Treatment Following Progression in Metastatic Melanoma: the State of the Art from Scientific Literature to Clinical Need.

INTRODUCTION: In the last few years, the advent of targeted therapy and immunotherapy has improved the management and the prognosis of metastatic melanoma, but the spread of resistance mechanisms can lead to disease progression. The clinical management in this setting can be challenging because the oncologist has to decide what is the best treatment strategy among therapy beyond progression (TBP), therapy change, and the rechallenge approach. This review of the relevant scientific literature is intended to clarify which patients with progressing metastatic melanoma will benefit from continuation of ongoing therapy and which ones will not. The data are based on a total of about 4300 patients coming from the main retrospective studies in the chosen field. The article body is divided into four sections which analyze respectively the targeted therapy beyond progression, the immunotherapy beyond progression, the possible treatment sequences, and finally the rechallenge strategy. RECENT FINDINGS: Despite the possible approaches of TBP or rechallenge, the patient may not have an optimal response and may need new therapy, which is currently missing. To broaden the pharmacological offer in the fight against melanoma, cancer research is studying new disease targets, like the NRAS, PI3K, and cKIT pathways or combination treatment of targeted therapy plus immunotherapy. Despite the limitations of this work, mainly due to the limited number of studies, their retrospective nature and the lack of comparative studies, the analysis performed allows us to draw some important conclusions: therapy beyond progression, both targeted therapy and immunotherapy, represents a valid treatment option with positive effects on disease control and survival outcomes for patients with low clinical risk, expressed as low disease burden, normal LDH levels, and good performance status; moreover, the prognosis and quality of life of these patients improve when TBP is associated with locoregional treatments. In patients with progressive metastatic melanoma and high clinical risk (high disease burden, high LDH levels, and poor performance status), it is recommended to change therapy, without ever forgetting the possibility of enrolling the patient in a clinical trial. Finally, an efficacious treatment alternative is the rechallenge strategy; this approach consists in a re-treatment with the same drug after a variable interval of discontinuation. Preliminary studies seem to have demonstrated that patients retreated with targeted therapy achieved a greater benefit if they had a low clinical risk and if the drug doublet (BRAF + MEK inhibitors) was used. On the side of immunotherapy, the rechallenge strategy produced a major benefit in patients who prior experienced a severe toxic episode.

Sigma adenocarcinoma and a scalp lipoma: skin metastases from colorectal cancer.

Skin metastases from colorectal cancer are a rare phenomenon that occurs only in 4,4% of cases. The presence of a cutaneous lesion at the Romatime of diagnosis is even more uncommon (0,05% of cases), and represents a sign of widespread, poor prognosis and terminal disease. Skin involvement by colorectal cancer can occur in four different pathways: lymphatic, hematogenous, direct invasion of contiguous tissues or iatrogenic implantation. We describe a case of a 68-year-old patient affected by a pT4b pN1 M1 sigma carcinoma with a head lesion that, at the time of diagnosis, mimics a lipoma at the head CT scan.

The "Pavia model" of experimental small bowel transplantation in pigs: technical variations for ischemia reperfusion injury studies.

Ischemia reperfusion injury (IRI) is a major field of study in small bowel transplantation because of its implications regarding intestinal immunity. In this study, we have introduced some variations to the described models of IRI in pigs to make possible a complete isolation of the small bowel for IRI studies. In swine, two anatomical barriers make impossible a complete isolation of the small bowel at the origin of superior mesenteric artery (SMA) and vein (SMV): the main colic vessels, which originate distally to form SMA and SMV, and the blood supply of the distal portion of the duodenum and the cephalic part of the pancreas. In a group of Large White pigs (n = 5), we have performed a complete isolation of the small bowel, including sub-total colectomy and pancreaticoduodenectomy. Both SMA and SMV were isolated at the origin from the aorta and at the junction of the splenic vein, respectively. Intestinal continuity was restored with duodenojejunal anastomosis and with ileotransverse colon anastomosis. One pig died on postoperative day 5 from intestinal occlusion due to adhesions. The remaining four pigs were killed on postoperative day 7 after an uneventful postoperative course. No complications were found at autopsy. In swine, resection of part of the pancreas and duodenum and removal of the large bowel does not affect short-term survival, allowing a full isolation of the entire small bowel mimicking the transplantation procedure. Thus, this model appears to be attractive for IRI studies in the field of intestinal transplantation.

Technical aspects of living-related liver donation: single-center experience.

Living-related donor liver transplantation is the newest and both technically and ethically most challenging evolution in liver transplantation and has contributed to reduction in donor shortage. We briefly report the technical aspects of surgical procedures performed to achieve a partial graft from a live donor. Eighty-four adult and two pediatric recipients underwent living-related donor liver transplantation at our center. There were no donor deaths, and all patients returned to their normal activities after the perioperative period. This single-center experience may contribute to refinement of the surgical technique required to improve the outcome of these complex operations.

Experimental small bowel transplantation from non-heart-beating donors: a large-animal study.

INTRODUCTION: The shortage of organs in the last 20 years is stimulating the development of new strategies to expand the pool of donors. The harvesting of a graft from non-heart-beating donors (NHBDs) has been successfully proposed for kidney and liver transplantation. To our knowledge, no studies are available for small bowel transplantation using NHBDs. In an experimental setting of small bowel transplantation, we studied the feasibility of using intestinal grafts retrieved from NHBDs. MATERIALS AND METHODS: Twenty five Large White piglets underwent total orthotopic small bowel transplantation and were randomly divided as follow: NHBD group (n = 15) received grafts from NHBDs; heart-beating donor (HBD) group (n = 10) received grafts from HBDs. The NHBD pigs were sacrificed inducing the cardiac arrest by a lethal potassium injection. After 20 minutes (no touch period = warm ischemia), they underwent cardiac massage, laparotomy, and aorta cannulation for flushing and cooling the abdominal organs. In HBDs, the cardiac arrest was induced at the time of organ cold perfusion. In both groups, immunosuppression was based on tacrolimus oral monotherapy. The animals were observed for 30 days. The graft absorptive function was studied at day 30 using the D-xylose absorption test. Histological investigation included HE (Hematoxilin and Eosin) microscopical analysis and immunohistological staining. RESULTS: Animals in the NHBD group died due to infection (n = 3), acute cellular rejection (n = 2), technical complications (n = 2), and intestinal failure (n = 8). In the HBD group, all animals but two were alive at the end of the study. The D-xylose absorption was significantly lower among the NHBD compared with the HBD group (P < .05). CONCLUSIONS: This study confirmed that intestinal mucosa is sensitive to ischemic injury. When the intestinal graft is harvested from NHBDs, the infectious-related mortality was higher and the absorptive function lower. Histological examination confirmed a higher grade of ischemic injury in the NHBD grafts that correlated with the clinical data. Therefore, this experimental study suggested that non-heart-beating donation may not be indicated for small bowel transplantation.

Prolonged survival with FK778 (malononitrilamide) monotherapy after small bowel transplantation: a large animal study.

Malononitrilamide 715 (FK778) is a new class of immunosuppressant, derived from the active metabolite of leflunomide A77 1726. We investigated the efficacy of two different immunosuppressive induction protocols with tacrolimus plus FK778 followed by FK778 monotherapy. In a swine model of small bowel transplantation, we observed three groups, divided by different therapy regimens: group 1 (n = 5): no immunosuppressant (control group); group 2 (n = 10): oral tacrolimus (from postoperative day [POD] 0 to 30) and FK778 (from POD 0 to 60); group 3 (n = 8): oral tacrolimus, as group 2, and FK778 (from POD 7 to POD 60). Median survival was 11, 60, and 21 days in groups 1, 2, and 3, respectively. In group 1 all animals died of acute rejection; in group 2 the causes of death were technical complication (n = 1) and sepsis (n = 1); in group 3, one animal died from obstruction, two from pneumonia, one from peritonitis, one from sepsis. Group 2 accounted for 0.5 infection episode/animal versus 0.62 in group 3 (P < .05). Acute rejection was absent or mild in 66% and 75% of group 3 and 2 biopsies, respectively (P < .05). The D-xylose absorption curves from groups 2 and 3 were similar to those of the nontransplanted healthy animals. In conclusion, FK778 monotherapy after a consistent induction period with tacrolimus combined immunosuppression is able to extend survival and preserve optimal absorptive capacity of the small bowel allograft in our pig model. The association of tacrolimus and FK778 from day 1, compared to the delayed administration of FK778 from day 7, results in a significant reduction of infections and postoperative complications.

Elemental enteral nutrition preserves the mucosal barrier and improves the trophism of the villi after small bowel transplantation in piglets.

The main goals for a successful small bowel transplantation (SBTx) are the control of acute rejection and maintenance of the mucosal barrier, which plays a key role in preventing bacterial translocation and preserving absorptive capacity. According to recent evidence that sustaining enteral nutrition (EN) as rehabilitative therapy improves the integrity of the mucosal barrier after SBTx, we studied the trophic effect of a new elemental enteral solution whose proteinic supply is represented by oligomeric-aminoacidic chains. In a swine SBTx model we studied three groups, divided by the different postoperative feeding: group 1 (n = 5): standard swine chow, group 2 (n = 5): polymeric enteral solution, group 3 (n = 5): elemental enteral solution (Peptamen, Nestlè Corp). All animals were immunosuppressed with a tacrolimus/FK778 combined oral therapy. The nutritional indices evaluated were: body weight, episodes of diarrhea, D-xylose absorption test, and histopatological and villi morphometric analysis. Three pigs died before the end of the study, two in group 1 (pneumonia and sepsis), one in group 2 (pneumonia). Mean days of diarrhea were 15, 10, and 3 in groups 1, 2, and 3, respectively (P < .05). The final/starting weight ratio was 1.08 for group 3 and 0.92 for group 2 (P < .05); the D-xylose curves showed a statistically significant difference for group 3 versus the groups 2 and 1 (P < .05), as well as for the villi height (P < .01) and width (P < .05). In conclusion, elemental enteral solution, with its basic protein supply, does not require a very complex enzymatic system to be metabolized. Thus, it may contribute to a faster recovery of the mucosal barrier and to limit the hypercatabolic state.

FK778 does not impair intestinal allograft absorption in a preclinical model of total small bowel transplantation.

Malononitrilamide 715 (FK778), a new low-molecular weight immunosuppressant, inhibits both T-cell and B-cell function by acting on the pathway for de novo pyrimidine biosynthesis. Pyrimidines are important for intestinal trophism; their inhibition may predispose to metabolic and functional impairments, such as diarrhea and malabsorption. In this study we assessed the absorptive capacity of intestinal allografts in a large-animal model of small bowel transplantation (SBTx) in pigs chronically treated with FK778. Ten outbred pigs underwent total orthotopic SBTx. Immunosuppression consisted of oral tacrolimus (trough levels 5-15 ng/mL) and oral FK778 (4 mg/kg per day) administered for 60 days. The D-xylose absorption test was performed at day 60 to evaluate carbohydrate absorption. Results were compared to normal controls. Eight of the 10 animals were alive and in good condition at day 60. All of their allografts were free of rejection. The animals had a mean maximal weight loss of 6.4% during the study period; the final weight was comparable to the initial weight (P > .05). Diarrhea was present in all animals (mean 16% of postoperative days). The D-xylose curves showed that absorption in the transplanted animals at day 60 was similar to that in the untreated controls (P > .05). The absence of differences was confirmed by the statistical analysis. In conclusion, our preclinical study in pigs showed that chronic treatment with FK778 in combination with tacrolimus did not impair carbohydrate absorption by the allograft after SBTx.

FK778 and tacrolimus combination therapy to control acute rejection after pig intestinal transplantation.

Malononitrilamide 715 (FK778) is a new class of low molecular weight immunosuppressant. Experimental studies in heart, liver, and kidney transplantation have shown a strong synergism when FK778 is used in combination with tacrolimus and when its administration is delayed by 7 days after the transplant. Following this indication, in a swine model of orthotopic small bowel transplantation (SBT), we assessed the efficacy of combined low dose tacrolimus and FK778 administered from day 0 or day 7. The entire small bowel was replaced in 16 piglets: group 1 (n = 5), no immunosuppression; group 2 (n = 6) oral tacrolimus to maintain whole blood trough levels between 5 and 15 ng/mL plus FK778 4 mg/kg per day; group 3 (n = 6) oral tacrolimus as in group 2 plus FK778 4 mg/kg per day administered after a 7-day delay posttransplant. The median survival was 8 days in group 1, 60 days in group 2, and 13 days in group 3. The differences between group 2 and 1 and between group 2 and 3 are statistically significant. Three episodes of major bacterial infection were detected in both group 2 and 3 (0.5 episode/animal). The infectious-related mortality was 0% in group 2 and 50% in group 3 (P < .05). Acute cellular rejection was absent or mild in all group 2 and 3 stomal biopsies. In conclusion, combining tacrolimus and FK778 allowed prolonged survival after SBT in swine when FK778 was started at the time of SBT. The delayed administration of FK778 resulted in a high incidence of lethal infectious complications.

Early outcome of different steroid-free regimens in small bowel transplantation: a large-animal study.

The intestine is a highly immunogenic organ that requires heavy immunosuppression (IS); therefore corticosteroid withdrawal after clinical small bowel transplantation (SBT) has not been standardized. In this study, we compared different immunosuppressive regimens (none with steroid or induction treatment) in a SBT pig model. Large White unrelated piglets were transplanted and divided into four groups as follow: group 1 (n = 3): no IS; group 2 (n = 10): IS with tacrolimus only; group 3 (n = 10): IS with tacrolimus and mycophenolate mofetil; group 4 (n = 5): IS with tacrolimus and rapamycin. Follow-up time was 30 days. All IS drugs were given orally; tacrolimus whole blood levels ranged between 5 and 15 ng/mL in all groups except for group 2 whose tacrolimus whole blood levels ranged between 15 and 25 ng/mL. Group 1 pigs died of graft acute rejection (ACR) after a median of 12 days. Overall survival in groups 2, 3, and 4 at day 30 was 40%, 80%, and 60%, respectively. Biochemical parameters, including glycemia and cholesterol, were into the normal range with no significant differences between groups. At the end of the study, one animal in group 2 and another one in group 4 showed histological signs of moderate to severe ACR. The incidence of infection was higher in group 2 (2.1 episodes/pig) compared to group 3 (1.25) and group 4 (1.6). This large-animal study demonstrates that tacrolimus-based IS without corticosteroids allows, in the early postoperative period (30 days) after SBT, good survival rates without an increased risk in the incidence of rejection.

Incidence of graft rejection in small bowel transplanted pigs after immunosuppression withdrawal.

As intestinal grafts require heavy immunosuppression, there are no reports of immunosuppression withdrawal after clinical small bowel transplantation. In this large-animal study, we investigated the occurrence of graft rejection in intestinal-transplanted pigs after withdrawal. Large-White unrelated piglets were transplanted and divided in three groups: group 1 (n = 5), intestinal transplantation (ITx) with no immunosuppression; group 2 (n = 7), Itx and 60 days of treatment with tacrolimus and mycophenolate mofetil; group 3 (n = 5), Itx and donor bone marrow infusion (DBMi) and 60 days of treatment with tacrolimus and mycophenolate mofetil. Follow-up time after withdrawal was 120 days. Group 1 pigs died of graft acute cellular rejection (ACR) after a median of 11 days. In group 2, two pigs died of ACR-related infection and another two of ACR within 90 days. The remaining three animals (43%) were sacrificed at day 180, and their grafts showed no signs of ACR. In group 3, two pigs died of ACR-related infection and one of graft versus host disease within 80 days; at day 180 the two surviving animals showed signs of chronic rejection in the allograft. This study demonstrates that total withdrawal after ITx is followed by sudden and lethal ACR (or ACR-related infection) in more than 50% of the recipients. When a tolerance-inducing strategy as DBMi is applied, lethal graft versus host disease may also occur. In group 3, the intestinal allograft, to which the recipients were partially tolerant, developed chronic rejection that was probably associated with a decline with time of donor-leukocytes chimerism, as recently demonstrated in rats.

Efficacy of malononitrilamide FK778 in a preclinical model of small bowel transplantation.

In a swine model of orthotopic small bowel transplantation, we assessed the efficacy of combined immunosuppressive therapy with low-dose tacrolimus plus FK778, compared with high-dose tacrolimus monotherapy. The small bowel was replaced in 23 piglets: group 1 (n = 5), no immunosuppression; group 2 (n = 12), oral tacrolimus to maintain whole blood trough levels between 15 and 25 ng/mL; and group 3 (n = 6), oral FK778 4 mg/kg/d, plus oral tacrolimus to maintain whole blood trough levels between 5 and 15 ng/mL. Follow-up time was limited to 60 days. Overall survival rates at 30 and 60 days were 0% and 0% in group 1, 30% and 0% in group 2, and 66% and 66% in group 3, respectively. The median survival time was 11 days in group 1, 28 days in group 2, and more than 60 days in group 3. The differences between groups 3 and 1 and between groups 3 and 2 were statistically significant. The numbers of major bacterial infections were 19 in group 2 (1.9 episodes per animal) and 3 in group 3 (0.75 episodes per animal). The infectious-related mortality rate was 70% in group 2 (7 cases) and 0% in group 3 (P < .05). Acute cellular rejection was absent or mild in 85% of group 2 stomal biopsy specimens and in 100% of group 3 biopsy specimens. In conclusion, combination therapy of low-dose tacrolimus is potentiated by FK778 to prevent acute cellular rejection and prolong small bowel transplant survival in pigs.

[Experimental kidney transplantation: a comparison between different models]. / Trapianto di rene sperimentale nel suino. Modelli a confronto.

AIM: Two different models of kidney transplantation have been compared using 3 different techniques. The kidney grafts were procured from living donors (laparoscopic or laparotomic technique) and from cadaveric donors. METHODS: Twenty-four outbred piglets (Large White, weight range 24-27 kg) underwent kidney transplantation. We divided the recipients into 2 groups with the following characteristics: group 1 (n=12) was represented by orthopic kidney recipients whose grafts were retrieved by laparoscopic or lapartomic technique from living unrelated donors; group 2 (n=12) was constituted by heterotopic kidney recipients whose grafts were retrieved by laparotomic technique from unrelated cadaveric donors. In both groups, Grogoire-Lich technique and Politano-Laedbetter technique were used in order to perform ureteral-vescical anastomosis together with a new technique developed from our experience called Politano-Laedbetter modified. All transplanted pigs underwent double immunosoppressive steroid therapy (tacrolimus and micofenolate mofetil). The pigs were observed for 60 days. RESULTS: The survival rates in group 1 and in group 2 were 75% (n=9) and 66% (n=8), respectively. No significative differences were noted in length of operative time, creatinemia and ureamia levels in both study groups. The Gregoire-Lich technique was associated with a higher rate of complications. CONCLUSION: Two different experimental models of kidney transplantation are feasible in pigs. The classic technique could be combined with the orthopic one based on the type of study needed.