4A after access: a new mnemonic to aid timely administration of IV/IO treatment in trauma patients.

Administration of medication is a well-established part of prehospital trauma care. Guidance varies on the types of recommended medications and when they should be administered. Mnemonics have become commonplace in prehospital medicine to facilitate recall and retention. However, there is no comprehensive aid for the administration of medication in trauma patients. We propose a new mnemonic for the delivery of relevant intravenous or intraosseous medications in trauma patients. A '4A after Access' approach should enhance memory recall for the efficient provision of patient care. These 4As are: antifibrinolysis, analgesia, antiemesis and antibiotics. This mnemonic is designed to be used as an optional aide memoire in conjunction with existing treatment algorithms in the military prehospital setting.

Transcriptional subtyping and CD8 immunohistochemistry identifies poor prognosis stage II/III colorectal cancer patients who benefit from adjuvant chemotherapy.

PURPOSE: Transcriptomic profiling of colorectal cancer (CRC) has led to identification of four consensus molecular subtypes (CMS1-4), which have prognostic value in stage II/III disease. More recently, the Colorectal Cancer Intrinsic Subtypes (CRIS) classification system has helped to define the biology specific to the epithelial component of colorectal tumors. However, the clinical value of these classifications in predicting response to standard-of-care adjuvant chemotherapy remains unknown. PATIENTS AND METHODS: Using samples from 4 European sites, we assembled a novel stage II/III CRC patient cohort and performed transcriptomic profiling on 156 samples, targeted sequencing and generated a tissue microarray to enable integrated "multi-omics" analyses. We also accessed data from 2 published stage II/III CRC patient cohorts: GSE39582 and GSE14333 (479 and 185 samples respectively). RESULTS: The epithelial-rich CMS2 subtype of CRC benefitted significantly from adjuvant chemotherapy treatment in both stage II and III disease (p=0.02 and p<0.0001 respectively), while the CMS3 subtype significantly benefitted in stage III only (p=0.00073). Following CRIS sub-stratification of CMS2, we observed that only the CRIS-C subtype significantly benefitted from adjuvant chemotherapy in stage II and III disease (p=0.0081 and p<0.0001 respectively), while CRIS-D significantly benefitted in stage III only (p=0.0034). We also observed that CRIS-C patients with low levels of CD8+ tumor-infiltrating lymphocytes were most at risk of relapse in both stage II and III disease (p=0.0031). CONCLUSION: Patient stratification using a combination of transcriptional subtyping and CD8 immunohistochemistry analyses is capable of identifying poor prognostic stage II/III patients who benefit from adjuvant standard-of-care chemotherapy. These findings are particularly relevant for stage II disease, where the overall benefit of adjuvant chemotherapy is marginal.

Squamous cell carcinoma of the larynx in HIV-positive patients: difficulties in diagnosis and management.

Patients who are infected with human immunodeficiency virus (HIV) are at increased risk of developing laryngeal squamous cell carcinoma. This malignancy on average appears in a younger age group at a more advanced stage and has a more aggressive course in HIV patients. These patients have difficult management challenges, diagnostically, in staging, and particularly in determining the optimal treatment for each individual patient because their underlying HIV infection can markedly increase morbidity associated with active treatments. They frequently have problems associated with swallowing both before and after treatment. We present two cases that highlight difficulties in the diagnosis and management of these patients as well as post-treatment complications, with particular emphasis on swallowing problems.

Murine RARbeta4 displays reduced transactivation activity, lower affinity for retinoic acid, and no anti-AP1 activity.

The biological actions of retinoic acid (RA) are mediated by retinoic acid receptors (RARalpha, beta, and gamma) and retinoid X receptors (RXR alpha, beta, and gamma). Each of the RARs is expressed as four to seven different isoforms. Four isoforms of RAR beta (beta1, beta2, beta3, and beta4), which differ only in their N-terminal sequence (A domain) have been described. These RARbeta isoforms display a specific pattern of expression in developing and adult animals and are highly evolutionarily conserved suggesting that they mediate distinct cellular effects of vitamin A. Experiments were performed to examine directly the RA-binding activity, transactivation activity, and anti-AP1 activity of each of these four RARbeta isoforms. The results demonstrate that RARbeta1, beta2, and beta3 bind RA with a similar K(d) value, have a similar EC(50) value in RA-dependent transactivation assays and inhibit AP1 activity to a similar level. By contrast, RARbeta4 has an elevated K(d) for RA, an increased EC(50) value in RA-dependent transactivation assays and does not display the ability to inhibit AP1 activity. This provides additional evidence that at least one RAR isoform, RARbeta4, may mediate distinct activities within a cell. Furthermore, these data suggest that the presence of an A domain in RARbeta is important for modulating these activities of RARs.

The potential role of integrin receptor subunits in the formation of local recurrence and distant metastasis by mouse breast cancer cells.

BACKGROUND: The mechanisms by which surgical injury fosters tumor growth are examined. METHODS: TA3Ha mouse breast tumor line and its subline (TA3AD) differing in their metastatic abilities as tested by two models were used. In model a, TA3Ha/TA3AD tumors were grown in the mammary fat pads of mice and then surgically removed with a curative intent. In model b, TA3Ha/TA3AD cells were injected intravenously into mice subjected to liver or spleen wedge resection. Frequency of tumor formation at various sites was assessed. Expression of integrin, immunoglobulin, and proteoglycan cell adhesion receptors on TA3Ha and TA3AD cells was examined by flow cytometry. The roles of these receptors in metastasis were examined by blocking them by selected ligands and/or antibodies. RESULTS: Frequencies of local recurrence and axillary metastasis after surgical resection, were 43% (32/74), and 37% (27/74) with TA3Ha tumors and 4% (1/29) at both sites with TA3AD tumors. Tumors at surgically injured spleen and the liver were seen in 75% (141/189) and 45% (107/240) of the mice with TA3Ha cells and in 8% (3/38) and 10% (4/42) of the mice with TA3AD cells. alpha 5 and CD44 receptors were expressed by TA3Ha cells but not by TA3AD cells. Other receptors examined were similarly expressed by both cell lines. Blocking of alpha 5 receptor by fibronectin reduced tumor implantation in a dose-dependent manner. CONCLUSIONS: The data suggest a correlation among the ability to implant at surgically injured sites, to form local recurrence, and to express the fibronectin receptor subunit.

An objective assessment of speech and swallowing following free flap reconstruction for oral cavity cancers.

In this prospective study, eight consecutive patients underwent excision of oral cavity cancer and reconstruction with a microvascular free flap. Six patients had one pre- and two postoperative assessments of speech and swallowing at four to six weeks and four to six months respectively. One patient could not attend for the preoperative assessment and another for the first postoperative assessment. The speech assessment consisted of an intelligibility score and an articulation score. The swallowing assessment consisted of a videofluoroscopic examination. Five patients had an excellent postoperative speech assessment score, two had a moderate and one a poor result. Videofluoroscopy demonstrated minor swallowing problems preoperatively in one patient. Postoperatively, three patients had severe or moderate loss of control of bolus. Significant aspiration was detected in two and mild aspiration in one patient at the second postoperative assessment. The abnormalities of speech and swallowing were minor in the majority of the patients and the overall outlook was good. This information should be of value for preoperative counselling.

Endocrine and paracrine hormones in the promotion, progression and recurrence of breast cancer.

Both normal and neoplastic breast tissues are stimulated by endocrine and paracrine hormones. Epidemiological studies have demonstrated the significant role that hormones, growth factors and cytokines have in the promotion, progression and recurrence of breast cancer. Significant variations in the hormonal environment occur based on age, the cyclical changes occurring during the menstrual cycle and (mammographically determined) variations in breast composition. These variations have a significant influence on rates of local recurrence of breast cancer and survival. This review analyses data relevant to these issues and suggests means by which operative results may be improved.

Pre-, peri-, and postoperative chemotherapy for breast cancer: is one better than the other?

The purpose of the present study was to determine the relative efficacy of pre-, peri-, and postoperative chemotherapy in the prevention of breast cancer relapse and prolongation of host survival. The studies were performed using an experimental mouse breast cancer model. TA3Ha mouse mammary adenocarcinoma was transplanted into the mammary fat pad of syngeneic mice to obtain tumors in their natural organ. The tumors were surgically excised with a "curative" intent. A single treatment with 10 mg/kg doxorubicin was given intravenously pre-, peri-, or postoperatively. Among 74 mice whose tumors were resected but no doxorubicin was given, local recurrence, axillary metastasis, and lung metastasis were seen in 43%, 37%, and 16% of the mice, respectively. Seventeen (23%) mice had no evidence of disease. Doxorubicin given 4 days preoperatively reduced the rate of growth of primary tumor. Local recurrence was reduced in these mice by 30% and metastasis to the axillary lymph nodes and lung was completely prevented. Disease-free survival was increased to 70% (P < 0.01). Similar beneficial effects were obtained when chemotherapy was administered 2 days prior to surgery. The peri-operative chemotherapy group showed 8% (2/26) local recurrence, 4% axillary metastasis, and 0% lung metastasis. Proportion of mice without any evidence of disease increased to 92% (P < 0.00001). Chemotherapy given 4 days postoperatively resulted in 63% (10/16) local recurrence, 38% axillary metastasis, and 6.3% lung metastasis. Only 38% of the mice were disease-free. Thus in the model studied, perioperative chemotherapy offers the best chance for reduced recurrence and for improved disease-free survival.

Role of cytokines and growth factors in promoting the local recurrence of breast cancer.

The pathogenesis of local recurrence in breast cancer is not well understood. Breast-conserving surgery is particularly prone to local recurrence as it leaves behind breast tissue that may harbour occult cancer, and lends itself to enhanced intraoperative shedding of cancer cells due to narrower resection margins and transection of lymphatic channels. A review of clinical breast cancer studies as well as experimental research strongly suggests that these persisting cancerous cells are unlikely to develop into clinically evident disease if their environment remains unstimulated. However, an inordinately high local recurrence rate occurs at the surgical scar, and such recurrence must be triggered by the release of growth factors and cytokines into the healing wound. These factors can stimulate any available cancer cells which express the proper growth factor receptors. Perioperative strategies to neutralize this tumour cell-growth factor interaction should maximize local control.

Influence of smoking on the development of lung metastases from breast cancer.

BACKGROUND: This study examined the association between cigarette smoking status and the development of lung metastases in a group of 835 women diagnosed with primary malignant unilateral breast cancer. METHOD: Female patients with breast cancer diagnosed between 1982 and 1991 at Roswell Park Cancer Institute (RPCI) in Buffalo, New York, who provided information on their cigarette smoking history at the time of their diagnosis were included. The subsequent disease status of patients was monitored by the RPCI Tumor Registry. The Cox regression model was used to estimate the relationship between smoking status and the development of lung metastases, adjusting for the patient's age, stage of disease at diagnosis, and body weight. RESULTS: Of those patients who developed lung metastases, 8.7% were nonsmokers, 14.1% were former smokers, and 14.3% were current smokers. Tests showed that nonsmokers had significantly fewer lung metastases than either of the two smoking groups (P < 0.01). The estimated relative rates of lung metastases developing adjusting for age, stage, and body weight in women who smoked less than 10,000, between 10,001 and 20,000, and more than 20,000 packs over their lifetimes compared with nonsmokers were 1.06 (95% CI, 0.51-2.20), 3.10 (95% CI, 1.5-6.3), and 3.73 (95% CI, 1.6-8.9) respectively. The Cox regression model showed that every 1000 packs of cigarettes consumed over a lifetime increased a woman's risk of developing lung metastases by about 3% to 7% (P < 0.001). CONCLUSION: This study found a significant association between cigarette smoking history and risk of lung metastases developing in women diagnosed with primary invasive unilateral breast cancer. The risk of lung metastases developing increased as the number of cigarettes smoked in a lifetime increased.

Growth and metastasis of human breast cancers in athymic nude mice.

To evaluate critically the merit of utilizing a wound model for growing human tumors, a series of increasingly difficult human tumor types were tested for growth at sites of trauma in athymic nude mice. In vitro tumor lines as well as fresh tumors from the breast, colon, rectum, lung, and a metastasis from an unknown primary were intraperitoneally injected into mice subjected to intra-abdominal organ injury. Successful xenografts were obtained from nine of 10 cell lines and 14 of 24 fresh tumors. The latter included five of six (83%) colon cancers, one lung tumor, metastatic tumor of unknown primary, three of four (75%) metastatic breast cancers and four of six (67%) estrogen receptor (ER)-negative breast primary tumors. Six ER-positive breast tumors tested failed to grow in mice without estrogen supplementation. Xenografts from two breast, two colon and the lung cancers formed spontaneous metastases and all xenografts tested were able to yield serial transplants in the surgical wound model. Histologically, all xenografts and their metastases were identical to their respective donor tumors. Transplantability in mice without exogenous estrogen supplementation was linked to the absence of estrogen and progesterone receptors in breast tumors. Transplantability of the cell lines was associated with the expression of cell surface receptors for fibronectin and hyaluronic acid. Receptors for other extracellular matrix components, namely, laminin, vitronectin, collagen, fibrinogen or von Willebrand factor were not associated with transplantability. These results demonstrate that a large proportion of human tumors, including the breast tumors, can be successfully xenografted into athymic mice by providing them with a healing wound environment, and that such xenografts grown at ectopic sites exhibit metastatic ability.

T/Tn antigen vaccine is effective and safe in preventing recurrence of advanced breast carcinoma.

Since 1974, and as of March, 1993, we have used T/Tn antigen vaccine in safe, specific, effective, long-term intradermal vaccination against recurrence of advanced breast carcinoma (CA). Staging is by the pathologic TNM system. Treatment is ad infinitum. Of 19 consecutive breast carcinoma patients vaccinated, six Stage IV, six Stage III, and seven Stage II all survived > 5 years postoperatively. Three Stage III, three Stage IV, and five Stage II patients (i.e., 11) survived > 10 to > 18 years. Five others are alive but have not reached 10 years; three of them have no evidence of disease (NED). Three patients died of CA before reaching 10 years. An additional three breast CA patients are being treated for > 2 years, but, < 5 years postoperatively, they are NED. The vaccination are presented as a delayed-type hypersensitivity reaction with significant inflammation with increase of helper T lymphocytes and decrease of T suppressor/cytotoxic cell ratio.

Effect of trauma on implantation of metastatic tumor in bone in mice.

We studied the influence of surgical trauma to the iliac bone on the implantation of I.V. injected tumor cells, which formed tumor in the surgical wounds of 27/84 mice (32%). None of these mice or nonsurgical mice developed tumor in the opposite or uninjured pelvic bone (P < 0.0001). When different numbers (10(5), 5 x 10(5), and 10 x 10(5)) of TA3Ha cells were injected I.V. immediately after surgery, the frequency of tumor formation showed an increase (respectively, 32%, 63%, 71%). As the interval between induction of trauma and tumor cell injection was increased from 0 to 15 days, the frequency of tumor formation declined from 32% to 0%. These results suggest that the healing wound is a privileged site for experimental metastasis, particularly in the early stages. It is likely that the proteins in the blood clotting cascade are involved in local tumor implantation.

T/Tn antigen vaccine is effective and safe in preventing recurrence of advanced human breast carcinoma.

For nearly 20 yrs, we used T/Tn antigen vaccine in safe, specific, effective, long-term intradermal vaccination against recurrence of advanced breast carcinoma. Treatment is ad infinitum. All 18 breast carcinoma patients treated, pTNM Stages IV (6), III (6), and II (6), survived > 5 yrs postoperatively; 10 survived > 10 to > 18 yrs; of the latter, three patients each are Stages III and IV. Five additional 5 yr survivors have not yet reached 10 yrs. The probability that our survival results are due to chance, with NCI "1991 Standard PDQ Data" as control, for all three stages taken together is: 5-yr survival: p < 1 x 10(-8); 10-yr survival: p < 1 x 10(-5). There were no untoward side effects. The vaccination area presented as a delayed-type hypersensitivity reaction, but at variance with the PPD reaction, with significant inflammation, increase of helper T lymphocytes and decrease of the T suppressor/cytotoxic cell ratio.

The role of fibronectin in tumor implantation at surgical sites.

Fibronectins are a family of glycoproteins with modular functional domains. They mediate cell-cell and cell-matrix interactions which are important in embryogenesis, wound healing, metastasis and other processes. We present data on the influence of fibronectin on wound implantation of a murine mammary carcinoma line, TA3Ha. Fibronectin used in these studies was derived from bovine plasma, human serum, human foreskin fibroblasts, and mouse embryo cultures. TA3Ha cells rarely form tumors in the liver of syngeneic mice when injected intravenously but after hepatic wedge resection, 45% (107/240) of the mice develop tumors in the hepatic wound. Wound implantation is markedly reduced when the cells are pre-exposed to 200 micrograms/ml bovine plasma fibronectin (13%, P = 0.007), human serum fibronectin (0%, P = 0.02), human cellular fibronectin (0%, P = 0.02), or mouse cellular fibronectin (0%, P = 0.04). Lung colonization is also reduced by these fibronectins. These effects are not due to a cytotoxic action of fibronectin, since intraperitoneally injected fibronectin-treated cells form ascites tumor as effectively as do control untreated cells. Local application of a solution containing 0.25 mg/ml mouse cellular fibronectin to the hepatic wound reduces the frequency of tumor implantation from 45% to 5% (1/21, P = 0.001). No tumor implantation inhibition is seen when only suspending medium or albumin in suspending medium is used. The mechanism by which topical application of fibronectin reduces hepatic wound implantation of tumor cells is unclear, but this finding raises an exciting possibility of preventing local recurrence of cancer.

Do cancers invade veins?

It is postulated that all malignant tumors spread in the same way. They invade through the basement membrane, spread through the interstitial compartment for variable distances, enter a lymphatic vessel through natural clefts, and reach the vascular compartment through lymphatic venous anastomoses or terminal lymphatics. The brain would seem to be an ideal site to test these ideas since it contains no lymphatic vessels. Injections of a well-characterized murine mammary tumor into the brains of 123 mice resulted in growth of the tumor in 82 mice (67%). Autopsy revealed only five cases in which there was distant tumor that had invaded beyond the brain.

Inhibition of tumor implantation at sites of trauma by Arg-Gly-Asp containing proteins and peptides.

We report on the inhibition of wound implantation by TA3Ha mammary carcinoma cells by Arg-Gly-Asp containing proteins and peptides using a hepatic wedge resection model. Intravenously injected TA3Ha cells rarely form tumor in the liver of syngeneic mice, but after hepatic wedge resection, 45% (107/240) of the mice develop tumors in the hepatic wound. Hepatic wound implantation is significantly (P = 0.01) inhibited by pretreating the cells with whole mouse plasma, but not with fibrinogen-depleted plasma or serum. Tumor inhibition is also achieved by pretreatment of cells with fibrinogen (P = 0.05-0.0004), fibronectin (P = 0.007) and laminin, but not by albumin. The active domain appears to be the RGDS sequence since the deca- and tetrapeptides containing RGDS inhibit wound implantation (P less than 0.05). However, the tetrapeptide Arg-Gly-Glu-Ser has no such activity. None of these agents affects ascites tumor formation by the intraperitoneally injected cells, suggesting that anchorage independent growth of cells is not affected. We propose that proteins and peptides containing RGD occupy the binding sites and prevent the cells from interacting with cell adhesion proteins in healing wounds. Proteins and/or peptides containing RGD may be useful for preventing local recurrence in postsurgical cancer patients.