The influence of surgical trauma on experimental metastasis.

Influence of surgical trauma on experimental metastasis in healing wounds is investigated using a transplantable murine mammary carcinoma cell line, TA3Ha. Intravenous injection of 10(5), 10(6), and 2 x 10(6) TA3Ha cells into syngeneic Strain A mice led to liver or kidney tumor development in none of the 96, ten, and ten mice tested, respectively. In contrast, injection of 10(5) cells into mice immediately after hepatic wedge resection performed using milliwatt carbon dioxide laser and electrocautery resulted in tumor formation at the site of trauma in 21/37 (57%) and 25/52 (48%) mice, (P less than 0.001) respectively. Similar results were obtained in mice subjected to partial nephrectomy using the laser (nine of 18) and electrocautery (eight of 13). These results clearly demonstrate that surgical trauma renders a nonprivileged organ susceptible to experimental metastasis formation, and that at least in this model both laser and electrocautery have similar effects. Tumor cell injection 1, 7, and 10 days posthepatic surgery resulted in 36%, 20%, and 0% tumor formation, respectively, indicating that the earlier events in wound healing support tumor implantation and/or growth better than those later on. Frequency of tumor formation at sites of trauma in the peritoneum induced by scalpel blade, laser, and electrocautery were 28%, 50% and 82%, respectively. Peritoneal tumors were seen in 33% of the nonsurgical mice. Skin incisions induced with the three above probes had little influence on experimental metastasis formation. Thus the influence of trauma on tumor formation is not uniform in every organ.

Partial nephrectomy in mice with milliwatt carbon dioxide laser and its influence on experimental metastasis.

We have developed a surgical model to perform partial nephrectomy in mice using the milliwatt CO2 laser and have used this model for studying the influence of the sequel of surgery on experimental tumor metastasis. Strain A mice were subjected to partial nephrectomy using the milliwatt CO2 laser. The surgical procedure was time efficient, the blood loss was minimal, and the postoperative mortality was 6%. Immediately after surgery, the wound consisted of a superficial layer of charring and a deeper layer of thermal damage (coagulative necrosis). The wound healing was completed within 30 days and was accompanied by fibroblast infiltration and tubular regeneration but minimal inflammatory response. Seventy surgical mice were injected I.V. with TA3Ha murine mammary adenocarcinoma cells at different intervals (immediately to 30 days) after surgery. Among 38 mice inoculated with tumor cells immediately or up to 3 days after surgery, 18 (47%) showed histologically confirmed tumors at the site of surgical trauma. None of the 38 unoperated kidneys showed any evidence of tumor. This difference is statistically significant at a P value of less than 0.001. As the interval between surgery and tumor inoculation was increased to 7, 15, and 30 days, the frequency of tumor formation at the site of surgery decreased to 20% (2/10), 14% (2/14), and 0% (0/8), respectively. The results demonstrate that a) partial nephrectomy in mice is feasible with minimal mortality or apparent morbidity, b) the laser-induced surgical trauma favors implantation and growth of tumors, c) the frequency of tumor formation is related to the stage of wound healing, and d) the tumors are anatomically related to the healing wound but do not invade into the parenchymal tissue.

Enhanced therapeutic efficacy of cisplatin by combination with diethyldithiocarbamate and hyperthermia in a mouse model.

A spontaneously metastasizing solid tumor model derived by transplanting the TA3Ha murine mammary carcinoma into the s.c. tail tissue of mice was used to develop a treatment strategy for enhancing the therapeutic efficacy of cisplatin (CDDP). This strategy was based on the findings that diethyldithiocarbamate (DDTC) reduces the toxicity of CDDP, and that localized hyperthermia (HT) augments the antitumor efficacy of CDDP. DDTC (500 mg/kg) reduced the CDDP-induced nephrotoxicity and gastrointestinal toxicity as well as increased the CDDP LD10 from 8 to 20 mg/kg in strain A mice. When CDDP and DDTC were used in multiple treatment schedules at 5-day intervals, DDTC protected the hosts but not the tumors against the toxicity of CDDP. HT administered locally to the tumor 1 h after the injection of CDDP (8 mg/kg) in 1 ml Hanks' balanced salt solution increased the antitumor effect but not the host toxicity. While administration of 8 mg/kg CDDP alone or with HT three times at 5-day intervals caused 100% host mortality, this dose of CDDP could be used with no mortality by combining it with DDTC. A combination of 8 mg/kg CDDP with DDTC (750 mg/kg) and HT (43 degree C for 60 min), administered three times at 5-day intervals, retarded the local tumor growth significantly compared to the untreated, CDDP plus DDTC plus HT control groups of mice. The frequency of lung metastasis in these groups on day 30 of tumor inoculation were 0, 90, 90, and 80%, respectively. The mean survival days of the mice treated with CDDP plus DDTC plus HT was 61 +/- 6 compared to 34 +/- 5 in the controls. The results presented here demonstrate that by combining CDDP with DDTC, high doses of CDDP can be safely administered. When localized HT is combined with high dose CDDP and DDTC, the tumor growth retardation and the host survival prolongation are significantly better than those obtained with the highest tolerable dose of CDDP alone or CDDP plus HT.

Milliwatt carbon dioxide laser and hepatic surgery in mice: surgical technique and pathology.

The milliwatt carbon dioxide laser was used to induce focal lesions and to perform wedge resections in the livers of 75 strain A mice. The procedures were feasible and well tolerated by the mice, with only one postoperative death in the wedge resection group in an early experiment. The hepatic lesions produced by the laser were characterized histologically by an inner area of vaporization, an intermediate area of coagulation necrosis, and an outer rim of cells with variable damage. The lesions healed by fibroblastic proliferation and scar formation with no hepatocytic contribution. The small vessel and bile ductule sealing effect of CO2 laser, together with the sound healing of laser-induced wounds, highlights the usefulness of this modality in liver surgery in general, and suggests its particular application in the treatment of liver trauma and a variety of hepatic focal lesions, neoplastic or otherwise.

Syndrome of postoperative depression of vital functions in poor-risk patients: its treatment.

Loss of proprioception due to depressed neuromuscular transmitter following continued action of skeletomuscular relaxant drugs may not be the main cause of stupor, respiratory depression, and suppression of motor and sensory reflex activity in the immediate or delayed post-operative period in surgical patients. Those with a chronic history of suffering (termed poor-risk types because of other associated derangements in electrolytes, body water, etc.), hyper-react to surgical stress as well as postoperative pain and apprehension. This leads to the release of large quantities of stress products (noradrenaline and its cognates) into the central nervous system (CNS), thus inducing a phase of depression of the cerebral cortex and other vulnerable parts of the CNS in such a way that the stupor analgesic stage is induced in the affected persons (called the "syndrome of post-operative depression of vital functions"). Treatment of such a syndrome thus involved removal of the stress products from the CNS as well as from peripheral circulation by extraction therapy (20% mannitol administration), coupled with judicious use of atropine and neostigmine to stimulate the CNS itself, i.e., the production of acetylcholine in the mesencephalic reticulo-activating system.

Epidural anesthesia and the lateral position.

The effect of the lateral position on the onset, maximum spread, and duration of anesthesia were observed using a standardized epidural anesthetic technic. Anesthesia appeared 2 minutes earlier on the dependent side, spread 2 spinal segments higher, and lasted 75 minutes longer. These results support the clinical practice of placing the patient in the lateral position with the operative side dependent for induction of epidural anesthesia.

Syndrome of depressed vital functions in the immediate post-operative period of surgical patients: some aspects of its pathogenesis.

Fifty adult male and female surgical patients (age 25--40 years) undergoing elective and emergency surgical procedures were subjected to isocapnoeic, hypocapnoeic and hypercapnoeic ventilation during anaesthesia; the PaCO2 ranged between 22--90 mm Hg. Three developed the syndrome of depressed vital functions in the post-surgical period by scoring less than 7 out of 10, the others recovered normally with complete resotration of reflex activity, consciousness and skeletomuscular tone, scoring on an average 8 out of 10 points. The role of muscle relaxant drugs in this syndrome and also the depression of the central nervous system is discussed.

Role of thiopentone, nitrous oxide and relaxant anaesthesia in causing the syndrome of post-operative paralysis in man.

Forty-seven patients undergoing elective/emergency surgery were investigated for the recovery pattern by numerically scoring the state of consciousness, skeletomuscular tone, respiration and blood pressure after the neuromuscular transmission at the level of thenar muscles returned to normalcy. Anaesthesia in them consisted of thiopentone induction and passive ventilation with nitrous oxide and oxygen mixtures (4 1/2:2 1/2 1) with consequent changes in PaCO-2 (22.0 to 90 mm Hg) after using 0.43 to 0.68 mg/kg d-tubocurarine or 2.3 to 3.8 mg/kg gallamine. In this series twelve patients were selected at random and biological assay of cerebrospinal fluid in them for curare/gallamine after 15 min anaesthesia and in the recovery phase was carried out on frog rectus muscle. All the patients recovered satisfactorily and did not present clinical signs of depression of central nervous system, even though all of them showed the presence of curare (ranging from 0.05 to 0.33 mug/ml) and gallamine (from 0.1 to 0.75 mug/ml) in the cerebrospinal fluid. This study therefore indicates that thiopentone, nitrous oxide and relaxant type of anaesthesia does not cause clinical syndrome of post-operative paralysis even when mild to moderate degree of hypocapnia is present and even when such a technique of anaesthesia is administered in poor-risk patients with associated changes in acid-base balance, electrolytes etc. Significant quantities of skeleto-muscular relaxant drug (used during the technique) when found in cerebrospinal fluid after the technique of anaesthesia need not induce post-operative paralysis in man.

Passage of gallamine from blood into the liquor space in man and in dog.

1. Patients receiving an intravenous injection of 2-3.8 mg/kg gallamine showed gallamine-like activity in their lumbar c.s.f. collected 15 and 70-100 min after the injection. The activity assayed on acetylcholine contractions of frog rectus muscle was equivalent to between 0.1 and 0.75 mug/ml gallamine.2. In anaesthetized dogs an intravenous injection as well as an intravenous infusion of gallamine led to the appearance of gallamine-like activity in the cisternal c.s.f. and, on perfusion of the cerebral ventricles, in the effluent collected from the cisterna magna.3. After an intravenous injection of 1 mg/kg the activity in the cisternal c.s.f. corresponded to between 0.2 and 1 mug/ml and in the effluent to between 130 and 175 ng/min during the first 15 min perfusion and then declined.4. On intravenous infusion of gallamine at a rate of 10 (mug/kg)/min for 2 h the cisternal c.s.f. showed a uniform gallamine-like activity corresponding to between 0.4 and 0.67 mug/ml during the infusion. In the cisternal effluent the gallamine-like activity rose initially to between 20 and 90 ng/min but declined before the infusion was ended.5. The intravenous injection of gallamine caused respiratory paralysis but did not affect arterial blood pressure; its intravenous infusion caused no respiratory paralysis and did not affect arterial blood pressure.