Surgical management of large hepatocellular carcinoma: the first single-center study from western india / Manejo cirúrgico de grandes carcinomas hepatocelulares: primeiro estudo de um único centro da índia ocidental

ABSTRACT Background: Majority of patients with large size HCC (>10 cm) are not offered surgery as per Barcelona Clinic Liver Cancer (BCLC) criteria and hence, their outcomes are not well studied, especially from India, owing to a lower incidence. Aim: To analyze outcomes of surgery for large HCCs. Methods: This retrospective observational study included all patients who underwent surgery for large HCC from January 2007 to December 2017. The entire perioperative and follow up data was collected and analyzed. Results: Nineteen patients were included. Ten were non-cirrhotic; 16 were BCLC grade A; one BCLC grade B; and two were BCLC C. Two cirrhotic and three non-cirrhotic underwent preoperative sequential trans-arterial chemoembolization and portal vein embolization. Right hepatectomy was the most commonly done procedure. The postoperative 30-day mortality rate was 5% (1/19). Wound infection and postoperative ascites was seen in seven patients each. Postoperative liver failure was seen in five. Two cirrhotic and two non-cirrhotic patients had postoperative bile leak. The hospital stay was 11.9±5.4 days (median 12 days). Vascular invasion was present in four cirrhotic and five non-cirrhotic patients. The median follow-up was 32 months. Five patients died in the follow-up period. Seven had recurrence and median recurrence free survival was 18 months. The cumulative recurrence free survival was 88% and 54%, whereas the cumulative overall survival was 94% and 73% at one and three years respectively. Both were better in non-cirrhotic; however, the difference was not statistically significant. The recurrence free survival was better in patients without vascular invasion and the difference was statistically significant (p=0.011). Conclusion: Large HCC is not a contraindication for surgery. Vascular invasion if present, adversely affects survival. Proper case selection can provide the most favorable survival with minimal morbidity.

RESUMO Racional: A maioria dos pacientes com CHC de grande porte (>10 cm) não tem indicação cirúrgica conforme os critérios do Barcelona Clinic Liver Cancer (BCLC) e, portanto, seus resultados não são bem estudados, principalmente na Índia, devido a uma menor incidência. Objetivo: Analisar os resultados da cirurgia para HCCs de grande porte. Métodos: Este estudo observacional retrospectivo incluiu todos os pacientes submetidos à cirurgia para grandes CHC de janeiro de 2007 a dezembro de 2017. Todos os dados perioperatórios e de acompanhamento foram coletados e analisados. Resultados: Dezenove pacientes foram incluídos. Dez não eram cirróticos; 16 eram BCLC grau A; um BCLC grau B; e dois eram BCLC C. Dois cirróticos e três não-cirróticos foram submetidos à quimioembolização transarterial sequencial pré-operatória e embolização da veia porta. Hepatectomia direita foi o procedimento mais comumente realizado. A taxa de mortalidade pós-operatória em 30 dias foi de 5% (1/19). Infecção da ferida e ascite pós-operatória foram observadas em sete pacientes cada. Insuficiência hepática pós-operatória foi observada em cinco. Dois pacientes cirróticos e dois não cirróticos apresentaram vazamento de bile no pós-operatório. O tempo de internação foi de 11,9±5,4 dias (mediana de 12 dias). A invasão vascular estava presente em quatro pacientes cirróticos e cinco não cirróticos. O acompanhamento médio foi de 32 meses. Cinco pacientes morreram no período de acompanhamento. Sete tiveram recorrência e sobrevida mediana livre de recorrência foi de 18 meses. A sobrevida livre de recorrência cumulativa foi de 88% e 54%, enquanto a sobrevida global cumulativa foi de 94% e 73% em um e três anos, respectivamente. Ambos eram melhores em não-cirróticos; no entanto, a diferença não foi estatisticamente significante. A sobrevida livre de recidiva foi melhor nos pacientes sem invasão vascular e a diferença foi estatisticamente significante (p=0,011). Conclusão: CHC grande não é contraindicação para cirurgia. Invasão vascular, se presente, afeta adversamente a sobrevida. Seleção adequada de casos pode fornecer sobrevida mais favorável com morbidade mínima.

Effect of histamine on wound healing.

Using incision, excision and dead space wound models in rats, a study was conducted on the effect of histamine on wound healing. Exogenous histamine given either ip or locally was without any effect. Semicarbazide as (histamine synthesis inhibitor) suppressed healing process (breaking strength of skin incision wound), decreased breaking strength and hydroxyproline content of granulation tissue and delay in period of epithelization. On the other hand compound 48/80 (a promoter of histamine forming capacity) was found to promote wound healing. Exogenous histamine (topical) reversed the anti-healing effect of semicarbazide on incision and excision wounds.

Effects of antihistamines on wound healing.

Role of antihistamines (H1 and H2 blockers) in wound healing by utilizing incision and dead space wound models in albino rats was investigated. H1 blockers (mepyramine and promethazine) were found to decrease breaking strength of 10 day old dermal incision wounds and collagen content (as hydroxyproline) and breaking strength of granulation tissue harvested over tubular implant. On the other hand H2 blockers (Cimetidine and ranitidine) did not alter the above parameters. The findings that H1 blockers suppress healing implicate H1 receptors in alleged prohealing effect of histamine, and suggest clinical evaluation of these agents for suppression of overhealing states like keloid, adhesions and strictures.

A simple method to quantify maturation of wound collagen.

While investigating the effect of NSAIDs and Zn(II) (NSAIDs)2 complexes on healing of dead space wounds we found that both NSAIDs and Zn(II) (NSAIDs)2 reduced collagen content to a comparable extent yet only NSAIDs reduced breaking strength (BS) of wounds. Since collagen content and maturation are the two important determinants of BS it was obvious that only NSAIDs reduced maturation. A simple method to assess the extent of maturation in available collagen is being reported in the present study. While all NSAIDs significantly reduced the maturation of collagen, Zn(II) (NSAIDs)2 complexes per se did not affect the maturation of collagen of 10-day old. Though, chronologically, granulation tissues obtained from both the treated groups were 10-day old, maturation-wise the age of NSAIDs and Zn(II) (NSAIDs)2 treated granulation was 6 and 12 days respectively.

Comparative evaluation of tolmetin & tolmetin-zinc on wound-repair & inflammation.

In view of the reported healing-suppressant activity of some NSAIDs and absence of this adverse effect in their zinc-complexes, tolmetin (Tol), a recently introduced NSAID and its zinc-complex (Tol-Zn) were compared for their wound healing and antiinflammatory profiles in male albino rats. Tolmetin-zinc (Tol-Zn) significantly reversed (P less than 0.01) the suppressant effect of Tol on gain in breaking strength of skin incisions and dead space wounds (breaking strength, g: for control, Tol and Tol-Zn were: 313 +/- 7, 250 +/- 11, 294 +/- 16 in skin wounds; 244 +/- 7, 137 +/- 18, 195 +/- 16 in dead space wounds). Tol-Zn shared the significant (P less than 0.001) suppressant effect of Tol on granuloma formation (granuloma weight, mg: control - 69 +/- 3, Tol - 36 +/- 3.03, Tol-Zn - 37 +/- 2.75) and its collagen content (total hydroxyproline per tissue, microgram: control - 1955 +/- 55, Tol - 1400 +/- 200, Tol-Zn - 1410 +/- 150). Rat paw edema induced by carrageenin was significantly (P less than 0.001) reduced by Tol as well as Tol-Zn. In the chronic model both the agents suppressed significantly (P less than 0.001) granuloma formation by 50 per cent. Zinc sulphate by itself reduced the rat paw edema by 39 per cent (P less than 0.02) and did not affect the other parameters. Zinc-complex appears to be an improved version of tolmetin as an antiinflammatory agent with no adverse effect on the healing process. Tolmetin-zinc promotes gain in breaking strength, not by increasing the collagen content, but by favouring better maturation of available collagen at the wound site.

Biochemical mechanisms and effects of Mimosa pudica (Linn) on experimental urolithiasis in rats.

Urolithiasis, following implantation of Zn discs in urinary bladder (foreign body insertion technique), was examined in albino rats of either sex. Marked variation was observed between sex, regarding the formation of bladder stones. Ethylene glycol (1%) mixed in drinking water for 4 weeks, was unable to augment Zn disc-induced stone deposition. Chemical nature of stones was identified as of magnesium ammonium phosphate type. Neither urinary pH nor infection in the urinary bladder/tract affected chemical nature and quantity of stone formed. There was no significant influence of electrolytes or metabolic products on the uroliths. No correlation could be drawn between the quality and quantity of uroliths formed and the urinary electrolytes concentration. M. Pudica was not effective in either preventing stone deposition or dissolving preformed stones.

Effects of procoagulants on wound healing.

As blood coagulation is a prelude for wound healing, a systemic haemocoagulant (Botropase) and local procoagulants (thrombin and fibrin) were evaluated on physical (wound breaking strength, wound half-closure time and period of epithelization), biochemical (granuloma-hydroxyproline and hexosamine) and histological attributes of healing wounds in albino rats. Botropase prompted all phases of tissue repair. Thrombin delayed wound contraction whereas fibrin had no discernable action. The findings that procoagulants modify healing process has bearing on their surgical use.

Pretreatment with phenobarbitone modifies suppressant effect of cyclosporine on wound healing.

Cyclosporine has been reported to suppress the tensile strength of healing incision wound. Prednisolone, an inducer of hepatic microsomal enzymes, abolished the tensile strength suppressant effect of cyclosporine. Cyclosporine is metabolized by the hepatic cytochrome P-450 enzymes. Induction of microsomal enzymes with phenobarbitone was evaluated for its effect upon the wound healing suppressant effect of cyclosporine. Pretreatment of male rats with phenobarbitone (75 mg/kg/day, ip) for 3 days resulted in alleviating the tensile strength suppressant effect of cyclosporine (5 mg/kg/day, po for 10 days). Phenobarbitone, per se, did not affect the tensile strength. That phenobarbitone prevents cyclosporine induced nephrotoxicity without affecting the humoral immunosuppressant action of cyclosporine has recently been reported. The possibility of modulating microsomal enzymes with phenobarbitone offers another approach in preventing cyclosporine-associated toxicities during immunosuppression.

Estradiol induced vaginal cornification in spayed rats: a model to study hepatic microsomal enzyme induction.

Utilizing vaginal cornification as a response for bioassay, a study was conducted to observe the variation in the median cornification dose (cED50) of estradiol, a hepatic-first-pass candidate, given either ip or sc in spayed rats, with or without enzyme induction by rifampin. Comparisons within and between the groups showed that after enzyme induction cED50 was increased fourfold and cED50 ip/cED50 sc ratio was doubled. The findings clearly demonstrate that this animal model faithfully reflects alterations in hepatic enzyme activity and could serve as an alternate for conventional hexobarbitone sleeping time test to study enzyme induction.

Wound healing profile of Septilin.

Septilin, a proprietary preparation claimed to be useful in inflammatory conditions was tested for anti-inflammatory and wound healing effects in albino rats. It significantly enhanced gain in tensile strength in incision wounds and wound contraction and epithelization in excision wounds. It also suppressed acute inflammation (rat paw edema) significantly without affecting chronic inflammation (cotton pellet granuloma).

Effects of enfenamic acid and its zinc salt on wound-healing.

Dose-matched comparison between zinc-salt of enfenamic acid and the parent compound was carried out in experimentally wounded male albino rats bearing either sutured incision, dead-space or excision wounds. Result showed that enfenamic-acid significantly decreased breaking-strength of incision wounds and this effects was totally reversed by zinc present in enfenamic acid-zinc salt. Both the parent compound and the salt had significant granulation suppressant effect in dead-space wounds. In excision wounds epithelization was enhanced by enfenamic acid only. The wound contraction was not affected by either test compound.

Steroid depressed wound healing and Tridax procumbens.

Dexamethasone 0.33 mg/kg (I.M.) on first day and half this dose thereafter daily, depressed wound contraction, epithelization, tensile strength and process of granulation of wounds in experimental animals. Juice from the leaves of Tridex procumbens (T.P. 1 ml, I.P., daily) resembled dexamethasone in effects on wound contraction and granulation; but it significantly (P less than 0.001) counteracted the effects of dexamethasone on tensile strength and epithelization. TP caused increase in adrenal weight and decrease in thymus weight. These observations suggest that TP exerts a direct pro-healing effect along with an indirect anti-healing influences probably mediated through release of adrenal steroids.