Clinical, pathological, and demographic factors associated with development of recurrences after surgical resection in elderly patients with neuroendocrine tumors.

BACKGROUND: Incidence of locoregional neuroendocrine tumors (NETs) is rising. However, after curative resection, the patterns and risk factors associated with recurrence remain unknown. Consensus guidelines recommend surveillance every 6-12 months for up to 10 years after surgery for resected, well-differentiated NETs irrespective of patient demographics, site, grade or stage of tumor with few exceptions. PATIENTS AND METHODS: From the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we identified localized and regional stage NET patients who underwent surgical resection between January 2002 and December 2011. Development of recurrence was identified by capturing at least two claims indicative of metastatic disease until 31 December 2013. RESULTS: Of the 2366 identified patients (median age 73 years), 369 (16%) developed metastatic disease within 5 years and only an additional 1% developed metastases between years 5 and 10 with the majority dying due to unrelated causes. The 5-year risk of developing metastases (hazard ratio, HR) varied significantly (log-rank P < 0.001) by grade: 9.9% versus 25.9% (2.2) versus 48.1% (4.4) for grades 1, 2, and ≥ 3, respectively; stage: 10.3% versus 31.1% (2.8) for localized versus regional; primary tumor size: 7.6% versus 15% (1.3) versus 26.6% (1.5) for <1, 1-2, and > 2 cm, respectively; and site: ranging from 11.3% for colon to 23.9% for pancreas. CONCLUSIONS: Contrary to current guidelines, our study suggests that surveillance recommendations should be tailored according to patient and tumor characteristics. Surveillance past 5 years may be avoided in elderly patients with competing morbidities or low risk of recurrence. Pancreatic, lung, higher grade, and regional NETs have a higher risk of recurrence and may be considered for future adjuvant trials.

Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study.

Background: In the phase 3 RADIANT-2 study, everolimus plus octreotide long-acting repeatable (LAR) showed improvement of 5.1 months in median progression-free survival versus placebo plus octreotide LAR among patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The progression-free survival P-value was marginally above the prespecified threshold for statistical significance. Here, we report final overall survival (OS) and key safety update from RADIANT-2. Patients and methods: The RADIANT-2 trial compared everolimus (10 mg/day, orally; n = 216) versus placebo (n = 213), both in conjunction with octreotide LAR (30 mg, intramuscularly, every 28 days). Patients, unblinded at the time of progression or after end of double-blind core phase following primary analysis, were offered open-label everolimus with octreotide LAR (open-label phase). In the open-label phase, patients had similar safety and efficacy assessments as those in the core phase. For OS, hazard ratios (HRs) with 95% CIs using unadjusted Cox model and a Cox model adjusted for prespecified baseline covariates were calculated. Results: A total of 170 patients received open-label everolimus (143 crossed over from the placebo arm; 27 in the everolimus arm continued to receive the same treatment after unblinding). The median OS (95% CI) after 271 events was 29.2 months (23.8-35.9) for the everolimus arm and 35.2 months (30.0-44.7) for the placebo arm (HR, 1.17; 95% CI, 0.92-1.49). HR adjusted for baseline covariates was 1.08 (95% CI, 0.84-1.38). The most frequent drug-related grade 3 or 4 AEs reported during the open-label phase were diarrhea (5.3%), fatigue (4.7%), and stomatitis (4.1%). Deaths related to pulmonary or cardiac failure were observed more frequently in the everolimus arm. Conclusion: No significant difference in OS was observed for the everolimus plus octreotide LAR and placebo plus octreotide LAR arms of the RADIANT-2 study, even after adjusting for imbalances in the baseline covariates. Clinical Trial Number: NCT00412061, www.clinicaltrials.gov.

A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial.

Background: Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarily targeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generation SSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced, well-differentiated, progressive pancreatic NET. Patients and methods: Patients were randomized 1 : 1 to receive a combination of everolimus (10 mg/day, orally) and pasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSA use, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker response was evaluated in an exploratory analysis. Results: Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographics and disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8 months in combination arm versus 16.6 months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses were observed in 20.3% versus 6.2% of patients in combination arm versus everolimus arm; however, overall disease control rate was similar (77.2% versus 82.7%, respectively). No significant improvement was observed in median overall survival. Adverse events were consistent with the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively. Conclusions: The addition of pasireotide to everolimus was not associated with the improvement in PFS compared with everolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.

A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer.

BACKGROUND: The contribution of induction chemotherapy (IC) before preoperative chemoradiation for esophageal cancer (EC) is not known. We hypothesized that IC would increase the rate of pathologic complete response (pathCR). METHODS: Trimodality-eligibile patients were randomized to receive no IC (Arm A) or IC (oxaliplatin/FU; Arm B) before oxaliplatin/FU/radiation. Surgery was attempted ∼5-6 weeks after chemoradiation. The pathCR rate, post-surgery 30-day mortality, overall survival (OS), and toxic effects were assessed. Bayesian methods and Fisher's exact test were used. RESULTS: One hundred twenty-six patients were randomized dynamically to balance the two arms for histology, baseline stage, gender, race, and age. Fifty-five patients in Arm A and 54 in Arm B underwent surgery. The median actuarial OS for all patients (54 deaths) was 45.62 months [95% confidence interval (CI), 27.63-NA], with median OS 45.62 months (95% CI 25.56-NA) in Arm A and 43.68 months (95% CI 27.63-NA) in Arm B (P = 0.69). The pathCR rate in Arm A was 13% (7 of 55) and 26% (14 of 54) in Arm B (two-sided Fisher's exact test, P = 0.094). Safety was similar in both arms. CONCLUSIONS: These data suggest that IC produces non-significant increase in the pathCR rate and does not prolong OS. Further development of IC before chemoradiation may not be beneficial. Clinical trial no.: NCT 00525915 (www.clinicaltrials.gov).

Quality of life, resource utilisation and health economics assessment in advanced neuroendocrine tumours: a systematic review.

Neuroendocrine tumours (NET) are often diagnosed at an advanced stage when the prognosis is poor for patients, who often experience diminished quality of life (QoL). As new treatments for NET become available, it is important to characterise the associated outcomes, costs and QoL. A comprehensive search was performed to systematically review available data in advanced NET regarding cost of illness/resource utilisation, economic studies/health technology assessment and QoL. Four rounds of sequential review narrowed the search results to 22 relevant studies. Most focused on surgical procedures and diagnostic tools and contained limited information on the costs and consequences of medical therapies. Multiple tools are used to assess health-related QoL in NET, but few analyses have been conducted to assess the comparative impact of available treatment alternatives on QoL. Limitations include English language and the focus on advanced NET; ongoing terminology and classification changes prevented pooled statistical analyses. This systematic review suggests a lack of comparative economic and outcomes data associated with NET treatments. Further research on disease costs, resource utilisation and QoL for patients with advanced NET is warranted.

Pre-existing Symptoms and Healthcare Utilization Prior to Diagnosis of Neuroendocrine Tumors: A SEER-Medicare Database Study.

The incidence and prevalence of neuroendocrine tumors (NETs) are continually increasing. While it is known that NET symptoms often predate diagnosis, their prevalence and impact on resource utilization and costs are largely unknown. We identified 9,319 elderly patients diagnosed with NETs between 1/2003 and 12/2011 from the Surveillance, Epidemiology and End Results (SEER)-Medicare. We examined the patients' conditions potentially associated with NET, resource utilization and costs during the year before diagnosis. We found that NET patients were more likely to have diagnoses of hypertension (63.8% vs. 53.3%), abdominal pain (22.2% vs. 7.6%), heart failure (11.7% vs. 8.0%), diarrhea (5.8% vs. 1.8%), peripheral edema (5.4% vs. 3.8%) and irritable bowel syndrome (1.2% vs. 0.5%) compared to the non-cancer control group. They also had much higher resource utilization including number of outpatient visits (mean: 22.1 vs. 17.2), percentage with ER visits (20.9% vs. 11.6%), and hospitalizations (28.4% vs. 17.0%). Similarly, NET patients incurred significantly higher total (mean: $14602 vs. $9464), outpatient (mean: $5987 vs. $4253), and inpatient costs (mean: $8615 vs. $5211). This first population-based study on the pre-diagnosis symptoms and healthcare utilization found that NET patients were more likely to have certain conditions and incur higher resource utilizations and costs.

[Features of cognitive function in patients with laryngeal carcinoma].

Objective:To study the differences in cognitive function between patients with laryngeal carcinoma and healthy volunteers. Method:Patients with laryngeal carcinoma who have been first diagnosed with laryngeal carcinoma, but not received treatment at the Department of Otolaryngology in two hospitals in Shanxi Province and healthy volunteers of the same age, gender-matched and similar education were studied for the purpose to evaluate the cognitive status by using the Wechsler memory scale.Result:No significant difference of age, gender and educational level was found between both groups（P>0.05）.The score of Memory Quotient was significantly lower in the laryngeal carcinoma group than that in healthy control group (P<0.05). There were significant differences in the results of Wechsler memory scale except for Experience, Orientation and Association test (P<0.05).Conclusion:The memory, attention and computing power of patients in the laryngeal carcinoma group were not as good as those of patients in the healthy control group. Patients with laryngeal carcinoma have cognitive impairment or lower ability , so we need to pay more attention to the patients during their rehabilitation. The early detection of cancer-related cognitive impairments can help patients improve their cognitive function early, reduce the burden on their families and society, and promote better return of patients to society.

Effect of everolimus on the pharmacokinetics of octreotide long-acting repeatable in patients with advanced neuroendocrine tumors: An analysis of the randomized phase III RADIANT-2 trial.

In the RADIANT-2 trial, addition of everolimus to octreotide long-acting repeatable (LAR) exhibited a clinically meaningful 5.1-month improvement in progression-free survival (PFS) in patients with advanced functional neuroendocrine tumors. In this study, we characterized the effects of everolimus co-administration on octreotide LAR pharmacokinetics and its relationship with efficacy and safety. At least one evaluable blood everolimus and plasma octreotide predose minimum concentration (Cmin ) was available for 182 patients and 294 patients, respectively. Concomitant everolimus administration increased octreotide Cmin with a geometric mean ratio (everolimus/placebo) of 1.47 (90% confidence interval [CI] = 1.32-1.64). Risk for progression was consistently reduced when everolimus Cmin was increased twofold, regardless of octreotide exposure (hazard ratio [HR] = 0.74; 95% CI = 0.46-1.18; HR = 0.54; 95% CI = 0.32-0.92 for 6 ng/mL and 4 ng/mL octreotide, respectively). Risk for pulmonary or metabolic events was associated with increased everolimus Cmin . Co-administration of everolimus plus octreotide LAR increased octreotide Cmin , which did not impact efficacy.

Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome.

PURPOSE: Preoperative chemoradiotherapy may increase the R0 (curative) resection rate, overall survival (OS) duration, and disease-free survival (DFS) duration. We evaluated paclitaxel-based induction chemotherapy and chemoradiotherapy in patients with localized gastric or gastroesophageal adenocarcinoma to determine its feasibility, impact on the R0 resection rate, type of pathologic response, OS, and DFS. PATIENTS AND METHODS: Patients with operable, localized gastric, or gastroesophageal adenocarcinoma were eligible. Staging included endoscopic ultrasonography (EUS) and laparoscopy. Patients received two 28-day cycles of induction chemotherapy of fluorouracil, paclitaxel, and cisplatin followed by 45 Gy of radiation and concurrent fluorouracil plus paclitaxel. The cancer was restaged and surgery was attempted. Postsurgery pathologic findings and R0 resection were correlated with OS and DFS. RESULTS: Forty-one patients were enrolled. Most carcinomas were proximal (83%) and pretreatment stage EUST3 (85%). Forty patients (98%) underwent surgery, and 78% had an R0 resection. We observed a pathologic complete response (pathCR) rate of 20% and a pathologic partial response (pathPR) rate of 15% (< 10% residual cancer cells in the resected specimen). No pretreatment parameter (sex, cancer location, baseline T stage, or baseline N stage) predicted the type of postsurgery pathologic response, OS, or DFS. However, pathCR (P = .02), pathCR + pathPR (P = .006), R0 resection (P < .001), and postsurgery T and N stages (P = .01 and P < .001, respectively) were associated with OS. Same parameters were significantly correlated with DFS. Toxicity was manageable. CONCLUSION: The type of pathologic response but not pretreatment parameters was associated with OS and DFS. Efforts to increase the rate of pathologic response and better systemic cancer control are warranted.

[Cervical pains in Pott's disease: Epidemiological, clinical and radiological aspects concerning 26 cases in Abidjan]. / Atteinte cervicale dans le mal de Pott: Aspects epidemiocliniques et radiologiques a propos de 26 cas a abidjan.

In this study, we report the results of the experience of the Rheumatology Department of Cocody University Hospital in the management of the cervical spinal tuberculosis in Abidjan area. This was a retrospective study of 26 cases collected over a 7 year period (January 2006 to December 2013). The objective of this work was to illustrate the epidemiological, clinical and radiological profile of the cervical localization of tuberculosis in our practice. The prevalence of cervical disease was 4.87%. The average age of our patients was 48.27 years, with a slight male predominance (60.7%). The duration of disease progression was long (8 months on average); symptomatology was dominated by pain associated with stiffness in all patients (100%). One third of patients had already consulted at the stage of neurological complications (1 case of Brown Sequard syndrome, 2 cases of tetraparesis, 5 cases of paraplegia). Computer tomography was performed in all patients, followed by an MRI scan for 6 patients, which revealed the predominance of damage to the C3-C4 floor (34.62%) and 3 cases of sub occipital localization. Spondylodiscitis was the main radiological anatomical lesion (88.46%), lesions were multi-stage in 61.54% of cases, the prevalence of retropharyngeal abscess was high (84.61% of cases), that of the epiduritis was 76.92% and radiological spinal cord compression was recorded in a third of cases. All patients benefited from an antituberculous treatment associated with cervical immobilization.

Nous rapportons dans cette étude, les résultats de l'expérience du service de Rhumatologie du CHU de cocody dans la prise en charge du mal de pott cervical dans la région d'Abidjan. Il s'agissait d'une étude rétrospective de 26 cas colligés sur une période de 8 ans (janvier 2006 au décembre 2013). L'objectif de ce travail était d'illustrer les différents aspects épidémiologiques, cliniques et radiologiques de la localisation cervicale de la tuberculose dans notre pratique. La prévalence de l'atteinte cervicale était de 4,87% .L'âge moyen de nos patients était de 48,27 ans, avec une légère prédominance masculine (60,7%). La durée d'évolution de la maladie était longue (8 mois en moyenne); la symptomatologie était dominée par la douleur associée à une raideur chez tous nos patients (100%). Un tiers des patients consultait déjà au stade de complications neurologiques (1 cas de Syndrome de Brown Séquard, 2 cas de tétraparésie, 5 cas de paraplégie). La TDM a été réalisée chez tous nos patients, et complétée par l'IRM chez 6 patients, ce qui a permis de déceler la prédominance de l'atteinte à l'étage C3-C4 (34,62%) et une localisation sous occipitale dans 3 cas .La spondylodiscite était la principale lésion anatomo radiologique (88,46 %), Les lésions étaient pluri-étagées dans 61,54 % des cas, la prévalence des abcès retro pharyngiens était élevée (84,61 % des cas), une épidurite dans 76,92 %, et une compression médullaire radiologique dans un tiers des cas. Tous nos patients ont bénéficié d'un traitement antibacillaire associé à une immobilisation du foyer pottique.

Adjuvant therapy for gastric carcinoma: closing out the century.

Gastric cancer is often advanced and unresectable at diagnosis. Even when a curative resection is possible, the 5-year survival rate for patients with T2 or higher tumors is less than 50%. Survival rates are even lower if lymph node metastases are present at surgery. Many phase III trials of adjuvant therapy have been conducted around the world during the past 4 decades, but their interpretation varies in the East and West. In the West, postoperative treatment modalities have not proven to be superior to postsurgical observation alone. Thus, at present, the routine use of postoperative therapy should be discouraged. In the Orient, however, routine use of postoperative chemotherapy and/or immunotherapy is common after a surgical procedure. Further investigations that correlate treatment response with molecular markers are needed. Improved clinical trial designs, including better preoperative staging, standardized surgical techniques, inclusion of adequate numbers of patients, and the continued use of a surgery-alone control group, are essential. In addition, the incorporation of newer active agents, radiotherapy, and new strategies, such as preoperative therapy and selection of patients based on tumor biology, would result in much-needed advances. Less toxic approaches with novel mechanisms of action, such as antiangiogenesis therapy, tumor vaccines, monoclonal antibodies, and matrix metalloproteinase inhibitors, also hold promise.

Tamoxifen-induced thrombocytopenia.

Thrombocytopenia (platelet count < 100,000/microl) is a rare side effect of tamoxifen (Nolvadex). We report a case of thrombocytopenia that developed 6 months after tamoxifen was given as an adjuvant treatment for breast cancer. The patient received no concurrent cytotoxic chemotherapy or radiation therapy. The thrombocytopenia resolved after the tamoxifen was stopped, reappeared promptly when the tamoxifen was restarted, and resolved again after the second withdrawal, at which time anastrozole (Arimidex) was substituted for the tamoxifen. The patient's platelet count remained normal for more than 6 months thereafter.

Pilot study of concurrent 5-fluorouracil/paclitaxel plus radiotherapy in patients with carcinoma of the esophagus and gastroesophageal junction.

Preoperative concurrent chemotherapy and radiotherapy can be highly effective but are often associated with significant rates of morbidity and even mortality. We studied the toxicity of continuous infusion of 5-fluorouracil (5-FU) and weekly paclitaxel combined with radiotherapy. Patients had histologic proof of local-regional carcinoma of the esophagus or gastroesophageal (GE) junction, a Karnofsky performance status of 70 or greater, and normal liver, renal, and bone marrow functions. Chemotherapy consisted of continuous infusion of 5-FU (300 mg/m2/d) for 5 days a week for 5 weeks, plus paclitaxel (45 mg/m2) given during 3 hours every week for 5 weeks. Based on the tumor location and its resectability, the total dose of concurrent radiation varied between 45 Gy and 50.4 Gy. Nine men and one woman, with a median age of 61 years, were evaluated. One had GE junction cancer, six had distal esophageal cancer, and three had midesophageal cancer. Weight loss, nausea, vomiting, and dysphagia of grades I and II were noted. The hematologic toxicity was mild. No patients required transfusion. There was no leukopenia or thrombocytopenia. None of the patients was hospitalized during chemoradiation; all patients completed treatment as outpatients. Five patients had subsequent surgical resections: one had a pathologically complete response, and two had a partial response (>90% necrosis). Continuous infusion of 5-FU plus paclitaxel given concurrently with radiotherapy was well tolerated. We plan to study this regimen further in upper gastrointestinal cancers.

Primary rhabdomyosarcoma of the prostate. Diagnosis by needle biopsy and immunocytochemistry.

Needle aspiration biopsy of the prostate in a patient who initially presented with multiple metastatic lesions in the lungs and a pleural effusion showed the presence of many malignant cells. These cells appeared either as noncohesive round and oval cells or as clusters. The cytologic impression that these were sarcoma cells was confirmed by subsequent histologic and immunochemical studies. By correlating the cytologic, histologic and immunochemical findings with the clinical findings, it was possible to determine that the primary site of the tumor in this patient was the prostate. Our experience in this case suggests that air-dried smears stained with Romanowsky stains are suitable and useful for cytodiagnosis.

First Report of Sclerotium rolfsii on Star-cluster (Pentas lanceolata) in Taiwan.

Star-cluster (Pentas lanceolata (Forssk.) Deflers) has recently become popular as a bedding plant in Taiwan. During the summer of 2000, a sudden wilt of 60-day-old plants was observed in a nursery in Tainan City (southern Taiwan). Initial symptoms included stem necrosis at the soil line and yellowing and tan discoloration of leaves. As stem necrosis progressed, infected plants wilted and died. Necrotic tissues were covered with white mycelium that differentiated into reddish brown, spherical (1 to 2 mm in diameter) sclerotia. Sclerotium rolfsii was consistently recovered from the surface of symptomatic stem sections that were disinfected for 1 min in 0.5% NaOCl and plated on potato dextrose agar amended with 100 ppm streptomycin sulfate. Pathogenicity of three isolates of S. rolfsii was confirmed by inoculating 90-day-old plants of P. lanceolata that were grown in pots. Three plants each were inoculated with a 5-mm plug of agar with mycelium or two sclerotia of the pathogen. Inoculum was placed on the soil surface against the stem of each plant. Three noninoculated plants served as controls. All plants were kept in a growth chamber at 20 to 30°C with relative humidity >85%. The pathogenicity test was repeated. Inoculated plants developed symptoms within 7 days, while control plants remained symptomless. Sclerotia developed on infected tissues and S. rolfsii was reisolated from symptomatic tissues. Although this disease has been observed on many species of plants (1), to our knowledge, this is the first report of southern blight of P. lanceolata caused by S. rolfsii in Taiwan. Reference: (1) Tsai, Y. P., ed. List of Plant Diseases in Taiwan. The Plant Protection Society of the Republic of China and The Phytopathological Society of the Republic of China. 1991.

First Report of Sclerotium rolfsii on Island Ash Seedlings in Taiwan.

Island ash (Fraxinus formosana Hay.) is a large, semideciduous tree in Taiwan. It is used for forestation, a shade tree, and producing wood for furniture. During the summer of 2001, a sudden wilt of 1-year-old plants was observed in a nursery in northern Taiwan. Initial symptoms included stem necrosis at the soil line and yellowing and tan discoloration of the leaves. As stem necrosis progressed, infected plants wilted and died. Necrotic tissues were covered with white mycelium that differentiated into reddish brown, spherical (1 to 2 mm in diameter) sclerotia. Sclerotium rolfsii was consistently recovered from the surface of symptomatic stem sections that were disinfected for 1 min in 0.5% NaOCl and then plated on potato dextrose agar (PDA) amended with 100 ppm of ampicillin. Pathogenicity of two S. rolfsii isolates was confirmed on 1-year-old island ash seedlings grown in 12.7 cm- (5-in) plastic pots in a sterilized mixture of peat moss and vermiculite (3:1). Seedlings were inoculated with mycelia and sclerotia of the pathogen grown on PDA. Three plants each were inoculated with four disks (5 mm) of agar with mycelium and three were inoculated with 10 sclerotia that were placed on the soil surface around the base of each plant. Noninoculated plants served as controls. All plants were kept in a growth chamber at 25 to 35°C and >95% relative humidity. The test was repeated once. All inoculated plants developed symptoms within 14 days, while control plants remained symptomless. Sclerotia developed on infected tissues, and S. rolfsii was reisolated from symptomatic tissues. This disease has been observed on many species of plants (1), but to our knowledge, this is the first report of Southern blight of Island ash seedlings caused by S. rolfsii in Taiwan. Reference: (1) Y. P. Tsai ed. List of Plant Diseases in Taiwan. The Plant Protection Society of the Republic of China and The Phytopathological Society of the Republic of China, 1991.