Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer

Even with current promising antitumor antibodies, their antitumor effects on stroma‐rich solid cancers have been insufficient. We used mild hyperthermia with the intent of improving drug delivery by breaking the stromal barrier. Here, we provide preclinical evidence of cetuximab + mild hyperthermia therapy. We used four in vivo pancreatic cancer xenograft mouse models with different stroma amounts (scarce, MIAPaCa‐2; moderate, BxPC‐3; and abundant, Capan‐1 and Ope‐xeno). Cetuximab (1 mg/kg) was given systemically, and the mouse leg tumors were concurrently heated using a water bath method for 30 min at three different temperatures, 25°C (control), 37°C (intra‐abdominal organ level), or 41°C (mild hyperthermia) (n = 4, each group). The evaluated variables were the antitumor effects, represented by tumor volume, and in vivo cetuximab accumulation, indirectly quantified by the immunohistochemical fluorescence intensity value/cell using antibodies against human IgG Fc. At 25°C, the antitumor effects were sufficient, with a cetuximab accumulation value (florescence intensity/cell) of 1632, in the MIAPaCa‐2 model, moderate (1063) in the BxPC‐3 model, and negative in the Capan‐1 and Ope‐xeno models (760, 461). By applying 37°C or 41°C heat, antitumor effects were enhanced shown in decreased tumor volumes. These enhanced effects were accompanied by boosted cetuximab accumulation, which increased by 2.8‐fold (2980, 3015) in the BxPC‐3 model, 2.5‐ or 4.8‐fold (1881, 3615) in the Capan‐1 model, and 3.2‐ or 4.2‐fold (1469, 1922) in the Ope‐xeno model, respectively. Cetuximab was effective in treating even stroma‐rich and k‐ras mutant pancreatic cancer mouse models when the drug delivery was improved by combination with mild hyperthermia.     

A comparative study of degree of colorectal distention with manual air insufflation or automated CO2 insufflation at CT colonography as a preoperative examination

Objectives

The purpose of this study was to compare the degree of colorectal distention between manual insufflation using room air and automatic insufflation using carbon dioxide for computed tomography colonography performed as a preoperative examination for patients with colon cancer.

Materials and methods

Participants comprised 200 patients who underwent computed tomography colonography immediately after colonoscopy from October 2011–2012. The first 100 patients were examined using manual insufflation, and the remaining 100 patients were examined using automated insufflation. Two radiologists independently assessed colorectal distention using a 4-point scale in six segments: cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum. Mean scores of the two radiologists were used to analyze whether any differences existed between techniques in terms of the degree of distention per segment.

Results

Mean distention values for the colonic lumen were better using the automated technique than with the manual technique in both positions (p < 0.05). In segments, distention was significantly better using the automated technique than using the manual technique in the sigmoid and descending colon for prone patients, and in all segments for supine patients.

Conclusions

Automated carbon dioxide insufflation offered significantly improved colorectal distention scores compared to manual room air insufflation.     

Two cases of atraumatic iliopsoas hematoma

We report two cases of atraumatic iliopsoas hematoma. First patient was a 76-year-old man admitted to our hospital from appetite loss. Blood transfusion did not improve his anemia. Five days after admission, suddenly he went into shock. CT scan revealed ileopsoas hematoma. He died from hemorrhagic shock in spite of conservative therapy. Second patient was a 70-year-old man admitted because of acute heart failure. Continuous hemodiafiltration was required to relieve anuria. The next day, he developed left leg and hip pain. CT scan revealed ileopsoas hematoma and he received CT guided aspiration drainage for decompression, but almost 7 days were needed to achieve successful pain control. In a case of iliopsoas hematoma, early diagnosis and adequate choise of therapy are necessary to improve prognosis of patients.     

Legionella pneumonia which occurred in a private whirlpool bath user

A 88 year old female with active rheumatoid arthritis treated by low dose of prednisolone and methotrexate was admitted to our hospital because of severe bilateral pulmonary infiltration and acute respiratory distress syndrome. On admission, she had consciousness disturbance and was intubated because of severe respiratory failure. We heard from her family of her habit she had taking a private whirlpool bath 2 or 3 times everyday. So, we suspected a Legionella pneumophila infection. We started intravenous erythromycin (EM) (1,500mg/day) and methylprednisolone pulse therapy (1,000mg x 3days) and full controlled mechanical ventilation supported with PEEP. Her respiratory failure was gradually improved and she was discharged on the 44 the hospital day. Legionella pneumophila (serogroup 6) was isolated in her sputum by B-CYE alpha culture. Legionella pneumophila (serogroup 6) was isolated in her private whirlpool bath too. Both samples revealed the same by genetic analysis with pulse field gel electrophoresis (PFGE). This is the first adult case of Legionella pneumophila pneumonia infected from a private whirlpool bath confirmed by genetic analysis. We should always suspect Legionella pneumonia as one of the severe community-acquired pneumonia, because Legionella pneumophila were frequently detected among various water sources including the private whirlpool bath.     

Delayed improvement of autonomic nervous abnormality after the Maze procedure: time and frequency domain analysis of heart rate variability using 24 hour Holter monitoring

Objective—To analyse heart rate variability in patients with atrial fibrillation after the Maze procedure, to investigate whether the procedure damages the cardiac autonomic fibres supplying the sinus node.
Design and patients—Time and frequency domain analyses of RR variability were performed using 24 hour Holter monitoring one month after surgery in 12 patients with atrial fibrillation who underwent the Maze procedure (Maze group) and in seven patients who underwent cardiac surgery without the Maze procedure (control group). Mean RR intervals (mRR) and the standard deviation of successive RR intervals (SDRR) were determined by time domain analysis, and high frequency (HF), low frequency (LF), and total power (TP) spectral components of RR variability were calculated by frequency domain analysis. Holter monitoring was also performed at six and 12 months after cardiac surgery in the Maze group.
Results—Circadian variation (mean (SD)) in mRR (daytime to night time difference: 119 (60) v 302 (143) ms), SDRR (daytime: 8.4 (3.3) v 37.0 (12.0) ms), TP (daytime: 46.7 (16.0) v 171.8 (30.4) ms), HF (daytime: 19.6 (9.9) v 36.7 (7.1) ms²), and LF/HF (daytime: 0.31 (0.07) v 1.18 (0.46)) was decreased in the Maze group at one month compared with the control group (p < 0.01), but showed improvement at six and 12 months (p < 0.05).
Conclusions—Surgery combined with the Maze procedure markedly suppressed the circadian variation of heart rate over a 24 hour period within one month after surgery, mainly because of damage to the innervation of the sinus node. However, at six and 12 months there was restoration of circadian variation, probably as the result of reinnervation of the sinus node.

Keywords: autonomic nervous system;  heart rate variability;  Maze procedure