p27kip1 Expression Is Associated With Tumor Response to Preoperative Chemoradiotherapy in Rectal Cancer

BACKGROUND: Our aim was to ascertain whether or not the response to preoperative chemoradiotherapy for rectal cancer is associated with p27kip1 and p53 protein expression. METHODS: Thirty-eight patients (27 male, 11 female) with a mean age of 59 years (age range 33-87) and stage II-III rectal cancer received preoperative chemoradiotherapy (45-50.4 Gy; 5-FU 350 mg/m2/day and leucovorin 10 mg/m2/day). Thirty-one underwent low anterior resection; seven underwent abdominoperineal excision. Endoscopic tumor biopsies, performed before adjuvant therapy, were evaluated for: histologic type, tumor differentiation, mitotic index, and p27kip1 and p53 protein expression which were immunohistochemically determined. p53 expression was graded as: a) absent or present in < or =10% of tumor cells; b) present in 11-25%; c) present in 26-75%; and d) present in >75% of tumor cells. p27kip1 expression was assessed using both light microscopy (percent of stained cells x10 HPF) and cytometry with an image analysis workstation. Tumor response, ascertained with histology, was classified using a scale from 0 (no response) to 6 (complete pathologic response). RESULTS: The mitotic index for the endoscopic biopsies was low in 14 cases, moderate in 17 cases, and high in 7 cases. p53 protein expression was found in 21 (a), 3 (b), 3 (c), and 11 (d) cases. The mean percentage of cells expressing the p27kip1 protein was 34 (range 0-77.14%). A close correlation was found between cytometric and light microscopy findings for p27kip1 (r2 = 0.92, P = .0001). Tumor differentiation was good in 5 cases, poor in 2 cases, and moderate in the remaining 31 cases. While the response to adjuvant therapy was good/complete in 25 (65.78%) cases, it was absent/poor in 13 (34.21%) cases. Univariate analysis associated type of adjuvant therapy (chemoradiotherapy, P = .0428) and p27kip1 protein lower expression (P = .0148) with a poor response to adjuvant treatment. Stepwise linear regression found overexpression of p53 and p27kip1 and young age to be independent variables that were linked to a good response to adjuvant therapy. CONCLUSIONS: Lack of p27kip1 and p53 protein expression in rectal cancer is associated with a poor response to preoperative adjuvant therapy.     

Preoperative versus postoperative dextran 70 for preventing adhesion formation.

Since serosal drying and tissue abrasion play an important role in adhesion formation, we tested the hypothesis that the peritoneal instillation of 32% high-molecular-weight dextran 70 (H) before, rather than after, a surgical procedure results in less postoperative adhesion formation and reformation. Twenty rabbits were subjected to a standardized surgical injury on one ovary, the ipsilateral uterine horn and adjacent parietal peritoneum. Three weeks later the animals underwent a second laparotomy to blindly score the adhesions and subsequently lyse them using microsurgical techniques. The animals were randomly assigned to one of two treatment groups, with H administered either before or at the end of each surgical procedure. Three weeks after the second surgical procedure, the animals were killed to blindly score adhesions. There was no difference in the mean adhesion scores between the two groups after either the first (2.0 versus 2.9, NS) or second surgical procedure (5.5 versus 5.1, NS). Thus, we conclude that preoperative instillation of H does not offer any advantage over postoperative instillation in the prevention of either adhesion formation or reformation.     

40-Hz steady-state responses in newborns and in children

The authors investigated the 40-Hz steady-state responses (SSR) in 32 full-term newborns and in 10 normal children (5-8 years old), using 500-Hz tone bursts. The 40-Hz SSR threshold is located at about 50 and 30 dB nHL in newborns and older children, respectively. The latencies of both P1 and N1 waves decreased significantly with age, while the amplitudes increased. No significant latency and amplitude intersex differences have been observed. Moreover, with age, the 40-Hz SSR became more stable, their test-retest replicability improved, and P1-N1 wave occurrence increased. The authors finally discuss the possible underlying mechanisms of these findings and conclude that the 40-Hz SSR are difficult to obtain and are scarcely reliable in defining the low-frequency threshold in newborns. The stability and reliability of the responses increase with age, and the electrophysiological and behavioral thresholds to low-frequency stimuli tend to overlap.     

Hyperprolactinemia and contraception: a prospective study

The authors measured serum concentrations by single and multiple sampling techniques in 347 women before, during, and after treatment with either hormonal or barrier methods of contraception. The prolactin responses to an intramuscular injection of estrogen also were evaluated in control and selected study patients. The incidence of hyperprolactinemia in oral contraceptive users was higher than control subjects (12 versus 5%). Hyperprolactinemia was best assessed by multiple blood sampling, it is often transient and resolves spontaneously in about 50% of women. The estrogen provocation study suggests that some women who develop hyperprolactinemia while taking oral contraceptives are more sensitive to the effects of exogenous estrogen and may be at greater risk of developing pill-related menstrual aberrations and hyperprolactinemia.     

Recent studies on lonidamine,the lead compound of the antispermatogenic indazol-carboxylic acids

Lonidamine (LND) or [1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid] is an anticancer and an antispermatogenic drug whose mechanism of action is still incompletely understood. LND is effective against a number of tumors, including head, neck and breast cancers, probably because of the inhibition of mitochondrial electron transport and the enzyme hexokinase and to the induction of apoptosis. Instead, the antispermatogenic activity of LND appeared to be related not only to its energolytic activity but also to other effects activities such as the inhibition of specific chloride channels in the epididymis and the disruption of the inter-Sertoli-germ cell junctions, leading to premature release of germ cells. In addition, we recently reported that, in the rat, LND at the dose of 100 mg/Kg b.w. p.o., a fully active but well tolerated dose, caused specific changes of the testicular and epididymal macroglobulins (alpha(2)-macroglobulin, alpha(1) inhibitor-3 and alpha(1)-macroglobulin). Further studies are needed to elucidate the mechanism of action of LND, the lead compound of an interesting class of antispermatogenic drugs based on the core structure of 1-(2,4-dichlorobenzyl)-indazole-3-carboxylic acid.     

An original approach in the diagnosis of early breast cancer: use of the same radiopharmaceutical for both non-palpable lesions and sentinel node localisation

A modern approach to the surgical treatment of early breast carcinoma requires intraoperative localisation of non-palpable lesions and assessment of the lymph node status. Localisation of breast lesions can be achieved by intratumoural injection of a small amount of radiotracer and intraoperative use of a gamma probe (i.e. radioguided occult lesion localisation, or ROLL). Assessment of the lymph node status is possible by means of the sentinel node approach. To date, two different radiopharmaceuticals have been used for localisation of tumour and sentinel node. We now propose the use of a single nanocolloidal tracer (Nanocoll, with a particle size of less than 80 nm) which is labelled with technetium-99m for simultaneous performance of ROLL and sentinel node identification. The aim of this study was to evaluate the feasibility of this approach, which should be easier and more practical than the dual-tracer injection method. We have employed this new technique in 73 patients with non-palpable, cytologically diagnosed breast cancer and non-palpable axillary lymph nodes. In all patients the radiocolloid, in a total volume of 0.3-0.4 cc, was injected under sonographic or stereotactic guidance. Half of the dose was injected intratumourally and half superficially, but very close to the tumour. Because of the slow lymphatic flow in the breast, Nanocoll must be injected some time before surgery in order to enable adequate migration to the axilla. We injected colloid in the afternoon before surgery (16-23 h before the start of the operation, with an average interval of 18 h). An average dose of 130 MBq (range 110-150) was injected in order to have about 10 MBq of radioactivity when surgery commenced. Lymphoscintigraphy was performed after 15-19 h, with an average interval of 17 h. The procedure was always successful in permitting the localisation of occult breast lesions. Lesions were always localised at the first attempt, and were always contained within the surgical margins. Histological examination revealed all 73 resected lesions to be malignant: there were 64 cases of infiltrating carcinoma and nine of intraductal carcinoma. All breast lesions were therefore confirmed to be early breast cancer. We achieved sentinel node localisation in 71 out of 73, either at scintigraphy or with the intraoperative probe; in two patients, radiopharmaceutical migration was absent. Lymphoscintigraphy showed only axillary drainage in 52 cases, only internal mammary chain (IMC) drainage in nine cases, and combined axillary and IMC drainage in eight cases. In two cases, lymphoscintigraphy suggested the sentinel node was located inside the same breast (intramammary lymph node). All the visualised sentinel nodes were biopsied except for four that were localised in the IMC. Histological examination of the nodes showed metastases in 20 cases: in 15 cases there were micrometastases, and in five, macrometastases. In conclusion, this study has demonstrated the feasibility of the proposed procedure. Simultaneous performance of ROLL and sentinel node localisation using a single tracer represents a useful and practicable choice in the management of early breast cancer.