Moshe Michowitz

Morgagni Hernia: Unique Presentations in Elderly Patients

We present case reports of 2 patients who were admitted to our ward for complications of Morgagni hernias. Both patients were elderly. Morgagni hernia is a rare condition. Its unique and late presentation are presented and discussed.

Ageing-apoptosis relation in murine spleen

Relatively few studies have been published with regard to modification of apoptosis in normal tissues as a function of ageing. The majority of these studies demonstrated an increase in programmed cell death (PCD) with age. However, opposite results, namely loss of apoptotic control with age, have also been reported. In the present study, we examined proliferation and apoptotic cell death in spleens of C57/BL mice of different ages. A tendency towards decrease in cell proliferative capacity was seen with age. By contrast, apoptosis was increased in spleens from aged animals. Moreover, the proliferative cell/apoptotic cell ratio decreased in function of age. Ladder type DNA degradation was much more pronounced in DNA derived from splenocytes of old mice. These results were supported by a decrease of Bcl-2 and an increase in Fas receptor expression as well as by increased activation of caspases 8, 3 and 9 in splenocytes from aged animals. In addition, cell surface molecular markers recognizable by macrophages in apoptotic cells, namely decreased sialic acid concomitant with increased unmasking of galactose residues, were more pronounced on splenocytes from old mice than on those from young animals. In addition to the experimental evidence which supports a role of apoptotic cell death in ageing, a series of theoretical reasoning, which could also favor this possibility, are discussed.

Spontaneous rupture of the normal stomach after sodium bicarbonate ingestion

Spontaneous rupture of the normal stomach is an unusual and highly lethal event. We present a case of spontaneous rupture of a normal stomach after ingestion of sodium bicarbonate, and review the seven similar cases previously reported.

Primary inflammatory malignant fibrous histiocytoma of the colon

A unique case of inflammatory malignant fibrous histiocytoma of the large bowel is presented. This lesion occurred in the colon of an elderly man suffering from weakness, anemia, anorexia, and weight loss. A right hemicolectomy was performed, and six months later, on follow-up, he was found to be well. The literature on visceral involvement by malignant fibrohistiocytic tumors is reviewed.

Efficacy of anti-angiogenic treatment of tumors in old versus young mice.

Cancer treatment in the older population, the most afflicted by the disease, is as yet, inefficient. A reduced aggressiveness of tumors is often observed in the elderly, implying the necessity for therapeutic modalities adjusted to age. A rational design of age-related cancer therapy could be based on the mechanisms of this phenomenon. It is suggested that, in addition to the patients old age-specific health problems (which prohibit the use of the aggressive cancer treatments now in use), the age-related differential tumor biology (apparently beneficial to the old) should also be considered for the design of treatment modalities suitable for the aged. Based on one mechanism of the reduced aggressiveness of tumors in the old (age-dependent decreased angiogenesis), we compared the effect of an anti-angiogenic treatment in young and old mice. TNP-470 treatment resulted in an inhibitory effect on B16 melanoma in both young and old mice but the effect was more pronounced in old animals. Moreover, a high percentage of long-term surviving animals was observed only in the old-treated mice. Treatment with TNP-470 of the AKR lymphoma produced similar results. We thus found a differential age-dependent therapeutic efficiency of an anti-angiogenic agent on two tumors. Importantly, the anti-angiogenic drug was more efficient against tumors of old animals.

Age-dependent differences in the efficacy of cancer immunotherapy in C57BL and AKR mouse strains

While tumor incidence increases with age, tumor growth and metastasis often proceed at a slower rate in aged organisms. The mechanisms underlying this age-related reduced tumor development may suggest therapeutic modalities appropriate for the aged. Decreased tumor aggressiveness in the old was shown to be related to altered immune response. Consequently, the aim of the present study was to assess whether cancer immunotherapy has an age-dependent effect. Only a few studies have compared cancer immunotherapy efficiency as a function of age, most showing lower inhibition in older animals. In the present study, we tested the effect of two immunomodulators, levamisole and BCG, on two tumors, B16 melanoma and AKR lymphoma, in mice of different ages. We demonstrated a higher efficiency of immunotherapy in aged as compared to young mice, particularly at low immunomodulator doses. While decreased T cell function during aging is apparently established, nonspecific immunity is more preserved or even enhanced in later life. We found an increased number of macrophages in tumors of old compared to young mice and an increase in MAC-1+ cells in old levamisole-treated compared to non-treated mice. The stronger therapeutic effect of this immunomodulator in old mice might thus be due to an increased macrophage-mediated anti-tumoral effect.

Role of immune response as determinant of tumor progression in function of host age in the B16 melanoma

Aging constitutes the major cause for the development of most neoplastic diseases. However, tumors in aged people present with a lower degree of aggressiveness than in young patients. The reasons for this paradoxical behavior are not clear. We attempted to verify whether the immune system has a role in the relation between host age, immune response and tumor progression. We compared the growth rate of B16 melanoma and a highly malignant variant, the B16/Col/R, in young and aged mice that have or have not undergone splenectomy. The following results were obtained: (1) Splenectomy stimulated growth in the parental melanoma in both young and aged mice, indicating a protective role of the spleen against this tumor at all ages; (2) Spleen ablation provoked inhibition of the highly-metastatic variant growth in young mice, suggesting a stimulatory role of the spleen in this case; (3) By contrast, in aged mice inoculated with the B16/Col/R variant, splenectomy enhanced tumor growth, indicating a defensive role of the spleen. Age favors a positive host response against the aggressive clone of the melanoma. Differential host response in young versus aged mice can explain, in this tumor system, the difference in tumor progression rate as a function of age.

Effect of Methylene Blue on Resuscitation After Haemorrhagic Shock

OBJECTIVE To compare prehospital hypotensive resuscitation with volume resuscitation, and find out whether reagents that inhibit free-oxygen radical formation, such as methylene blue, can improve resuscitation and survival. DESIGN Randomised controlled trial. SETTING Animal laboratory, Israel. ANIMALS 48 adult male Wistar rats. INTERVENTIONS After 30 minutes of controlled haemorrhage, rats were subjected to 60 minutes of uncontrolled haemorrhage with simultaneous resuscitation. Hartmanns solution alone, or with blood or with a bolus of methylene blue were infused to maintain the mean arterial pressure (MAP) at 80 or 40 mm Hg. Then haemorrhage was stopped and Hartmanns solution plus whole blood were infused to obtain a MAP that was within normal limits. MAIN OUTCOME MEASURES Volumes of shed blood and resuscitation fluids, MAP, packed cell volume, blood pH and base deficit, and survival. RESULTS During uncontrolled haemorrhage. a MAP of 80 mm Hg could not be reached in animals resuscitated with Hartmanns solution alone, and all died. All the rats given Hartmanns solution with a bolus of methylene blue or with whole blood achieved a higher MAP. MAP of 40 mm Hg was attained in all animals regardless of the resuscitation fluid. Only 15 of 24 animals resuscitated to a MAP of 80 mm Hg survived, compared with 22 survivors of the 24 rats resuscitated to a MAP of 40 mm Hg (p <0.04). Methylene blue or whole blood drastically reduced the volumes of shed blood and of fluids required, and moderated the reduction in packed cell volume, particularly during hypotensive resuscitation. CONCLUSION Hypotensive protocols should be used to improve survival. Methylene blue given with the electrolyte solutions could negate their detrimental effects during resuscitation.

Sensitivity to thermochemotherapy of AKR lymphoma and B16 melanoma variants of malignancy

Drug resistance, which so often accompanies tumor progression, has been shown to be related to changes in membrane properties which may result in decreased drug accumulation in the tumor cell. A correlation between sensitivity to thermochemotherapy and degree of malignancy was found in the AKR lymphoma system. Hyperthermia increased adriamycin (ADR) uptake and concomitantly its cytotoxicity to AKR lymphoma cells. Moreover, these effects were more pronounced on a variant of high malignancy (HM) than on a low malignancy (LM) one. Fluorescent microscopy, as well as cytofluorometry, indicated that lymphoma cells treated by ADR at 43°C were more permeable to the cytotoxic agent than those exposed to the chemotherapeutic substance at 37°C. Cytofluorometry indicated the presence of a minor cell subpopulation with low ADR uptake in the HM variant, not found in the LM one. Fluorocytometry also showed that the temperature-dependent increased ADR uptake was more marked in the HM than in the LM variant, explaining the differential effect of thermochemotherapy on the two lymphoma variants. However, correlation between degree of malignancy and sensitivity to thermochemotherapy is not a general feature. In contrast to the results obtained in the AKR lymphoma system, in the 1316 melanoma the low malignancy variant, F1, was more markedly affected by the combined treatment than the F10 variant. The increased cytotoxic effect of ADR by supranormal temperatures in the Fl variant was shown to be due to an augmented drug uptake. The results suggest that drug resistance in late stages of tumor progression can be overcome by an agent acting on the cell membrane. However, the data also indicate the necessity of assaying cancer treatment modalities, including those designed to circumvent drug resistance, on various tumor system models.

Designing ageing conditions in tumour microenvironment-a new possible modality for cancer treatment.

While tumour incidence is known to augment with age, paradoxically tumour growth and metastasis were often found to proceed at a slower rate at late ages. This age-related biological behaviour of tumours actually imposes a differential therapeutic approach to the old cancer patient. Several mechanisms of the age-related reduced tumour progression have been demonstrated: decreased tumour cell proliferation, increased apoptotic cell death, decreased angiogenesis and anti-tumoural immune response changes. We postulated that it might be possible to design age-adjusted treatment modalities based on the mechanisms responsible for the reduced tumour progression rate in the aged. Based on these mechanisms, we compared the effect of different treatments (apoptosis-inducing agents, Hydrocortisone and Adriamycin, anti-angiogenic agent, TNP-470, and immunomodulators-Levamisole and BCG) on two experimental tumours (B16 melanoma and AKR lymphoma) growing in young and old mice. Most treatments showed, in both tumours, a higher inhibitory effect on tumours growing in old mice than on those developing in young ones, to our knowledge, a feature not described before for anti-tumoural agents. We suggest that designing ageing conditions in tumours of young patients might possibly alleviate neoplastic aggressiveness in these patients as well.