Infections occurring following IL6 blockade for the management of cytokine release syndrome in onco-hematology patients.

BACKGROUND: Cytokine release syndrome (CRS) is a common adverse event of CAR T cell or bispecific antibody (bsAb) therapy. Anti-IL6/IL6R drugs are used in the management of auto-immune diseases. Some reports showed increased risk of bacterial infection in this context. In onco-hematology, there are few data about the occurrence of infection after administration of an anti-IL6/IL6R for CRS. METHODS: We retrospectively reviewed all consecutive patients treated in Gustave Roussy Cancer Campus between 2018 and 2021, who received anti-IL6/IL6R for CRS due to bsAb in phase I clinical trials or adoptive cellular therapy (ACT). We constituted a control group including all the patients treated in the same clinical trials or standard of care ACT, naïve of anti-IL6/IL6R. RESULTS: Fifty-two patients have been included. In the anti-IL6/IL6R group (n = 26), five patients developed a grade 2 to 5 infection within a month after anti-IL6/IL6R treatment, including two grade 5 infections. In the control group (n = 26), only one patient had a grade 3 infection. The two patients who had grade 5 infections were treated for diffuse large B cell lymphoma (DLBCL), one with bsAb and the other with CAR T cell. Fifty percent (3/6) of DLBCL patients who received an anti-IL6/IL6R presented an infection, one of which was a grade 5. In solid tumor patients treated with bsAb and anti-IL6/IL6R, only one patient (/9, 11%) developed a grade 2 viral infection. CONCLUSION: It seems that the use of anti-IL6/IL6R in CRS secondary to bsAb administration in solid tumors patients does not significantly increase the risk of infection, as opposed to DLBCL patients where secondary infection might be a concern.

Abdominal desmoplastic small round cell tumor without extraperitoneal metastases: Is there a benefit for HIPEC after macroscopically complete cytoreductive surgery?

BACKGROUND: Desmoplastic Small Round Cell Tumor (DSRCT) is a rare disease affecting predominantly children and young adults and for which the benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) after complete cytoreductive surgery (CCRS) remains unknown. METHODS: To identify patients with DSRCT without extraperitoneal metastases (EPM) who underwent CCRS between 1991 and 2015, a retrospective nation-wide survey was conducted by crossing the prospective and retrospective databases of the French Network for Rare Peritoneal Malignancies, French Reference Network in Sarcoma Pathology, French Sarcoma Clinical Network and French Pediatric Cancer Society. RESULTS: Among the 107 patients with DSRCT, 48 had no EPM and underwent CCRS. The median peritoneal cancer index (PCI) was 9 (range: 2-27). Among these 48 patients, 38 (79%) had pre- and/or postoperative chemotherapy and 23 (48%) postoperative whole abdominopelvic radiotherapy (WAP-RT). Intraperitoneal chemotherapy was administered to 11 patients (23%): two received early postoperative intraperitoneal chemotherapy (EPIC) and nine HIPEC. After a median follow-up of 30 months, the median overall survival (OS) of the entire cohort was 42 months. The 2-y and 5-y OS were 72% and 19%. The 2-y and 5-y disease-free survival (DFS) were 30% and 12%. WAP-RT was the only variable associated with longer peritoneal recurrence-free survival and DFS after CCRS. The influence of HIPEC/EPIC on OS and DFS was not statistically conclusive. CONCLUSION: The benefit of HIPEC is still unknown and should be evaluated in a prospective trial. The value of postoperative WAP-RT seems to be confirmed.

Retroperitoneal sarcomas: patterns of care in advanced stages, prognostic factors and focus on main histological subtypes: a multicenter analysis of the French Sarcoma Group.

BACKGROUND: Retroperitoneal sarcomas (RPS) are heterogeneous. Advanced stages include unresectable locoregional (LR) disease, abdominal sarcomatosis and distant metastasis. There is no available report assessing palliative chemotherapy in advanced RPS. This study analyzes management and outcome in a large cohort of patients with advanced RPS, considering main histological subtypes separately. PATIENTS AND METHODS: We conducted a retrospective analysis of adult patients diagnosed with a RPS between 1 January 1988 and 31 December 2008 across 12 centers of the French Sarcoma Group. All cases were centrally reviewed by an expert pathologist. RESULTS: Five-hundred eighty-six patients were included, 299 patients received palliative chemotherapy, with a median of two lines (range 0-8). Fifty patients underwent palliative surgery. Two hundred fifty-five patients (85%) were assessable for response after first line of chemotherapy. Among them, 69 patients (27%) had progressive disease, 145 (57%) had stable disease, 37 (14.5%) had partial response and 4 (1.5%) complete response. Median time from first line of palliative chemotherapy to progression was 5.9 months [4.9-7.3] and median overall survival (OS), 15.8 months [13-18]. In multivariate analysis, prognosis factors independently associated with poor OS were male gender, performance status (PS) >1 and grade >1. There was no difference according to stage of disease. Palliative surgery did not appear to add any survival benefit. CONCLUSION: These results emphasize the scarcity of available options for RPS in the advanced setting and the urgent need to develop new strategies. Patients with good PS should be included in clinical trials and best supportive care should be considered in those with poor PS.

A phase II trial of panobinostat in patients with advanced pretreated soft tissue sarcoma. A study from the French Sarcoma Group.

BACKGROUND: Soft tissue sarcomas (STS) are rare tumours for which treatment options are limited in the advanced setting. Histone deacetylase inhibitors have shown activity in preclinical models of STS. METHODS: We conducted a single-arm, open-label, multicentre phase II study to assess the efficacy and tolerability of panobinostat given orally, 40 mg thrice weekly in patients with advanced pretreated STS. The primary endpoint was the 3-month progression-free rate. RESULTS: Forty-seven STS patients were enrolled between January 2010 and December 2010. Median age was 59 (range 21-79) years, 22 (47%) patients were males. Panobinostat dose was lowered to 20 mg thrice weekly after nine patients were enrolled, based on the recommendation of an independent safety committee. The most common grade 3/4 adverse events were thrombocytopenia, fatigue, lymphopenia and anaemia. Forty-five patients were evaluable for the primary endpoint. Among them, nine patients (20%, 95% CI (10-35%)) were progression-free at 3 months. No partial response was seen, but 17 patients (36%) had stable disease (SD) as their best response. Six patients were progression-free at 6 months. CONCLUSION: Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited, although some patients had prolonged SD.

Intensive induction chemotherapy without methotrexate in adult patients with localized osteosarcoma: results of the Institut Gustave-Roussy phase II trial.

PURPOSE: To improve outcomes in localized osteosarcoma and to reduce the duration of preoperative chemotherapy, we conducted a phase ii trial assessing the efficacy of an intensive protracted regimen without methotrexate (api-ai regimen) in adolescent and adult patients with newly diagnosed disease. PATIENTS AND METHODS: Induction chemotherapy consisted of 2 cycles (4 courses) of doxorubicin 60 mg/m(2) (days 1 and 15), cisplatin 100 mg/m(2) (day 1), and ifosfamide 5 g/m(2) (days 2 and 15). The primary endpoint was good histologic response [ghr (≤5% identifiable tumour cells)]. RESULTS: From March 1993 to March 2000, 32 patients [median age: 21 years (range: 15-49 years)] were administered 126 induction courses. The median time between chemotherapy courses was 15 days (range: 12-32 days). All but 3 patients underwent conservative surgery. Toxicity was mainly hematologic, with febrile neutropenia occurring in 35% of patients and grades 3-4 thrombocytopenia in 35%. The ghr rate was 47%. The median follow-up was 64 months (range: 30-115 months). The 5-year event-free and overall survivals were 65% [95% confidence interval (ci): 48%-79%] and 69% (95% ci: 50%-83%) respectively. Two secondary hematologic malignancies occurred: 1 acute myelocytic leukemia (M5) in a poor responder with concomitant relapse, and 1 myelodysplastic syndrome in a patient achieving ghr. CONCLUSIONS: Despite hematologic toxicity, the results observed with the api-ai regimen compare favourably with those observed during previous induction chemotherapy containing methotrexate in adult patients and the pediatric population treated at our institution. These promising results have to be validated by an ongoing national multicentre trial coordinated by the French Sarcoma Group.

Identification of patients at risk for early death after conventional chemotherapy in solid tumours and lymphomas.

1-5% of cancer patients treated with cytotoxic chemotherapy die within a month after the administration of chemotherapy. Risk factors for these early deaths (ED) are not well known. The purpose of this study was to establish a risk model for ED after chemotherapy applicable to all tumour types. The model was delineated in a series of 1051 cancer patients receiving a first course of chemotherapy in the Department of Medicine of the Centre Léon Bérard (CLB) in 1996 (CLB-1996 cohort), and then validated in a series of patients treated in the same department in 1997 (CLB-1997), in a prospective cohort of patients with aggressive non-Hodgkin's lymphoma (NHL) (CLB-NHL), and in a prospective cohort of patients with metastatic breast cancer (MBC series) receiving first-line chemotherapy. In the CLB-1996 series, 43 patients (4.1%) experienced early. In univariate analysis, age > 60, PS > 1, lymphocyte (ly) count 1 (hazard ratio 3.9 (95% Cl 2.0-7.5)) and d1-ly count

Recurrence of a primary malignant giant cell tumour of bone 14 years after initial surgery.

Giant cell tumour (GCT) is usually considered a benign entity. A small fraction of these tumours become malignant with time, and an extremely rare fraction may be malignant at onset. We report herein an unusual case of primary malignant GCT of the bone that relapsed locally with the same histology 14 years after a simple surgical curettage.

Primary sarcomas of the central nervous system.

The medical files of 14 patients with primary brain and spine sarcomas were retrospectively reviewed. Ten patients had primary brain sarcomas and 4 primary spinal sarcomas. The tumors probably originated in the brain substance or blood vessels, in the meninges or in the inner aspect of the skull. The spinal tumors originated in the nerve roots of the cauda equina and in the spinal substance or blood vessels. The most common type was angiosarcoma. Removal of the brain tumors was performed in 95% of the patients. Radiotherapy was delivered to 6 patients with brain sarcomas and to all patients with primary spinal sarcomas. Metastatic disease to the lung or pleural effusion was evident in 2 patients who underwent total removal of their tumors followed by radiation therapy.

[Primary cutaneous leiomyosarcoma: 32 cases]. / Léiomyosarcomes cutanés primitifs: 32 cas.

BACKGROUND: Superficial leiomyosarcomas are rare tumors, which may be confined to the dermis or extend to subcutaneous tissues. PATIENTS AND METHODS: We report the results of a retrospective study of 32 patients treated for leiomyosarcomas through a twenty-two year period (from 1975 to 1997). RESULTS: Mean age was 45 years, with 50 p. 100 of patients less than 35 years of age. Forty seven percent of the tumors were located on the lower limbs and mean diameter was 2.8 cm. Three clinical types have been isolated: nodule beneath normal epidermis (50 p. 100), purple nodule ulcerated or not (28 p. 100), swelling tumor (22 p. 100). Sixteen percent were intradermal, whereas sixty nine percent involved subcutaneous tissues. With regard to tumor grade, 37 p. 100 of tumors were grade I, 44 p. 100 of tumors were grade II, and 19 p. 100 were grade III. Immunohistochemical staining showed positive reactions for all tumors with anti-vimentin and anti-alpha smooth muscle actin. Main treatment was complete surgical excision. Follow-up informations were available for all patients and 75 p. 100 of them had a follow up period longer than a year. Five patients with leiomyosarcomas involving the subcutis developed local recurrences, and two of them died of the disease. DISCUSSION: Leiomyosarcomas can occur at any age without predominant sex-ratio. Main prognostic factors are tumor size, distal location, depth of tumor invasion and pathological grade. Immunohistological staining with anti-alpha smooth muscle actin is more sensitive and specific than with anti-desmin or anti-HHF 35. Main treatment is surgical excision with wide margins.

Loss of chromosome 13 is the most frequent genomic imbalance in malignant fibrous histiocytomas. A comparative genomic hybridization analysis of a series of 30 cases.

Regional chromosome localizations of DNA copy number imbalances were studied by comparative genomic hybridization in 30 malignant fibrous histiocytomas: 13 primary tumors (2 myxoid, 9 storiform pleomorphic, and 2 with more undifferentiated phenotype) and 17 local recurrences (2 myxoid, 11 storiform pleomorphic, and 4 with more undifferentiated phenotype). Abnormal comparative genomic hybridization (CGH) profiles were observed in 25 tumors (83%). The most frequent gains (ratio > 1.2) corresponded, by order of frequency, to entire Xp, and bands 1q21, 19q13.1, 19p13, 5p13-p14, 1p31, 17p, 18p, 20q, 1p35, 17q23, and 22q12. High levels of gains (ratio > 1.5) were recurrently detected for Xp (10 cases), and in bands 1q21-q22 (8 cases), 3q27 (4 cases), 5p13-p14 (3 cases), 13q32-q34 (3 cases), 15q22-q26 (3 cases), and 17p11-p12 (3 cases). Losses of 13q12-q14 or 13q21 were observed in a large proportion of tumors (17 cases), suggesting that a gene localized in this region could act as a tumor suppressor gene. Losses of 11q23, 2q32, 11p13, 10p, 1q4, 9p2, 16q12, 4q3, 10q25, 3p23, 2p24, and 12p were also recurrently observed. Taken together, these results provide an overview of chromosome imbalances present in MFH, which could be of use for diagnostic purposes. They point to various chromosome regions which may harbor genes important for malignant fibrous histiocytomas (MFH) oncogenesis and progression.

Phase I/II study of paclitaxel plus cisplatin as first-line chemotherapy for advanced non-small cell lung cancer: preliminary results.

From March 1993 to May 1994, 32 chemotherapy-naive patients with advanced non-small cell lung cancer entered a phase I/II study to determine the maximum tolerated dose and the activity of the paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ)/cisplatin combination. The 21 men and 11 women had a median age of 59 years (range, 25 to 72 years) and a median performance status of 1 (range, 0 to 2). Histologic types were adenocarcinoma (13 cases), squamous cell carcinoma (10), and large cell carcinoma (nine). Nine patients had stage IIIB disease and 23 had stage IV disease. The first four dose levels of paclitaxel were 135, 175, 200, and 225 mg/m2 given with a fixed cisplatin dose of 100 mg/m2; at level 5, paclitaxel 225 mg/m2 was again given, and the cisplatin dose was increased to 120 mg/m2. Cycles were given every 3 weeks. Paclitaxel was administered as a 3-hour infusion followed by cisplatin, with standard premedication and hyperhydration. The maximum tolerated dose for the first cycle was not reached. Grades 3 and 4 neutropenia occurred in 24% and 16% of cycles (two cases with fever), respectively. Grades 2 and 3 peripheral axonal neurotoxicity occurred in two and 16 patients, respectively; the neurotoxicity appeared to be dose dependent and cumulative after a median total paclitaxel dose of 1,300 mg/m2. Of the 29 patients evaluable for efficacy, 11 (38%) had a partial response; efficacy was superior at paclitaxel doses of at least 200 mg/m2, with eight (47%) of 17 evaluable patients responding at these levels. In conclusion, at these doses of paclitaxel and cisplatin, the dose-limiting neurologic toxicity is dose dependent and cumulative after a total paclitaxel dose of approximately 1,300 mg/m2. This combination is highly active, with a total objective response rate of 38% and an objective response rate of 47% at paclitaxel doses of 200 mg/m2 or higher. Further evaluation is warranted.

Phase I-II randomized study on prehepatectomy recombinant interleukin-2 immunotherapy in patients with metastatic carcinoma of the colon and rectum.

BACKGROUND: This study, which investigates prehepatectomy immunostimulation with recombinant interleukin-2 (rIL-2), had two goals: to evaluate the tolerance of rIL-2 in association with major hepatectomy, and to verify whether preoperative immunostimulation is effective (neoadjuvant immunotherapy). In animal experiments, the conjunction of shed tumor cells into the circulation during surgery and severe surgery-induced immunodepression can promote the dissemination of the disease. Perioperative immunostimulation by rIL-2 reduces the incidence of metastases in animals. STUDY DESIGN: This prospective phase I-II randomized study included 19 patients with potentially resectable hepatic metastases from adenocarcinomas of the colon and rectum. Two-thirds were randomized to the rIL-2-treated group and one-third to the control group. Preoperative rIL-2 was administered by continuous intravenous infusion over five days and stopped two days before major hepatectomy. The dose of rIL-2 was gradually increased, from 3 x 10(6) IU/m2/day to 12 x 10(6) IU/m2/day. At least three patients were studied at each dose level before increasing the rIL-2 dose. Nineteen patients were eligible for the study (12 in the rIL-2 group and seven in the control group). Toxicity during infusion and intraoperative and postoperative complications were evaluated. Immunological monitoring consisted of repeated determination of lymphocyte counts and phenotypic analysis of lymphocyte subpopulations. Non-major histocompatibility complex-restricted cytotoxicity was assayed against K562 and DAUDI tumor cell lines. RESULTS: Toxicity during rIL-2 infusion was acceptable, similar to that of other phase I studies, and surgery was never delayed. Morbidity and mortality rates after major hepatectomy were not different between the two groups and it appeared that prehepatectomy rIL-2 at a dose of 12 x 10(6) IU/m2/day was well tolerated. During the postoperative course, the mean lymphocyte count was higher in the rIL-2 group (p < 0.05), without qualitative modification of the lymphocyte subsets. Immunological modifications were dose related. High cytotoxicity against K562 and DAUDI cells was constant at the 12 x 10(6) dose level. CONCLUSIONS: Preoperative five-day infusion of rIL-2 before major hepatectomy for colorectal metastases is well tolerated and reverses postoperative immunodepression.

Phase I study of prolonged low-dose subcutaneous recombinant interleukin-2 (IL-2) in patients with advanced cancer.

The present trial was designed to assess the feasibility of subcutaneous low-dose interleukin-2 (IL-2) given for 3 months in an outpatient setting. Twenty patients with advanced cancers (16 metastatic renal cell carcinoma) were included in this phase I study at the following three dose levels: 1, 3, and 6 x 10(6) IU/day (groups of 6, 6, and 8 patients, respectively). IL-2 was administered once daily 6 days a week for 12 weeks. Complete therapy was achieved in 13 of 20 patients, whereas 5 of 20 received at least 5 weeks of IL-2. Minor dose-dependent toxicities were observed including fatigue, transient grade 2-3 fever (11 of 18), and grade 1-2 digestive disorders (6 of 18) without significant biologic modifications but two cases of hypothyroidism. Doses were decreased from 6 to 3 x 10(6) IU/day in one patient (fever and allergic edema). All patients developed transient subcutaneous nodules at the injection sites. These side effects never required hospitalization nor discontinuation of therapy. A dose-dependent and sustained increase in peripheral blood eosinophils and lymphocytes was observed, demonstrating that subcutaneous injections in this low-dose range could have similar biologic effects to those achieved with more intensive schedules. Because it is safe, practicable, and low in cost, we conclude that s.c. low-dose IL-2 could be useful for the design of immunomodulation trials with potential new application fields.