[Two cases of thymic carcinoid treated with octreotide long-acting repeatable].

Thymic carcinoid is a rare disease that accounts for 3.1% of thymic tumors and 1.8-6% of all carcinoid tumors in Japan. Advanced thymic carcinoid has a 5-year survival rate of 28-31%.Compared with carcinoid tumors that arise in other organs, thyroid carcinoid tumors carry a relatively worse prognosis, and the most effective therapeutic strategy is thought to be surgical resection.However, for patients with recurrence and distant metastases, multimodal therapy including radiotherapy and/or chemotherapy is usually applied.No chemotherapy treatment regimen has been established in Japan, although the National Comprehensive Cancer Network Guidelines proposed the application of octreotide long-acting repeatable(LAR).In this report, we present two cases of thymic carcinoid that were treated with octreotide LAR and achieved long-term survival.

Combined adenocarcinoma-carcinoid tumor of transverse colon.

A 65-year-old male presented with painless hematochezia associated with episodic cramps in upper abdomen, watery diarrhea, and a slowly growing mass in upper abdomen. Examination revealed a firm 6 x 5 cm, intra-abdominal, epigastric mass. Colonoscopy up to 90 cm showed a stenosing, ulcero-proliferative lesion in the transverse colon. No synchronous lesion was detected. Biopsy revealed mucin secreting adenocarcinoma. Exploration showed the growth involving the transverse colon proximal to the splenic flexure with a part of ileum, approximately three feet proximal to ileo-caecal junction, adherent to it. No significant mesenteric lymph node enlargement was evident. The patient underwent resection of the growth along with the segment of adherent ileum. Continuity was re-established by a colo-colic and ileo-ileal anastomosis respectively. Patient received adjuvant chemotherapy. Post-operative histopathology demonstrated a composite histological pattern with an admixture of carcinoid tumor and adenocarcinoma, invasion of ileal serosa and adenocarcinomatous deposits in mesocolic lymph nodes, the tumor staging being (T4, N0, M0/Stage II) for carcinoid and (T4, N1, M0/Stage III) for adenocarcinoma. Patient was followed-up for a year and was doing well without any evidence of recurrence.

In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines.

INTRODUCTION: Chemotherapy for advanced well-differentiated carcinoids is characterised by low response rates and short duration of responses. The present study aimed to assess the in vitro activity of novel platinum-based chemotherapeutic drugs in combination with dichloroacetate (DCA), a sensitiser to apoptosis, against lung carcinoid cell lines. METHODS: Three permanent cell lines (UMC-11, H727 and H835) were exposed to 14 different established cytotoxic drugs and the novel platinum-based compounds as satraplatin, JM118 and picoplatin in combination with DCA, and viability of the cells was measured using a tetrazoliumbased dye assay. RESULTS: With exception of the highly chemoresistant UMC- 11 line, the carcinoid cell lines (H727, H835) were sensitive to the majority of chemotherapeutics in vitro. Among the platinum-based drugs, carboplatin and oxaliplatin showed highest efficacy. H835 cells growing as multicellular spheroids were 2.7-8.7-fold more resistant to picoplatin, satraplatin and its metabolite compared to single cell suspensions. DCA (10 mM) inhibited the growth of UMC- 11 cells by 22% and sensitised these highly resistant cells to carboplatin, satraplatin and JM118 1.4-2.4-fold. CONCLUSION: The highly resistant UMC-11 lung carcinoid cells are sensitive to carboplatin, oxaliplatin and the satraplatin metabolite JM118, but multicellular spheroidal growth, as observed in the H835 cell line and pulmonary tumourlets, seems to increase chemoresistance markedly. The activity of carboplatin and JM118 is significantly and specifically increased in combination with the apoptosis sensitiser DCA that promotes mitochondrial respiration over aerobic glycolysis. In summary, among the novel platinum drugs satraplatin has the potential for treatment of lung carcinoids and DCA potentiates the cytotoxicity of selected platinum drugs.

Anticancer activity of novel plant extracts from Trailliaedoxa gracilis (W. W. Smith & Forrest) in human carcinoid KRJ-I Cells.

BACKGROUND: Small intestinal (SI) neuroendocrine tumors (NETs) are rare neoplasms derived from neuroendocrine cells presenting distinct clinical symptoms according to the ability to secrete neuroamines. Nevertheless, many are asymptomatic and misdiagnosed. As response rates to chemotherapy are low, surgery remains the only effective treatment. Because many tumors have metastasized at the time of diagnosis, curative surgery is rarely achieved. Consequently, a substantial need for new therapeutic options has emerged. MATERIALS AND METHODS: The effects of novel plant extracts from Trailliaedoxa gracilis (W.W. Smith & Forrest) were investigated in the SI-NET cell line KRJ-I and in KRJ-I transplanted mice. Proliferation and viability were analyzed using cell counting and WST-1 cell proliferation assay. Apoptosis was determined by DAPI staining and electron microscopy, and quantified by luminescence assays for caspases 3/7, 6, 8, 9 and 2. RESULTS: Extracts of Trailliaedoxa gracilis showed a dose-dependent reduction of proliferation and induction of apoptosis in the KRJ-I cells. Normal fibroblasts were not impaired. Tumor growth inhibition was also observed in heterotransplanted SCID (severe combined immunodeficiency) mice. CONCLUSION: The in vitro and in vivo outcomes suggest a potential clinical effect of Trailliaedoxa gracilis in SI-NETs.

Combination therapy with histone deacetylase inhibitors and lithium chloride: a novel treatment for carcinoid tumors.

In carcinoid cell lines, the histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) activate the Notch1 pathway, whereas lithium inhibits glycogen synthase kinase-3beta (GSK-3beta). These compounds limit growth and decrease hormonal secretion in vitro. We hypothesized that lower-dose combination therapy of HDAC inhibitors and lithium chloride could achieve similar growth inhibition to that of the drugs alone. Gastrointestinal and pulmonary carcinoid cells were treated with either VPA or SBHA and lithium chloride for up to 48 hours. Western blot analysis was used to measure the effects on the Notch1 and GSK-3beta pathways and the neuroendocrine tumor marker chromogranin A (CgA). Growth was measured by a cellular proliferation assay. With lower-dose combination therapy, a decrease in CgA was observed. The HDAC inhibitors increased the amount of active Notch1 protein, whereas treatment with lithium was associated with inhibition of GSK-3beta. Moreover, growth was inhibited with lower-dose combination therapy. Treatment of carcinoid cells with either VPA or SBHA and lithium chloride suppresses the neuroendocrine marker CgA while upregulating Notch1 and inhibiting GSK-3beta. This combination effectively reduces growth. Thus, lower-dose combination therapy may be a viable therapeutic approach for carcinoid tumors.

Severe toxicity after permanent radioactive seed implantation for mediastinal carcinoid tumors.

PURPOSE: Permanent implantation of 125I seeds may be used when uninvolved surgical margins are unobtainable or close. Two cases of mediastinal carcinoid tumors with prior chemoradiation had tumors adherent to esophageal muscularis. Both underwent intraoperative permanent seed implantation and developed esophageal fistulas requiring surgical correction. METHODS AND MATERIALS: Custom permanent 125I seed mesh implants were fashioned intraoperatively in a geometrically coherent pattern. The implants were directly sutured to the partially resected esophageal wall. The postimplant CT scans were fused with the postfistula scans to provide dosimetric information at the fistula site. Doses were calculated from time of insertion to time of fistula formation. Neither patient showed evidence of disease recurrence at the time of fistula repair. RESULTS: Patient 1 developed an esophageal-pleural fistula 83 days after seed implantation. Patient 2 developed a broncho-pleural fistula 300 days after seed implantation. CONCLUSIONS: These cases demonstrated that implantation in the setting of extensive subcarinal space dissection and partial esophageal wall resection could cause fistula formation and the need for additional surgery. The high mucosal dose, despite the relatively low activity implant, was due to lack of geometric sparing of the mucosa. We recommend that extensive subcarinal space dissection be considered a contraindication to permanent seed implantation.

Surgical and chemotherapy treatment outcomes of goblet cell carcinoid: a tertiary cancer center experience.

BACKGROUND: Goblet cell carcinoid (GCC) is a rare malignant tumor with distinct histological and clinical features. Our goals were to review the surgical and chemotherapy outcomes of patients with GCC. METHODS: We performed a retrospective review of the Mayo Clinic database from 1984 to 2004 with a prospective follow-up of 57 patients with GCC. RESULTS: The age at diagnosis (mean +/- SE) was 55 +/- 13 years. The most common presentations were right lower quadrant pain mimicking appendicitis (70%) and right lower quadrant or pelvic mass (25%). Only patients with T4 lesions had positive mesenteric nodes, with a frequency of 28%. Fifty percent of female patients had metastasis to the ovaries. The disease-specific 5-year survivals for stages I, II, III, and IV were 100%, 76%, 22%, and 14%, respectively; the overall mean survival was 47 +/- 3 months. All stage I patients had simple appendectomy. The overall 5-year survival rates for patients with combined stages II to IV who underwent appendectomy versus right hemicolectomy were 43% and 34%, respectively (P = .604). The corresponding survival rates for adjuvant chemotherapy versus no chemotherapy were 32% and 27%, respectively (P = .151). CONCLUSIONS: The prognosis for patients with GCC tumors correlates well with the American Joint Committee on Cancer stage at initial presentation. Appendectomy alone seems adequate for stage I disease. For staging purposes, right hemicolectomy is appropriate for T4 tumors or stage II to III disease provided that it can be performed with minimal risk. Surgical debulking is a consideration but is controversial. Adjuvant chemotherapy with 5-fluorouracil and leucovorin regimen is minimally effective against GCC.

[Clinical course of an ileal carcinoid with mesenteric metastasis]. / Evolutie particulara a unui carcinoid ileal cu metastaza ganglionara în baza mezenterului.

This paper aim is to present the case of a male patient, age 63 admitted in hospital for non-specific gastroenterologic symptoms easily attributed to colecyst calculosis; the anamnesis and careful clinical examination have avoided a useless cholecystectomy and permitted to establish indication for laparotomy; during that was found an ileal tumor with massive metastasis in the base of mesentery. The surgical attitude was dictated by histological diagnostic difficulties (prostate adenocarcinoma metastasis), so it has given up the idea of tumor excision (unjustified intraoperative risk for a metastasis), performing a bypass of the ileal tumor by an enteroenterostomy, then the patient was sent to the Oncological Department. Postoperative evaluation of the patient finally permitted to establish the neuroendocrine origin of the tumor; after oncological treatment (chemotherapy), about 10 months after operation the patient didn't present any sign of tumor (tumor markers and CT scan within normal). The paper emphasizes the problem of practicing an aggressive surgical treatment for carcinoid intestinal tumors with mesenteric metastasis but also brings attention to nonsymptomatic forms of cholecyst calculosis that may hide associated malignant tumors undetected by laparoscopic cholecystectomy.

Influence of high-dose leucovorin and 5-fluorouracil chemotherapy regimen on P wave duration and dispersion.

BACKGROUND: Although 5-fluorouracil (5-FU)-related cardiotoxicity is well known, atrial arrhythmia, as a potentially serious complication has not been studied in detail. The aim of this study was to determine the P max and Pd in the electrocardiograms (ECG) of patients receiving 5-FU treatment. METHODS: Twenty-five patients (mean age: 62 years) receiving a 5-FU bolus plus continuous infusion with calcium leucovorin over 48 h and with normal pre-treatment cardiac physical examinations, ECG and echocardiography were enrolled. P maximum (P max), P minimum (P min) and P dispersion (Pd) (maximum minus minimum P wave duration) were measured from the 12-lead ECG at the 0th and 48th hour of the first chemotherapy cycle. Echocardiography was also obtained in all patients at the same times. RESULTS: Clinical cardiotoxicity was observed in two patients. P max and Pd were both significantly longer after 5-FU treatment at the 48th hour (P < 0.001). P min did not change (P > 0.05). CONCLUSION: Treatment with 5-FU based regimens may increase Pd and prolong the P max in cancer patients. These alterations may be predictive of patients at risk of atrial arrhythmias during 5-FU treatment.

Hypocalcemia and azotemia associated with zoledronic acid and interferon alfa.

OBJECTIVE: To describe severe hypocalcemia and acute renal failure associated with zoledronic acid and interferon alfa in a patient with metastatic carcinoid tumors. CASE SUMMARY: A 39-year-old white man with metastatic carcinoid tumor tolerated treatment with subcutaneous long-acting octreotide monthly and interferon alfa 6 million units 3 times weekly for 6 months. Due to multiple bony metastases, zoledronic acid was prescribed as a monthly 4-mg intravenous infusion over 30 minutes to prevent skeletal-related events. Although the first infusion went well, the patient developed severe hypocalcemia and acute renal failure after the second zoledronic infusion. DISCUSSION: Bisphosphonates may infrequently cause symptomatic hypocalcemia, especially among patients who have vitamin D deficiency or hypoparathyroidism or receive treatment with an aminoglycoside. Our literature review suggests that zoledronic acid and interferon alfa may exert additive effects on the inhibition of osteoclasts, thus potentially precipitating hypocalcemia. Renal dysfunction may not be a direct consequence of interferon alfa. However, altered mental function due to hypocalcemia may lead to dehydration and further exacerbate renal dysfunction, a known adverse effect of zoledronic acid. Since therapeutic indications of both interferon alfa and zoledronic acid continue to expand, clinicians should be aware of these serious adverse reactions and potential interaction. Supportive treatment with hydration, calcium supplement, and oral calcitriol resulted in resolution of hypocalcemia, but only partial improvement of azotemia. CONCLUSIONS: In our patient with metastatic carcinoid tumor, treatment with zoledronic acid and interferon alfa was associated with symptomatic hypocalcemia and acute renal failure.

Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors.

BACKGROUND: Although patients with neuroendocrine tumors typically exhibit an indolent clinical course, the pace of disease accelerates and the prognosis deteriorates once objective progression of disease begins. Thirty-four patients with advanced neuroendocrine tumors were treated with octreotide as antineoplastic therapy. This treatment was begun only after documentation of clear objective progression of disease. METHODS: A Phase II trial was performed at a tertiary comprehensive cancer center. RESULTS: The median survival for this patient population from the start of octreotide therapy has not been reached, with a median follow-up of 29 months (range, 1-47 months). No major objective tumor regressions were seen. Seventeen patients (50%) experienced a computed tomography-documented stabilization of disease that was maintainable for a minimum of 2 months (median, 5 months; range, 0-27 months). Of the 34 patients, 20 patients received octreotide as their first antineoplastic therapy. The median survival for these 20 patients has not been reached, with a median follow-up also of 29 months (range, 12-41 months). CONCLUSIONS: Octreotide may influence the natural history of neuroendocrine tumors. The survival in patients treated with octreotide, as measured from the time of progression of disease, compares favorably with that of historical controls. Proof of a survival advantage for patients treated with octreotide would require a multicenter, randomized trial.

Chemotherapy with 5-fluorouracil and streptozotocin in carcinoid tumors of gastrointestinal origin: experiences with 13 patients.

The Authors report their experiences on the treatment of 13 consecutive cases of gastro-intestinal carcinoid tumors observed over the last 11 years. The primary sites were as follows: intestine (5 cases), appendix (3 cases), colon (1 case) and peritoneum (4 cases); only 3 patients presented systemic signs. Ten patients in advanced phase were treated with a chemotherapeutic regimen containing 5-fluorouracil (5-Fu) and streptozotocin (STZ). One case was excluded from the study because of a concomitant gastric carcinoma. Of the 9 evaluable patients, two achieved partial remission (22%) with a duration of 18+ and 66 months respectively; 4 (44.5%) had stable disease for periods ranging from 7 to 40 months and 3 cases progressed. Severe toxicity (thrombocytopenia and diarrhea) occurred in 2 cases and disappeared with the suspension of therapy. The systemic signs disappeared with treatment and did not appear in 2 cases out of 3. The prospective of the employment of new drugs such as alpha-interferon and, above all, somatostatin provides hope that this uncommon disease may have an improved response rate to treatment in the future.

Treatment of malignant midgut carcinoid tumours with a long-acting somatostatin analogue octreotide.

Treatment with the somatostatin analogue octreotide, SMS 201-995 (Sandostatin), has been carried out in a series of 23 patients with malignant midgut carcinoid tumours. The patients received initially 50 micrograms twice a day for six months, thereafter a median of 100 micrograms twice daily. Six of 22 evaluable patients (28%) showed objective tumour response lasting for 6 to 30 months. Stable disease was observed in 8 of the 22 patients (36%) and progressive disease in a further 8 patients (36%). A subjective response with decrease of diarrhoea or flushing was noted in 11 out of 22 patients (50%). Two out of 6 patients with objective response demonstrated a significant decrease of tumour size lasting for 6 and 30 months respectively. In order to maintain the clinical response, the dose had to be increased in all 6 responders. The adverse effects included development of diabetic blood glucose levels in 8 out of 22 patients (36%). Albumin-modified serum calcium levels were significantly reduced after treatment with octreotide 50 micrograms twice a day. One patient developed symptoms of hypocalcemia which was reversed by supplementation with calcium and D-vitamins. The somatostatin analogue SMS 201-995 has a beneficial effect in the treatment of patients with the carcinoid syndrome. However, the precise role of the drug in the long-term management of these patients has to be further investigated.

[Primary carcinoid tumor of the testis: a case report].

A case of pure, primary testicular carcinoid tumor in a 27-seven-year-old male is reported. The patient presented with a painless enlargement of the right testis but the serum markers for testicular cancer, including alpha-fetoprotein, beta-human chorionic gonadotropin and lactate dehydrogenase, were not elevated. Right orchiectomy was performed. Histologically, the tumor showed a typical appearance of carcinoid tumor. Further examinations such as barium studies, computed tomographic scan and Ga scintigraphy, showed no other lesions, and he received an adjuvant chemotherapy of cyclophosphamide, 5-fluorouracil and adriamycin. He is well and free from symptoms 17 months after surgery.