The Landmark Series: Surgical Treatment of Colorectal Cancer Peritoneal Metastases

Background

Peritoneal metastases (PM) are a form of metastatic spread affecting approximately 5-15% of colon cancer patients. The attitude towards management of peritoneal metastases has evolved from therapeutic nihilism towards a more comprehensive and multidisciplinary approach, in large part due to the development of cytoreductive surgery (CRS), usually coupled with heated intraperitoneal chemotherapy (HIPEC), along with the constant improvement of systemic chemotherapy of colorectal cancer. Several landmark studies, including 5 randomized controlled trials have marked the development and refinement of surgical approaches to treating colorectal cancer peritoneal metastases.

Methods

This review article focuses on these landmark studies and their influence in 4 key areas: the evidence supporting surgical resection of peritoneal metastases, the identification and standardization of important prognostic variables influencing patient selection, the role of surgery and intraperitoneal chemotherapy in prevention of colorectal PM and the role of intraperitoneal chemotherapy as an adjuvant to surgical resection.

Results

These landmark studies indicate that surgical resection of colorectal PM should be considered as a therapeutic option in appropriately selected patients and when adequate surgical expertise is available. Standardized prognostic variables including the Peritoneal Cancer Index and the Completeness of Cytoreduction Score should be used for evaluating both indications and outcomes.

Conclusions

Current evidence does not support the use of second look surgery with oxaliplatin HIPEC or prophylactic oxaliplatin HIPEC in patients with high risk colon cancer nor the use of oxaliplatin HIPEC with CRS of colorectal PM.

     

Born this Way–or Not? The Relationship Between Essentialism and Sexual Minorities’ LGBTQ+ Identification and Belonging

Archives of Sexual Behavior - Bisexual people experience lower levels of belonging in the LGBTQ+ community than gay and lesbian people. We investigated one of the factors that may reduce bisexual...     

Familial hyperextensible proximal interphalangeal joints

Summary Hyperextensibility of the proximal interphalangeal joints was noted in 3 males and 6 females in 3 generations of a Japanese family. The proposita, a 14-year-old girl, had hyperextensible proximal interphalangeal joints of the 2nd, 3rd, 4th, and 5th fingers giving swan-neck appearance during the extension. She was asymptomatic and had no other features of skin involvement. Her father, younger sister, grandmother, two aunts, and three cousins on the father's side had hyperextensible proximal interphalangeal joints. No instance of male to male transmission was present. The condition was thus inherited as an autosomal or X-linked dominant trait.     

Genetic markers in primary open-angle glaucoma

Purpose: To investigate possible associations between genetic markers and Primary Open-Angle Glaucoma (POAG). Methods: A number of genetic markers were typed in 84 unrelated patients with POAG and compared with a random sample of healthy individuals. The markers were Transferrin, Group Specific Component, G1m (1), G1m (2) and G3m (5) Allotypes, Adenylate Kinase, Adenosin Deaminase, Glyoxalase I and Acid Phosphatase and PCR-based markers HLA-DQA1 and D1S80. Results: No significant differences were found except the strong association between the group of POAG patients and Acid Phosphatase ACP^*C allele (² = 32.86; p < 0.0001). Conclusions: Since Acid Phosphatase gene is localized to chromosome 2p23, this result could be a first comprehensive step in the localization of POAG genes.     

Inward transport of 3H-MPP+ in freshly isolated rat hepatocytes: evidence for interaction with catecholamines

1-Methyl-4-phenylpyridinium (MPP⁺), the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is efficiently taken up and accumulated by rat hepatocytes. However, the nature of the mechanism(s) involved in the hepatic uptake of MPP⁺ remains partially unknown. The aim of the present study was to further characterize the hepatic uptake of ³H-MPP⁺, namely by investigating the interactions of catecholamines (which are also efficiently taken up by rat hepatocytes) with MPP¹ transport.The accumulation of ³H-MPP⁺ in isolated rat hepatocytes occurred through saturable and non-saturable mechanisms. The kinetics of the saturable component of ³H-MPP⁺ uptake was as follows: V_max = 181.3 ± 11.1 pmol mg protein^–1 min^–1 and K_m = 47.1 M (27.9, 66.3) (n = 5). The diffusion constant (in ml mg protein^–1 min^–1) for the non-saturable uptake of ³H-MPP⁺ was 0.00068 (0.00052, 0.00083) (n = 5). From the analysis of the time course of ³H-MPP⁺ accumulation at a substrate concentration of 100 nM ³H-MPP⁺, it was found that the rate constant of inward transport of ³H-MPP⁺ into hepatocytes (k_in) was 15.7 ± 3.8 l mg protein^–1 min^–1, the rate constant of outward transport of ³H-MPP⁺ from hepatocytes (k_out) was 0.077 ± 0.023 min^–1 and the equilibrium accumulation (A_max) of ³H-MPP⁺ was 20.2 ± 2.0 pmol mg protein^–1 (n = 36). Decynium22 (1,1-diethyl-2,2-cyanide; 1 M) significantly reduced k_in to 6.1 ± 1.8 l mg protein^–1 min^–1 (P < 0.05) and the equilibrium accumulation (A_max) of ³H-MPP⁺ to 9.6 ± 1.3 pmol mg protein^–1 (P < 0.005) (n = 36). ³H-MPP⁺ accumulation (in cells incubated with 200 nM ³H-MPP⁺) was sensitive to (–)-adrenaline, (–)-isoprenaline, (–)-dopamine, (±)-adrenaline and (–)-noradrenaline. The most potent catecholamine in inhibiting ³H-MPP⁺ uptake was (–)-adrenaline, with an IC₅₀ of 99 (22, 449) M (n = 6). (–)-Adrenaline competitively inhibited ³H-MPP⁺ uptake, as it significantly increased the K_m value of ³H-MPP⁺ uptake (to 125.4 M (63.6; 187.1); P < 0.02; n = 3) but did not change the V_max value. The cyanide-derivatives decynium22 and cyanine863 (1-ethyl-2-([1,4-dimethyl-2-phenyl-6-pyrimidinylidene]methyl)quinolinium), which inhibit uptake₂ as well as the apical type of the renal transporter for organic cations, potently inhibited ³H-MPP⁺ uptake with IC₅₀'s of 1.4 (0.4–5.3) (n = 6) and 6.5 (2.6–16) (n = 4) M, respectively. Under conditions of monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT) inhibition with either pargyline (500 M + Ro01-2812) (3,5-dinitropyrocatechol; 2 M) or pargyline (500 M) + U-0521(3,4-dihidroxy-2-methyl-propiophenone; l2 M)), (–)-adrenaline (up to 1 mM) had no inhibitory effect on the uptake of ³H-MPP⁺. Moreover, the uptake of ³H-MPP⁺ in the presence of pargyline + Ro 01-2812 was significantly lower (66.9 ± 30.4%; P < 0.05; n = 4) than in the absence of these compounds. Therefore, the effect of these MAO and COMT inhibitors on ³H-MPP⁺ uptake was examined. Interestingly enough, pargyline, Ro 01-2812 and U-0521 were found to inhibit the uptake of ³H-MPP⁺ (in cells incubated with 200 nM ³H-MPP⁺): 500 M pargyline, 2 M Ro 012812 and 100 M U-0521 decreased the accumulation of ³H-MPP⁺ to 38.1 ± 6.8 (n = 5), 60.5 ± 10.1(n = 7) and 71.3 ± 14.5 (n = 7) % of control, respectively.It is concluded that ³H-MPP⁺ is efficiently taken up by rat hepatocytes by a carrier-mediated mechanism sensitive to catecholamines, decynium22 and cy anine863, and to the enzyme inhibitors pargyline, Ro 01-2812 and U-0521.     

Influence of acid-base alterations on myocardial sensitivity to catecholamines

Summary The influence of respiratory and metabolic acid-base alterations on the myocardial sensitivity to catecholamines was studied in the isolated rat atria. The ability of noradrenaline for increasing the atrial rate was enhanced during alkalosis and conversely, it was decreased by acidosis. These changes in sensitivity shifted the concentration-effect curve for noradrenaline to the right by about 0.5 log unit when the pH was lowered from 7.60 to 7.00. No changes in the maximum attainable response were detected. Essentially the same shifts of the concentration-effect curves were obtained with changes in pH brought about by altering the pCO₂ or at constant pCO₂. The decrease in the pH produced a similar shift to the right of the concentration-effect curve for isoprenaline, after the extraneuronal uptake inhibition by hydrocortisone and also in atria tissue with low content of endogenous noradrenaline (reserpine-pretreated and newborn rats). The ability of isoprenaline for increasing cyclic AMP levels in atrial tissue was also enhanced by alkalosis and decreased by acidosis. However, the shift to the right of the concentration-effect curve for cyclic AMP induced by the decrease in the pH was greater than the shift detected in the chronotropic-effect curve. In addition a decrease in the maximum increment of cyclic AMP was detected under acidosis, in spite of equal maximal chronotropic response.Our results support the hypothesis that the alterations in the sensitivity to catecholamines induced by the changes in pH are not due to a release of endogenous noradrenaline nor to alterations of the mechanisms which remove catecholamines from the biophase. The fact that cyclic AMP response to catecholamines was also reduced by acidosis strongly suggests that the mechanism(s) involved is located in the earlier steps of the events leading to the chronotropic effect of the -agonists.     

Alcohol and Sober Mood State in Female Social Drinkers

The goals of the present study were to measure the relationship between alcohol consumption in 93 female social drinkers and their cognitive functioning and mood in the sober state, and to investigate the possible causal effects of alcohol consumption on these variables. In the first test session, a limited relationship was seen between previous alcohol consumption and sober cognitive performance. A strong relationship was found between alcohol consumption and self-reported depression and anger in the sober state. Either a prolonged reduction in alcohol consumption or a prolonged maintenance of alcohol consumption was undertaken by random subsets of the original sample. In the second test session 6 weeks later, women who had been randomly selected to reduce their alcohol intake showed decreases in depression, anger, and mental confusion when they were sober, relative to women who maintained or increased their alcohol consumption over the same period of time. We found no changes in cognitive performance in these groups. We concluded that the simplest explanation of the findings is that relatively low levels of alcohol consumption produce substantial increases in depression and anger in the sober state in female social drinkers. The value of considering alcohol consumption as a continuous variable rather than a dichotomous variable with "safe" and "unsafe" zones was discussed.