Biological Pathways Associated With the Development of Pulmonary Toxicities in Mesothelioma Patients Treated With Radical Hemithoracic Radiation Therapy: A Preliminary Study

Radical hemithoracic radiotherapy (RHR), after lung-sparing surgery, has recently become a concrete therapeutic option for malignant pleural mesothelioma (MPM), an asbestos-related, highly aggressive tumor with increasing incidence and poor prognosis. Although the toxicity associated to this treatment has been reduced, it is still not negligible and must be considered when treating patients. Genetic factors appear to play a role determining radiotherapy toxicity. The aim of this study is the identification of biological pathways, retrieved through whole exome sequencing (WES), possibly associated to the development of lung adverse effects in MPM patients treated with RHR. The study included individuals with MPM, treated with lung-sparing surgery and chemotherapy, followed by RHR with curative intent, and followed up prospectively for development of pulmonary toxicity. Due to the strong impact of grade 3 pulmonary toxicities on the quality of life, compared with less serious adverse events, for genetic analyses, patients were divided into a none or tolerable pulmonary toxicity (NoSTox) group (grade ≤2) and a severe pulmonary toxicity (STox) group (grade = 3). Variant enrichment analysis allowed us to identify different pathway signatures characterizing NoSTox and Stox patients, allowing to formulate hypotheses on the protection from side effects derived from radiotherapy as well as factors predisposing to a worst response to the treatment. Our findings, being aware of the small number of patients analyzed, could be considered a starting point for the definition of a panel of pathways, possibly helpful in the management of MPM patients.

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Molecular Signatures Associated With the Development of Pulmonary Toxicities in Mesothelioma Patients Treated With Radical Hemithoracic Radiation Therapy

10.21203/rs.3.rs-652408/v1 ◽

2021 ◽

Author(s):

Sergio Crovella ◽

Alberto Relevant ◽

Elena Muraro ◽

Ronald Moura ◽

Lucas Brandão ◽

...

Keyword(s):

Pulmonary Toxicity ◽

Therapeutic Option ◽

Severe Toxicity ◽

Predictive Tool ◽

Curative Intent ◽

Grade 3 ◽

Radiotherapy Toxicity ◽

Definition Of ◽

The Impact ◽

Group Grade

Abstract Background. Radical Hemithoracic Radiotherapy (RHR), after lung-sparing surgery, has recently become a concrete therapeutic option for malignant pleural mesothelioma (MPM), an asbestos-related, highly aggressive tumor with increasing incidence and poor prognosis. Although the toxicity associated to this treatment has been reduced, it is still not negligible and must be considered when treating patients. Genetic factors appear to play a role determining radiotherapy toxicity. The aim of this study is the identification of genetic markers able to predict the relative susceptibility for newly diagnosed MPM patients to develop lung adverse effects if they were to be treated with RHR. Methods. The study included individuals with MPM, treated with lung-sparing surgery and neoadjuvant chemotherapy, followed by RHR with curative intent, and followed up prospectively for development of pulmonary toxicity. Due to the impact of grade 3 pulmonary toxicities on the quality of life, for further genetic analyses patients were divided into a none or tolerable pulmonary toxicity group (Grade ≤2) and a severe pulmonary toxicity group (Grade=3). Whole exome sequencing (WES) was performed to identify genetic variants in biological pathways associated to pulmonary toxicity after radiotherapy.Results. We identified crucial pathways driving the lung response to ionizing radiations in patients affected by mesothelioma: by affecting both the fibrinolytic activity and RNA editing pathways, irradiation could be responsible of the severe toxicity events reported by some patients, who present specific mutations in genes involved in these pathways. Conclusions. Our preliminary results could pave the way for the definition of a panel of predictive genomic variants, capable of supporting the management of MPM patients. By allowing for early identification of patients at high risk for treatment-dependent pulmonary toxicity, this predictive tool could play a major role in the design of new therapeutic combinations.

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Safety of Vinflunine in Patients with Advanced Urothelial Carcinoma Refractory to Platinum-based Chemotherapy: A Prospective Pilot Study

Current Drug Safety ◽

10.2174/1574886313666181001120752 ◽

2019 ◽

Vol 14 (1) ◽

pp. 31-36

Author(s):

Raafat Abdel-Malek ◽

Kyrillus S. Shohdy ◽

Noha Abbas ◽

Mohamed Ismail ◽

Emad Hamada ◽

...

Keyword(s):

Pilot Study ◽

Adverse Events ◽

Urothelial Carcinoma ◽

Transitional Cell ◽

Chemotherapeutic Agents ◽

Serious Adverse Events ◽

Platinum Based Chemotherapy ◽

Number Of Patients ◽

Advanced Urothelial Carcinoma ◽

Grade 3

Background: Several single chemotherapeutic agents have been evaluated as the second-line treatment of advanced urothelial carcinoma. Despite encouraging efficacy outcomes, toxicity has often led to dose modifications or discontinuation. We aimed to assess the safety of vinflunine in a particular population of advanced transitional cell carcinoma of urothelium (TCCU), that were exposed to the previous toxicity of chemotherapy. Methods: This is an open-label, prospective, single-center pilot study to evaluate the response rate and safety profile of vinflunine in patients with advanced TCCU. It was planned to enroll 25 evaluable patients. Eligible patients are those with progressive disease after first-line platinum-based regimen for advanced or metastatic disease. Results: The study was prematurely closed due to two sudden deaths that were judged by the review board as treatment-related. Only ten patients were evaluated and received at least one cycle of vinflunine. All but one were male and seven underwent radical surgery. Eight had a distant metastasis (mainly lung and/or liver). Disease control rate was 40%, four patients had a partial response with median duration of response of 3.5 months. The median overall survival was 3.2 months (95% CI:1.67- 4.73). There were three serious adverse events namely two sudden deaths and one grade 4 thrombocytopenia. Nine grade 3/4 adverse events occurred. The most common all-grade adverse events were fatigue (50%), constipation (40%) and vomiting (40%). Moreover, grade 3 fatigue occurred in 30% of patients. Only one patient, who achieved PR for 5 months, was fit to receive further cytotoxic chemotherapy. Conclusion: The activity of vinflunine in advanced urothelial carcinoma came at the expense of its safety. The use of vinflunine has to be limited to the selected group of patients. However, this is a single institute experience in a limited number of patients.

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A phase I study of AMN107 alone and in combination with imatinib in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.9545 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 9545-9545 ◽

Cited By ~ 6

Author(s):

P. Reichardt ◽

P. G. Casali ◽

J. Blay ◽

M. Von Mehren ◽

P. Schoffski ◽

...

Keyword(s):

Adverse Events ◽

Tyrosine Kinases ◽

Progressive Disease ◽

Serious Adverse Events ◽

Metastatic Gist ◽

18Fdg Pet ◽

Imatinib Resistant ◽

Number Of Patients ◽

Grade 3

9545 Background: Although imatinib induces durable clinical benefit in pts with metastatic GIST, resistance may emerge. AMN107 is a novel agent rationally designed to inhibit the PDGFR, KIT and Bcr-Abl tyrosine kinases. It has been shown to inhibit the proliferation of both imatinib-sensitive and imatinib-resistant GIST cells in vitro. Methods: Cohorts of imatinib-resistant GIST pts with radiological progressive disease (PD) were treated with AMN107 alone (400 mg p.o. bid) or with escalating doses of AMN107 (200 mg qd, 400 mg qd, or 400 mg bid) in combination with imatinib (400 mg p.o. bid). Pharmacokinetic (PK) analyses were performed for both AMN107 and imatinib. Serial tumor assessments included CT and 18FDG-PET scans. Results: As of 30 November 2005, 30 pts (13 women and 17 men), median age 51 yr (range 24–83) received AMN107 alone (n=18) or in combination up to 400 mg qd with imatinib (n=12) for 7 to 98 days (median 49 days). This study continues to accrue. Serious adverse events (SAE’s) reported in four patients deemed related to disease included abdominal pain, peritonitis and anemia. Grade 1/2 drug-related adverse events included hyperbilirubinemia, myalgias, peripheral edema and skin rash. Dose-limiting toxicity (Grade 3 elevated bilirubin) was reported in one pt on AMN107 alone. Efficacy data available for 18 patients show that three patients experienced progressive disease and 15 patients had stable disease, although the duration of follow-up was short. PK results in a limited number of patients showed that the effect of imatinib co-administration on AMN107 PK appears to be minimal, while AMN107 increases imatinib exposure on the average by 50%. Conclusions: AMN107 alone or in combination with imatinib has acceptable tolerability in patients with imatinib-resistant GIST. These initial data suggest there may be relevant activity of AMN107 alone and in combination with imatinib in imatinib-resistant metastatic GIST patients. [Table: see text]

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Definitive chemoradiotherapy for squamous cell carcinoma of the anal canal (SCCAC) with cisplatin and capecitabine: A prospective cohort—preliminary results.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15506 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15506-e15506

Author(s):

Abraão Dornellas ◽

Priscila Muniz Moraes ◽

Carolina Ribeiro Victor ◽

Renata Colombo Bonadio ◽

Maria Ignez Braghiroli ◽

...

Keyword(s):

Prospective Cohort ◽

Complete Response ◽

Disease Recurrence ◽

Study Data ◽

Definitive Chemoradiotherapy ◽

Curative Intent ◽

Underdeveloped Countries ◽

Number Of Patients ◽

Grade 3

e15506 Background: SCCAC is a rare disease. The standard care treatment with curative intent is chemoradiation with mitomycin (MMC) or cisplatin (CDDP) plus infusional 5-FU. Capecitabine may replace 5-FU in MMC doublet. However, MMC and infusional pumps are unavailable in many underdeveloped countries, and there is a lack of prospective data regarding the feasibility and safety of capecitabine combined with CDDP in definitive chemoradiotherapy. Methods: A Prospective cohort study aimed to evaluate the safety and efficacy of treatment with chemoradiation with CDDP60mg/m2 D1 and D29 plus capecitabine 825mg/m2/day BID in a population without MMC and infusional pump access. Eligible pts had T2-4/N0-3/M0 disease and were candidates to full curative CRT. Toxicity evaluation was the primary endpoint, secondary endpoint was response by RECIST v.1.1 at 8 weeks(w) and 6 months(m). The study data were prospectively collected using REDCap. Results: 23 pts were enrolled from Aug/2019 to Oct/2020 with a median follow-up of 7m. Median age 59 years; 76% (n=16) were stage III, 48% (n=11) were ECOG1, and 15% (n=3) were HIV+. All pts received concomitant radiotherapy, MVAT, with a median dose 54Gy in the primary tumor and 45Gy in elective nodes. At 8w, 18 patients were evaluable for response, 56% (n=10) had complete response (CR),39% (n=7) had partial response (PR) and 5% (n=1) progressive disease (PD). At 6 months 11 patients were evaluable for response, 64%(n=7) had CR, 18% (n=2) PR and 18% (n=2) PD. Any grade 3/4 toxicity was present in six pts, four of them radiodermatitis. The most frequent grade toxicities were nausea and radiodermatitis in all pts, anemia 81% (n=17), diarrhea 62% (n=13). Two older pts had definitive suspension of treatment due to toxicity. Three pts had hospitalization because of a skin infection. Six pts had disease recurrence, and two died by the cutoff date. One death related to diarrhea and vomiting toxicity in an older 84-year pt. OS and PFS are not reached. Conclusions: Definitive chemoradiotherapy with cisplatin and capecitabine is feasible; however, the older population is more vulnerable to treatment complications. Further prospective studies with a higher number of patients and longer follow up are required to evaluate SLP and OS.

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Multimodality treatment of colorectal peritoneal metastasis with perioperative systemic chemotherapy, cytoreductive surgery (CRS), and HIPEC: First safety results of the COMBATAC trial.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.lba382 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. LBA382-LBA382 ◽

Cited By ~ 1

Author(s):

Pompiliu Piso ◽

Michael Koller ◽

Dirk Arnold ◽

Hans J. Schlitt ◽

Gabriel Glockzin

Keyword(s):

Adverse Events ◽

Cytoreductive Surgery ◽

Peritoneal Metastasis ◽

Urinary Tract Obstruction ◽

Therapeutic Option ◽

Progression Free Survival ◽

Open Label ◽

Free Survival ◽

Number Of Patients ◽

Grade 3

LBA382 Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provide a promising therapeutic option as part of an interdisciplinary multimodal treatment regimen for selected patients with peritoneal metastasis arising from colorectal cancer. The COMBATAC trial evaluates the feasibility, safety, and efficacy of perioperative cetuximab-containing systemic polychemotherapy, CRS and bidirectional oxaliplatin-based HIPEC. Methods: The COMBATAC trial is a prospective, multicenter, open-label, single-arm, single-stage phase II trial recruiting patients with histologically proven wild-type KRAS colorectal or appendiceal adenocarcinoma and synchronous or metachronous peritoneal metastasis. The planned total number of patients to be recruited is 60. The primary endpoint is progression-free survival (PFS). Results: Preliminary data of the first 16 documented patients show a total number of 51 adverse events. According to CTCAE v4 the distribution of AE was 23 grade 1, 14 grade 2, 13 grade 3, and one grade 4, respectively. Of the 14 grade 3/4 adverse events three were chemotherapy-related, four surgery-related, and seven not directly treatment-related. Most common grade 3/4 complications were infection, thrombosis, and urinary tract obstruction. Conclusions: First data indicate that perioperative systemic polychemotherapy including cetuximab in combination with CRS and bidirectional HIPEC is feasible and might not lead to increased morbidity and toxicity rates. Nevertheless, the COMBATAC trial is still recruiting, and data regarding progression-free survival (PFS) and overall survival (OS) is not yet available. Clinical trial information: NCT01540344.

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Breast carcinoma in young females below the age of 35 years - histopathological and prognostic significance

Journal of Pathology of Nepal ◽

10.3126/jpn.v2i3.6021 ◽

1970 ◽

Vol 2 (3) ◽

pp. 198-202

Author(s):

D Ghartimagar ◽

A Ghosh ◽

OP Talwar ◽

R Narasimhan

Keyword(s):

Breast Carcinoma ◽

Young Women ◽

Early Stage ◽

Prognostic Significance ◽

Age Group ◽

Breast Cancers ◽

Young Females ◽

Younger Age ◽

Grade 3 ◽

Group Grade

Background: Breast cancers rarely occur in young women but are known to have more aggressive behaviors and poorer outcome. We here compare the significance of breast carcinoma in female below the age of 35 to the age over 35 whose specimens were submitted to Manipal teaching hospital, Pokhara. Materials and Methods: All cases of mastectomy with carcinoma from January 2000 to September 2011 were included in the study. Clinical and histopathological datas of all cases were reviewed and collated. Results: A total of 148 mastectomy specimens were received, among which, 23 cases (16%) were below 35 years; whereas 125 cases (84%) were above 35 years of age. In both groups, Stage II was the commonest stage but stage III was much more common in older group (33% versus 9%) and stage I was more common in younger age group (39% versus 27%). Bloom Richardson grading showed that in the older age group, grade 1 is the commonest grade (50%) while in the younger group; grade 3 is the commonest (39%). Patients were followed for a varying period of 6 months to 5 years. Two cases (2% of followed up cases) in older group and 3 cases (15% of followed up cases) in the younger group showed recurrence. Conclusion: Breast carcinoma in the patients younger than 35 years though presented at an early stage has higher grade tumor and poorer outcome. DOI: http://dx.doi.org/10.3126/jpn.v2i3.6021 JPN 2012; 2(3): 198-202

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Management of Patients with Pancreatic Ductal Adenocarcinoma in the Real-Life Setting: Lessons from the French National Hospital Database

Cancers ◽

10.3390/cancers13143515 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3515

Author(s):

Christelle de la Fouchardière ◽

Mustapha Adham ◽

Anne-Marie Marion-Audibert ◽

Antoine Duclos ◽

Claude Darcha ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Real Life ◽

Ductal Adenocarcinoma ◽

University Hospitals ◽

National Hospital ◽

Curative Intent ◽

The Real ◽

Oncological Treatment ◽

Real Life Setting ◽

Number Of Patients

Pancreatic ductal adenocarcinoma (PDAC) remains a major public health challenge, and faces disparities and delays in the diagnosis and access to care. Our purposes were to describe the medical path of PDAC patients in the real-life setting and evaluate the overall survival at 1 year. We used the national hospital discharge summaries database system to analyze the management of patients with newly diagnosed PDAC over the year 2016 in Auvergne-Rhône-Alpes region (AuRA) (France). A total of 1872 patients met inclusion criteria corresponding to an incidence of 22.6 per 100,000 person-year. Within the follow-up period, 353 (18.9%) were operated with a curative intent, 743 (39.7%) underwent chemo- and/or radiotherapy, and 776 (41.4%) did not receive any of these treatments. Less than half of patients were operated in a high-volume center, defined by more than 20 PDAC resections performed annually, mainly university hospitals. The 1-year survival rate was 47% in the overall population. This study highlights that a significant number of patients with PDAC are still operated in low-volume centers or do not receive any specific oncological treatment. A detailed analysis of the medical pathways is necessary in order to identify the medical and territorial determinants and their impact on the patient’s outcome.

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Clinical Outcomes of Digital Cholangioscopy-Guided Procedures for the Diagnosis of Biliary Strictures and Treatment of Difficult Bile Duct Stones: A Single-Center Large Cohort Study

Journal of Clinical Medicine ◽

10.3390/jcm10081638 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1638

Author(s):

Hirohito Minami ◽

Shuntaro Mukai ◽

Atsushi Sofuni ◽

Takayoshi Tsuchiya ◽

Kentaro Ishii ◽

...

Keyword(s):

Bile Duct ◽

Adverse Events ◽

Clinical Outcomes ◽

Significant Risk ◽

Histopathological Analysis ◽

Bile Duct Stones ◽

Serious Adverse Events ◽

Visualization System ◽

Visual Impression ◽

Number Of Patients

Although Spy DS (SpyGlass DS Direct Visualization System) is considered to be useful for the diagnosis of bile duct strictures and the treatment of bile duct stones, there is limited data to date validating its efficacy. We hence retrospectively evaluated the clinical outcomes of the use of Spy DS in a large number of patients. A total of 183 patients who underwent Spy DS-guided procedures for indeterminate bile duct strictures (n = 93) and bile duct stones (n = 90) were analyzed retrospectively. All patients (93/93) with bile duct strictures successfully underwent visual observation, and 95.7% (89/93) of these patients successfully underwent direct biopsy. The sensitivity, specificity, and overall accuracy were 94.7%, 83.3%, and 90.3%, respectively, for visual impression; 80.9%, 100%, and 89.2%, respectively, for histopathological analysis of a direct biopsy; and 96.5%, 91.7%, and 94.6%, respectively, for visual impression combined with biopsy. Successful visualization of the stones was achieved in 98.9% (89/90) of the patients, and complete stone removal was achieved in 92.2% (83/90) of the patients, with an average of 3.3 procedures. The adverse events rate was 17.5% (32/183; cholangitis in 15 patients, fever the following day in 25, pancreatitis in 1, hemorrhage in 1, and gastrointestinal perforation in 1). No administration of antibiotics before the procedure was found to be a statistically significant risk factor for the development of fever after the procedure (p < 0.01). Spy DS-guided procedures are effective for the diagnosis and treatment of bile duct lesions and can be performed with a low risk of serious adverse events.

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Novel free-hand T1 pedicle screw method: Review of 44 consecutive cases

Journal of Neurosciences in Rural Practice ◽

10.4103/0976-3147.139974 ◽

2014 ◽

Vol 05 (04) ◽

pp. 349-354 ◽

Cited By ~ 2

Author(s):

Mark A. Rivkin ◽

Jessica F. Okun ◽

Steven S. Yocom

Keyword(s):

Pedicle Screw ◽

Thoracic Spine ◽

Pedicle Screws ◽

High Rate ◽

Imaging Modalities ◽

Neurological Deficits ◽

Upper Thoracic Spine ◽

Starting Point ◽

Grade 3 ◽

Upper Thoracic

ABSTRACT Summary of Background Data: Multilevel posterior cervical instrumented fusions are becoming more prevalent in current practice. Biomechanical characteristics of the cervicothoracic junction may necessitate extending the construct to upper thoracic segments. However, fixation in upper thoracic spine can be technically demanding owing to transitional anatomy while suboptimal placement facilitates vascular and neurologic complications. Thoracic instrumentation methods include free-hand, fluoroscopic guidance, and CT-based image guidance. However, fluoroscopy of upper thoracic spine is challenging secondary to vertebral geometry and patient positioning, while image-guided systems present substantial financial commitment and are not readily available at most centers. Additionally, imaging modalities increase radiation exposure to the patient and surgeon while potentially lengthening surgical time. Materials and Methods: Retrospective review of 44 consecutive patients undergoing a cervicothoracic fusion by a single surgeon using the novel free-hand T1 pedicle screw technique between June 2009 and November 2012. A starting point medial and cephalad to classic entry as well as new trajectory were utilized. No imaging modalities were employed during screw insertion. Postoperative CT scans were obtained on day 1. Screw accuracy was independently evaluated according to the Heary classification. Results: In total, 87 pedicle screws placed were at T1. Grade 1 placement occurred in 72 (82.8%) screws, Grade 2 in 4 (4.6%) screws and Grade 3 in 9 (10.3%) screws. All Grade 2 and 3 breaches were <2 mm except one Grade 3 screw breaching 2-4 mm laterally. Only two screws (2.3%) were noted to be Grade 4, both breaching medially by less than 2 mm. No new neurological deficits or returns to operating room took place postoperatively. Conclusions: This modification of the traditional starting point and trajectory at T1 is safe and effective. It attenuates additional bone removal or imaging modalities while maintaining a high rate of successful screw placement compared to historical controls.

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Clinical Response in Heavily Pretreated Mycosis Fungoides with Pembrolizumab: A Case Report

Acta Haematologica ◽

10.1159/000518815 ◽

2021 ◽

pp. 1-3

Author(s):

Ginevra Lolli ◽

Beatrice Casadei ◽

Lisa Argnani ◽

Alessandro Pileri ◽

Cinzia Pellegrini ◽

...

Keyword(s):

Mycosis Fungoides ◽

Assessment Tool ◽

Therapeutic Option ◽

Rapid Responses ◽

Duration Of Response ◽

Heavily Pretreated ◽

Stage Ia ◽

Pretreated Patients ◽

Grade 3 ◽

The Moment

Mycosis fungoides (MF) is a disease almost impossible to cure. In the context of heavily pretreated patients, the anti-programmed cell death protein 1 (anti-PD-1) pembrolizumab is a valid therapeutic option. The alteration of the PD-1-PD ligand 1 (PD-L1) axis is often present in MF, and this aspect explains the feasibility of this therapy. We report the case of a 60-year-old woman diagnosed with MF in 2003, Olsen stage IA (T1M0NXBO). Since the moment of the diagnosis, she received 10 lines of therapy, with a short duration of response after each one of them. In April 2020, our patient started pembrolizumab 2 mg/kg every 3 weeks, and she achieved a partial response after the 4th cycle, consistent with the modified severity assessment tool (mSWAT) 1, which she is still maintaining after 10 cycles. No grade ≥3 adverse events were recorded. We conclude that pembrolizumab can induce extremely rapid responses in MF, with very low toxicity.

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