Perioperative TAS-118 plus oxaliplatin in patients with locally advanced gastric cancer: APOLLO-11 study.

BACKGROUND: We investigated the feasibility of perioperative chemotherapy with S-1 and leucovorin (TAS-118) plus oxaliplatin in patients with locally advanced gastric cancer. METHODS: Patients with clinical T3-4N1-3M0 gastric cancer received four courses of TAS-118 (40-60 mg/body, orally, twice daily for seven days) plus oxaliplatin (85 mg/m2, intravenously, day one) every two weeks preoperatively followed by gastrectomy with D2 lymphadenectomy, followed by postoperative chemotherapy with either 12 courses of TAS-118 monotherapy (Step 1) or eight courses of TAS-118 plus oxaliplatin (Step 2). The primary endpoints were completion rates of preoperative chemotherapy with TAS-118 plus oxaliplatin and postoperative chemotherapy with TAS-118 monotherapy (Step 1) or TAS-118 plus oxaliplatin (Step 2). RESULTS: Among 45 patients enrolled, the preoperative chemotherapy completion rate was 88.9% (90% CI 78.0-95.5). Major grade ≥ 3 adverse events (AEs) were diarrhoea (17.8%) and neutropenia (8.9%). The R0 resection rate was 95.6% (90% CI 86.7-99.2). Complete pathological response was achieved in 6 patients (13.3%). Dose-limiting toxicity was not observed in 31 patients receiving postoperative chemotherapy (Step 1, n = 11; Step 2, n = 20), and completion rates were 90.9% (95% CI 63.6-99.5) for Step 1 and 80.0% (95% CI 59.9-92.9) for Step 2. No more than 10% of grade ≥ 3 AEs were observed in patients receiving Step 1. Hypokalaemia and neutropenia occurred in 3 and 2 patients, respectively, receiving Step 2. The 3-year recurrence-free and overall survival rates were 66.7% (95% CI 50.9-78.4) and 84.4% (95% CI 70.1-92.3), respectively. CONCLUSIONS: Perioperative chemotherapy with TAS-118 plus oxaliplatin with D2 gastrectomy is feasible.

Laparoscopic Resection of Gastric Cancer in a Patient with Chronic Lymphocytic Leukemia Accompanied by Neutropenia.

AIM: We report an unusual case of early gastric cancer and T-cell-type chronic lymphocytic leukemia accompanied by severe neutropenia that was successfully treated by laparoscopic gastrectomy. CASE REPORT: A 76-year-old female was referred to our Hospital for resection of a gastric adenoma that was suspicious for malignancy. Routine preoperative laboratory studies showed severe neutropenia and increased atypical lymphocytes in the peripheral blood. Bone marrow biopsy confirmed the diagnosis of T-cell chronic lymphocytic leukemia. One day before surgery, granulocyte colony-stimulating factor was administered. Laparoscopic-assisted distal gastrectomy was performed. The patient's postoperative course was uneventful and she was discharged after 10 days. The histopathological findings revealed well-differentiated adenocarcinoma (pT1a, pN0, and stage IA). CONCLUSION: Laparoscopic gastrectomy may be considered a primary approach in patients with neutropenia because it is associated with lower risk of postoperative infection and a lower mortality rate compared to open resection.

Case Reports of Severe Congenital Neutropenia Treated With Unrelated Cord Blood Transplantation With Reduced-intensity Conditioning.

Allogeneic stem cell transplantation is a curative treatment for severe congenital neutropenia (SCN). However, a standard conditioning regimen and donor source have not been established. We report 3 consecutive cases of SCN who were successfully treated by cord blood transplantation (CBT) with reduced-intensity conditioning consisting of fludarabine, melphalan, and low-dose total body irradiation. All cases achieved complete donor chimerism without severe infectious complications and have maintained normal neutrophil counts for between 3 and 9 years after CBT. These results suggest that CBT with reduced-intensity conditioning can be an alternative therapy for SCN when human leukocyte antigen-matched bone marrow donor is unavailable.

Dental extraction in the neutropenic patient.

PURPOSE: To identify risks of dental extraction in patients with mild, moderate, and severe neutropenia. MATERIALS AND METHODS: The authors undertook an observational study of 116 patients diagnosed with neutropenia and undergoing dental extractions in the Mayo Clinic Division of Oral and Maxillofacial Surgery. Absolute neutrophil count (ANC) was no higher than 1,500/µL. Predictors were ANC, age, diagnosis, number of teeth removed, type and location of extraction, length of antibiotic use, presence and type of bacteremia at the time of consultation or extraction, reason for consultation, indication for extraction, and use of any granulocyte colony-stimulating factor (GCSF). Primary outcomes were total complications, surgical site infections, delayed healing, and prolonged postoperative pain. Descriptive and bivariate analyses were undertaken, with statistical significance set at a P value less than or equal to .05. RESULTS: One hundred sixteen patients underwent extraction while neutropenic. The overall complication rate was 8.6% (n=10). All were minor complications requiring simple interventions, if any. Complications were delayed healing, surgical site infection, and prolonged postoperative pain. Delayed healing was not associated with ANC. GCSF and related medications did not appear to affect outcomes in these patients. CONCLUSION: The results of this preliminary study suggest that extraction of teeth in patients at all stages of neutropenia can be conducted safely. Complications of extraction were few and should be easily controlled. Further studies are required to clarify and stratify risk for future patients.

[SFGM-TC recommendation on indications for allogeneic stem cell transplantation in children with congenital neutropenia]. / Indications d'allogreffe dans les neutropénies constitutionnelles : recommandation de la SFGM-TC.

In this report, we address the issue of allogeneic stem cell transplantation in children with congenital neutropenia. Constitutional disorders with neutropenia are exceptional. Treatment and prevention of severe infections are a major concern in the management of chronic neutropenia. These disorders, especially Kostmann's disease and Shwachman-Bodian-Diamond syndrome, are associated with an increased risk of leukemia. The role of allogeneic stem cell transplantation in these patients is still unclear. In an effort to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the fourth annual series of workshops which brought together practitioners from all member centers and took place in September 2013 in Lille.

Neurological findings and genetic alterations in patients with Kostmann syndrome and HAX1 mutations.

OBJECTIVES: To describe the clinical profile and the prevalence of severe congenital neutropenia (SCN) and HAX1 mutations, so-called Kostmann syndrome, in France. STUDY DESIGN: Two pedigrees were identified from the French registry. RESULTS: The study included five subjects (three males), which represent 0.7% of the 759 SCN cases registered in France. The age at diagnosis was 0.3 years (range: 0.1-1.2 years) and the median age at the last follow-up was 7.3 years (range: 1.2-17.8 years). A novel large homozygous deletion of the HAX1 gene (exons 2-5) was found in one pedigree; while, a homozygous frameshift mutation was identified in exon 3 (c.430dupG, p.Val144fs) in the second pedigree. Severe bacterial infections were observed in four patients, including two cases of sepsis, one case of pancolitis, a lung abscess, and recurrent cellulitis and stomatitis. During routine follow-up, the median neutrophil value was 0.16 × 10(9)/L, associated with monocytosis (2 × 10(9)/L). Bone marrow (BM) smears revealed a decrease of the granulocytic lineage with no mature myeloid cells above the myelocytes. One patient died at age 2 from neurological complications, while two other patients, including one who underwent a hematopoietic stem cell transplantation (HSCT) at age 5, are living with very severe neurological retardation. CONCLUSIONS: SCN with HAX1 mutations, is a rare sub type of congenital neutropenia, mostly observed in population from Sweden and Asia minor, associating frequently neurological retardation, when the mutations involved the B isoform of the protein.

Epileptic encephalopathy after HHV6 post-transplant acute limbic encephalitis in children: confirmation of a new epilepsy syndrome.

Generalised epilepsy and cognitive deterioration were recently described in three children following human herpesvirus 6 (HHV6)-associated post-transplant acute limbic encephalitis (PALE). Magnetic resonance imaging (MRI) showed bilateral signal change and/or atrophy in the medial temporal structures and there was no evidence of an ongoing viral or immune-mediated process. We report another child who developed this condition after cord blood transplantation for congenital neutropenia at the age of three. He presented with epileptic spasms four months after HHV6-associated PALE. Cognitive regression, prominent electroencephalographic abnormalities and different types of generalised seizures ensued during the following months and proved refractory to antiepileptic and immunomodulating treatment, which included steroids, immunoglobulin and rituximab. MRI was normal at onset of epilepsy but subsequently showed the development of right hippocampal sclerosis. Results from serial blood and cerebrospinal fluid (CSF) analyses were inconclusive, including lack of patient's CSF and serum reactivity with cultures of dissociated rat hippocampal neurons. This report confirms the existence of a new epilepsy syndrome featuring generalised seizures and epileptic encephalopathy after HHV6-associated PALE in children. Presentation with epileptic spasms, lack of CSF and serum reactivity with cultured rat hippocampal neurons, and rituximab inefficacy are novel features that contribute to delineate the syndrome and argue against an immune-mediated basis of this condition.

Allogeneic mesenchymal stem cell therapy for refractory cytopenias after hematopoietic stem cell transplantation.

BACKGROUND: Posttransplant cytopenias are a severe complication after allogeneic stem cell transplantation (allo-SCT) and their origin is often multifactorial or unknown. They are frequently refractory to standard therapy, which may include steroids and/or immunoglobulins. Mesenchymal stem cells (MSCs) are an attractive therapeutic tool in the allo-SCT setting for the ability to enhance engraftment as well as acting as immunosuppressants for graft-versus-host disease. There is no prior experience in the literature of the use of MSCs to treat cytopenias after allo-SCT. CASE REPORTS: In this work we report for the first time four cases of refractory posttransplant cytopenias (three patients with thrombocytopenia and one with neutropenia) that were treated with MSCs from a third-party donor. MSCs were expanded from 100 mL of marrow obtained under standard good manufacturing practice conditions. Most patients received more than one cell dose, and median dose of MSCs administered was 1 × 10(6) /kg. RESULTS: All patients recovered normal blood counts, with a mean follow-up of 12.5 months. There were no adverse events related to MSC administration. CONCLUSION: MSC therapy may contribute to the recovery of refractory posttransplant peripheral cytopenias in patients undergoing allo-SCT.

Hematopoietic stem cell transplantation for severe congenital neutropenia.

PURPOSE OF REVIEW: Hematopoietic stem cell transplantation (HCT) is the only curative option for patients with severe congenital neutropenia (SCN). Transplant success is dependent on identifying at-risk patients and proceeding to transplant before the development of severe infections or malignant transformation. This review focuses on recent advancements in risk stratification of SCN patients, indications for HCT, and review of published transplant studies. RECENT FINDINGS: Patients with poor neutrophil response despite high doses of granulocyte colony-stimulating factor (G-CSF) are at greatest risk for malignant transformation. Other studies demonstrate elevated risk with mutations in the G-CSF receptor gene and a specific mutation in the ELANE gene. These patients are at high-risk of sepsis or leukemia development and should proceed to transplant with best available donor. As recent published studies demonstrate, HCT is highly successful in patients without leukemia and, therefore, may be considered in selected low-risk patients given the life-long risk of malignancy and infection. SUMMARY: The decision whether to proceed to HCT in healthy patients maintained on G-CSF is difficult. As transplant-related mortality continues to decrease, the role of transplant in SCN is likely to expand to more patients.

Hematopoietic stem cell transplantation in patients with severe congenital neutropenia: an analysis of 18 Japanese cases.

We studied the outcome of allogeneic HSCT in patients with SCN. Between 1989 and 2005, 18 patients with SCN in Japan received HSCT for reasons other than malignant transformation, i.e., because of the lack of or a partial response to treatment with r-HuG-CSF. The median age of the patients at the first HSCT was three and a half yr (range 0.2-16.7 yr). Nine patients received stem cells from an HLA-identical sibling donor and nine from an alternative donor. Twelve and six patients received myeloablative and non-myeloablative conditioning regimens, respectively. Engraftment occurred at the first HSCT in 12 patients, four patients received a second HSCT for graft failure, and two patients died. The cause of death was renal failure and graft failure at the first and second HSCT, respectively. The cumulative incidence of grade II-IV acute GVHD and TRM at the first transplantation was 11% and 5.6%, respectively. Of our patients, 16 are alive and in complete remission, with a median follow-up of six and a half yr. Our results suggest that HSCT is beneficial for patients with SCN refractory to r-HuG-CSF treatment.

Congenital neutropenia.

Congenital neutropenia comprises a variety of genetically heterogeneous phenotypic traits. Molecular elucidation of the underlying genetic defects has yielded important insights into the physiology of neutrophil differentiation and function. Non-syndromic variants of congenital neutropenia are caused by mutations in ELA2, HAX1, GFI1, or WAS. Syndromic variants of congenital neutropenia may be due to mutations in genes controlling glucose metabolism (SLC37A4, G6PC3) or lysosomal function (LYST, RAB27A, ROBLD3/p14, AP3B1, VPS13B). Furthermore, defects in genes encoding ribosomal proteins (SBDS, RMRP) and mitochondrial proteins (AK2, TAZ) are associated with congenital neutropenia syndromes. Despite remarkable progress in the field, many patients with congenital neutropenia cannot yet definitively be classified by genetic terms. This review addresses diagnostic and therapeutic aspects of congenital neutropenia and covers recent molecular and pathophysiological insights of selected congenital neutropenia syndromes.

Immune mediated neutropenia and thrombocytopenia in 3 giant schnauzers.

Neutropenia, thrombocytopenia, and splenomegaly were recognized in 3 adult female giant schnauzers. Antineutrophil antibodies were demonstrated in 2 dogs. Following splenectomy, administration of prednisone and azathioprine resulted in normalization of neutrophil and platelet numbers in all dogs.

Gut overgrowth of vancomycin-resistant enterococci (VRE) results in linezolid-resistant mutation in a child with severe congenital neutropenia: a case report.

A child with severe congenital neutropenia was monitored with microbiologic surveillance cultures for 3 years. He had recurrent bacterial infections and carriage of vancomycin-resistant enterococci. Resistance to linezolid emerged in the colonizing vancomycin-resistant enterococci after each course of this antibiotic when enterococci were present in overgrowth in the gut before treatment. The child was successfully treated for his congenital neutropenia by unrelated donor stem cell transplantation.

A competing risks analysis of bloodstream infection after stem-cell transplantation using subdistribution hazards and cause-specific hazards.

After peripheral blood stem-cell transplantation, patients treated for severe haematologic diseases enter a critical phase (neutropenia). Analysis of bloodstream infection during neutropenia has to account for competing risks. Separate Cox analyses of all cause-specific hazards are the standard technique of choice, but are hard to interpret when the overall effects of covariates on the cumulative incidence function (CIF) are of interest. Proportional subdistribution hazards modelling of the subdistribution of the CIF is establishing itself as an interpretation-friendly alternative. We apply both methods and discuss their relative merits.

Results of a multicenter retrospective study of a combined medical and surgical approach to pulmonary aspergillosis in pediatric neutropenic patients.

BACKGROUND: Invasive aspergillosis (IA) is a serious problem in patients suffering from hematological malignancies. Surgical resection has been reported to improve disease control and patient survival. There are few reports describing the role of surgery in children with pulmonary IA. PROCEDURE: From October 1998 to September 2005, 21 patients fulfilled the inclusion criteria. Demographic and clinical data, as well as type and duration of antifungal therapy; surgery and related complications; time elapsing from surgery to resumption of chemotherapy were collected retrospectively through a specially designed form filled in by each investigator. RESULTS: Eleven males and 10 females, aged between 2 and 17 years underwent one or more surgical lung resections for diagnostic and therapeutic purposes. Surgical complications were reported in three patients. Two patients, who underwent a wedge resection and a lobectomy, respectively, had no fungal lesions detected at surgery. Seventeen of 20 patients with malignancy resumed chemotherapy after a median of 19 days from surgery, range 7-81, and 11 of them underwent hematopoietic stem cell transplantation after a median time of 60 days from surgery, range 19-110. After a median follow-up of 1.7 years, 12 patients are alive while 9 patients have died from progression of their underlying disease. CONCLUSIONS: This study suggests that the combination of medical antifungal therapy and early surgical excision is a feasible and an effective strategy in pediatric patients with IA. In order to avoid unnecessary surgical procedures, we advise checking the response to antifungal therapy by chest-computed tomography immediately before the date of surgery.

Neutrophil elastase and granulocyte colony-stimulating factor receptor mutation analyses and leukemia evolution in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden.

BACKGROUND AND OBJECTIVES: Severe congenital neutropenia (SCN) or Kostmann syndrome was originally reported to be an autosomal recessive disease of neutrophil production causing recurrent, life-threatening infections. Mutations in the neutrophil elastase gene (ELA-2) have previously been identified in patients with sporadic or autosomal dominant SCN. DESIGN AND METHODS: We studied 14 individuals (four patients with SCN and ten close relatives) belonging to the original Kostmann family in northern Sweden for mutations in the ELA-2 and the granulocyte colony-stimulating factor (G-CSF) receptor genes. RESULTS: One patient belonging to the original Kostmann family harbored a novel heterozygous ELA-2 mutation (g.2310T-->A;Leu92His) that was not inherited from her parents. The mutation was identified in DNA isolated from both whole blood and skin fibroblasts, suggesting a sporadic de novo mutation. As a young adult this patient sequentially acquired two mutations in the gene for the G-CSF receptor (G-CSFR) and therefore recently received a hematopoietic stem cell transplant, due to the risk of evolution to leukemia. Moreover, another patient developed acute leukemia and was treated with transplantation. No pathogenic ELA-2 or G-CSFR gene mutations were found in this patient or the other two patients, nor in any healthy relative. INTERPRETATION AND CONCLUSIONS: Our data are the first to document leukemia evolution and G-CSFR gene mutations in the original Kostmann kindred. In addition, our findings indicate that ELA-2 mutations are not the primary cause of SCN in the Swedish Kostmann family.

[Autoimmune neutropenia: which therapy?]. / Neutropenia autoimmune: quale terapia?

We observed a case of primary autoimmune neutropenia in a 10-months-old girl affected by a 4 x 6 cm latero-cervical abscess caused by a Staphylococcus aureus infection. The severity of this finding prompted us to start a G-CSF treatment (5 ug/Kg, 3 times-a-week). Granulocyte Colony Stimulating Factor immediately increased neutrophil count and led to a complete resolution of neutropenia in a 8-months period of time.

Outcomes of Hickman catheter salvage in febrile neutropenic cancer patients with Staphylococcus aureus bacteremia.

OBJECTIVE: To evaluate the outcome of attempted Hickman catheter salvage in neutropenic cancer patients with Staphylococcus aureus bacteremia who were not using antibiotic lock therapy. DESIGN: Retrospective cohort study. SETTING: A university-affiliated, tertiary-care hospital with 1,500 beds for adult patients. PATIENTS: All neutropenic cancer patients who had a Hickman catheter and S. aureus bacteremia (32 episodes in 29 patients) between January 1998 and March 2002. METHODS: Salvage attempts were defined as cases where the Hickman catheter was not removed until we obtained the results of follow-up blood cultures performed 48 to 72 hours after starting treatment with antistaphylococcal antibiotics. Salvage was considered to be successful if the Hickman catheter was still in place 3 months later without recurrent bacteremia or death. RESULTS: Catheter salvage was attempted in 24 (75%) of the 32 episodes. Of the salvage attempts, the success rate was 50% (12 of 24). Salvage attempts were successful in 14% (1 of 7) of the episodes with positive follow-up blood cultures, and in 65% (11 of 17) of those with negative follow-up blood cultures (P = .07). If the analysis is confined to cases with no external signs of catheter infection, salvage attempts were successful in 14% (1 of 7) of the episodes with positive follow-up blood cultures and in 80% (8 of 10) of those with negative follow-up blood cultures (P = .02). CONCLUSION: In neutropenic cancer patients with S. aureus bacteremia, attempted catheter salvage without antibiotic lock therapy was successful in 50% of the cases.

Clinical experience with the use of rhG-CSF in secondary autoimmune neutropenia.

This paper outlines the impact of granulocyte-colony stimulating factor (G-CSF) used as a single modality therapy in 17 patients with secondary autoimmune neutropenia (S-AIN) who had been treated a multiple number of times previously. Fifteen of these patients had demonstrable antineutrophil antibodies and two had cellular S-AIN with haemopoietic inhibitory T-cells present in the marrow. Prior to treatment, all had had problems with infection. All patients responded within 7 days of commencement of treatment. Provided G-CSF neutrophil counts were maintained above 1 x 109/l, no further infections occurred. This was achievable by using G-CSF administered as infrequently as once every 8 days. Eight of the 17 patients remained on G-CSF, although five switched to the glycosylated form because of side-effects. None have developed osteoporosis despite 47.29 patient years of total experience with G-CSF. In conclusion both glycosylated and nonglycosylated G-CSF can be used effectively in treating AIN on a long-term basis.