the CT examination to the course of the compromised cranial nerve from the brainstem to its peripheral innervation.