Background
Inhibitory Killer Immunoglobulin-like Receptors (KIR) negatively regulate Natural Killer (NK) cell-mediated killing of HLA class I-expressing tumors. Lack of KIR-HLA class I interactions ...has been associated with antitumor efficacy and increased survival in patients (pts) with AML in CR after haploidentical stem cell transplantation from KIR-mismatched donors(Ruggeri, Blood 2007). IPH2101, a fully human mAb designed to enhance antitumor effects of NK cells by blocking the major inhibitory HLA-C-specific KIR can be safely administered in elderly pts with AML (Vey, Blood 2012). Lirilumab is a 2nd generation anti-KIR mAb currently evaluated in multiple indications and combinations with encouraging preliminary results in combination with nivolumab in pts with squamous cell carcinoma of the head and neck (Leidner, SITC 2016). Here we report the results of a phase 2 trial with lirilumab as single agent in the maintenance therapy of elderly pts with AML in first CR. The objectives of this randomized phase 2 study were to determine if lirilumab could improve leukemia free survival (LFS) and to assess two dose schedules predicted from the phase 1 dose-escalation trial (Vey, ASCO 2015) to be associated with either continuous (CONT) or intermittent (INT) full KIR occupancy.
Methods
EFFIKIR was a randomized double-blind 3-arm placebo controlled trial (NCT01687387). Eligible pts were: aged 60 to 80 yrs, diagnosed with non-APL AML, in CR1 following standard induction (1 to 2 cycles) and consolidation (1 to 2 cycles) and had: ECOG performance status of 0-1, adequate hematologic, liver and renal function. Pts were randomly allocated to receive placebo or lirilumab given at either 0.1 mg/kg q 12 weeks (INT) or 1mg/kg q 4 weeks (CONT) according to a minimization algorithm adjusting for center, primary vs. secondary AML, number of consolidation cycles (1 vs. 2) and cytogenetics. Pts were to receive up to 2 yrs of therapy. The primary endpoint was LFS by independent central review.
Results
Between November 2012 and July 2014, 153 pts were randomized and 152 pts were treated; Pts characteristics are depicted in Table 1. All had received 7+3 induction therapy. Most pts (81%) received 2 cycles of consolidation prior to inclusion. Consolidation chemotherapy consisted of intermediate-dose single agent cytarabine (IDAC) in 53%, and 5+1 in 47% of the pts, according to the recommendations of the ALFA and FILO cooperative groups, respectively. Median time since diagnosis was 4.9 months (mo) 2.8-15.5. Median time between CR or the last consolidation and randomization were 3.3 1.1-5.9 and 1.5 mo 0.3-3.5, respectively. The 3 arms were well balanced apart from a slight trend in favor of the placebo arm for lower age, better ECOG, and use of IDAC as consolidation.
In March 2015, based upon DSMB recommendation, treatment of pts in CONT was discontinued in light of an excess of early relapses. Mean number of treatment cycles administered was 14.7, 8.8 and 13.8 in the INT, CONT and placebo arms respectively and only 6 pts had one cycle postponed in the lirilumab arms. Major reasons for study discontinuation were relapse (63%) and adverse events (AE) (10%).
AE rate was analyzed by taking into account the exposure across pts in each arm. Slightly more AE rate of G1-G2 asthenia, diarrhea and pruritus was observed in CONT arm. Occurrence of hematological disorders did not differ between the 3 arms. 17 pts (11%) experienced second primary malignancies across the 3 arms.
PK/PD results were in line with the model predictions: transient full KIR occupancy lasting 7-28 days for the majority of the INT arm pts and permanent full occupancy in the CONT arm. Lirilumab is not significantly immunogenic and does not induce major modifications in peripheral blood NK and T cell subsets.
With a median follow-up of 36.6 mo 33.4; 38.2, 108 pts experienced relapses and 2 pts died before relapse. LFS results are presented in Table 2.
Conclusions
Single agent lirilumab administered for up to 24 cycles was well tolerated. Lirilumab did not result in a statistically significant improvement of LFS in the challenging setting of maintenance in AML in elderly pts. Immune-pharmacological studies will be presented. Potential hypotheses relevant for AML and lirilumab monotherapy (e.g. dosage/schedule optimization, partial desensitization by continuous KIR blockade leading to an impaired immunosurveillance by NK cells) for the non-significant trends will be discussed.
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Recher:Novartis, Celgene, Jazz, Sunesis, Amgen: Consultancy; Celgene, Sunesis, Amgen, Novartis: Research Funding. Pautas:Pfizer: Honoraria. Rousselot:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; BMS: Research Funding. Castaigne:Pfizer: Honoraria, Research Funding. Jourdan:NOVARTIS: Consultancy, Honoraria. Gardin:Sunesis: Honoraria; AbbVie: Honoraria; Celgene: Honoraria. Delannoy:Innate Pharma: Honoraria. Beautier:Innate Pharma: Employment, Equity Ownership. Paturel:Innate Pharma: Employment, Equity Ownership. Andre:Innate Pharma: Employment, Equity Ownership. Zerbib:Innate Pharma: Employment, Equity Ownership. Dulphy:Celgene: Research Funding; Innate Pharma: Research Funding; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Olive:Imcheck Therapeutics: Other: Cofunder; GSK: Research Funding; Innate Pharma: Research Funding. Pigneux:Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogaran: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Dombret:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travels, Accommodations, Research Funding, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travels, Accommodations, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai/Roche: Consultancy.
Autologous stem cell transplant (ASCT) after high-dose chemotherapy (HDT) increases overall survival when used in relapsed non-Hodgkin lymphoma (NHL) in patients under 65 years old. Limited ...experience is available for older patients. We present a retrospective analysis of 73 consecutive patients aged over 65 years treated for aggressive or relapsed lymphoma by HDT with carmustine, etoposide, cytarabine and melphalan (BEAM) at full dosage followed by ASCT. Patient data were obtained from medical charts from two institutions. Median age was 67 years (65-74). Significant comorbidities were present in 24.7% of patients. The median number of days for grade 4 neutropenia was 9 (5-18). The early treatment-related mortality rate (< 100 days) was 2.7%. The estimated 2-year progression-free survival and overall survival rates were 67.2% and 78.5%, respectively. In conclusion, the full-dose HDT-ASCT regimen is feasible, safe and efficient in selected patients over 65 years old.
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BACKGROUND:
Invasive fungal infections (IFIs) including invasive candidiasis(IC), pulmonary invasive aspergillosis (IA) and other fungal species as mucor mycosis (IM), remain a major clinical ...problem in neutropenic patients receiving intensive chemotherapy for acute myeloid leukemia (AML) due to their high morbidity and mortality.
DESIGN:
We performed a prospective observational study on antifungal (AF) prophylaxis used in a prospective clinical trial of intensive chemotherapy within the Acute Leukemia French Association (ALFA 0702 study, ClinicalTrials.gov Identifier: NCT00932412). A total of 677 AML patients from 34 different centers were included, 45% were males, and median age was 46 years (18-60). Prognosis according to cytogenetics was favorable in 23% of patients, intermediate in 53% and unfavorable in 18%. All patients received daunorubicine and aracytine intensive induction chemotherapy. The trial protocol recommended posaconazole suspension as AF prophylaxis at the dose of 200 mg three times a day from day 4 after induction chemotherapy and until neutrophils recovery. Patients were considered evaluable for this study if they received posaconazole for a minimum duration of 7 days and not later than 10 days after the beginning of the induction chemotherapy. IFI were classified by the local investigators and were reviewed later by an independent expert according to the EORTC classification (possible, probable and proven), scanner images were requested for further investigations when needed.
The objective of this study was to describe the IFI prophylaxis strategies used in the different centers, to calculate the cumulative incidence of IFI according to different strategies, and to evaluate the overall survival and IFI related mortality.
RESULTS:
Among the 677 patients, 383 (57%) received posaconazole as AF prophylaxis for a median duration of 25 days (7-253). Posaconazole was introduced after a median time of 3 days after the beginning of the chemotherapy. We distinguished 4 groups, Group 1: patients without any prophylaxis (n = 203, 30%), Group 2: posaconazole alone (n=241, 36%), Group 3: posaconazole plus other prophylaxis (n=142, 21%), and Group 4: patients receiving other prophylaxis (n= 91, 13%). Overall, there were 72 IA 34 (47%) possible, 38 (53%) probable/proven, 17 IC (all probable/proven) and 7 IM 1 possible, 6 probable/proven. The median delay between posaconazole prophylaxis and IFI occurrence was 22 days (7-50) for IA, 18 days (15-60) for IC and 26 days (13-28) for IM compared to 10 days (3-180), 8 days (3-32) and 21 days (10-32) in case of other prophylaxis. The cumulative incidence of IFI was 2.4% at 10 days (IA: 2.4%, IC : 0%, IM : 0%), 11,2% at 30 days (IA: 8.4%, IC: 2%, IM: 0.7%), 14.2% at 60 days ( IA: 10.6%, IC : 2.5%, IM : 1%), and 14.2% at 100 days (IA:10.6%, IC : 2.5%, IM : 1%). When considering the prophylaxis groups, the cumulative incidence of probable/proven IA at day 60 was 8.37% for Group 1; 4.7% for Groups 2 and 3 combined and 3.3% for Group 4 (Figure 1).
After a median follow-up of 27.5 months (0.4- 73.4), 418 patients are alive and 259 (38.3%) died with 5.4% from IFI. Concerning the overall survival, the results were analyzed according to the presence or absence of IFI and AF prophylaxis (Figure 2) we observed a better survival without any IFI whatever the AF prophylaxis was and in case of AF prophylaxis there was an improvement of 2-years survival after chemotherapy induction. Concerning the global mortality and the IFI related mortality, the results were analyzed according to the prophylactic groups and the timing of prophylaxis, the multivariate analysis showed the negative impact of 2 factors on the mortality at day 100: Unfavorable cytogenetics: HR= 3.34 (1-11.20) p=0.05 and presence of IFI: HR = 5.63 (2.62-12.08) p<0.001.
CONCLUSION:
This study gives 3 important messages: 1) despite the trial protocol recommendations, this study shows that the ECIL recommendations are followed only in 57% of patients with in addition, an early switch in 37% of cases, 2) AF prophylaxis has a significant impact on IFI incidence and when we consider posaconazole alone and IA, this effect is only significant in case of probable/proven IA, 3) a better survival was obtained in patients without IFI whatever the AF prophylaxis was and in case of IFI an improvement of 2 year-survival was observed on AF prophylaxis with an IFI related mortality rate of 5.4%.
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No relevant conflicts of interest to declare.
Hodgkin Lymphoma HL can be cured in the large majority of younger patients, but prognosis for older patients, especially those with advanced-stage disease, has not improved substantially. The ...percentage of HL patients aged over 60 ranges between 15% and 35%. A minority of them is enrolled into clinical trials. HL in the elderly have some specificities: more frequent male sex, B-symptoms, advanced stage, sub diaphragmatic presentation, higher percentage of mixed cellularity, up to 50% of advanced cases associated to EBV. Very old age (>70) and comorbidities are factor of further worsening prognosis. Like in younger patients, ABVD is the most used protocol, but treatment outcome remains much inferior with more frequent, severe and sometimes specific toxicities. Few prospective studies with specific protocols are available. The main data have been published by the Italian Lymphoma Group with the VEPEMB schedule and the German Hodgkin Study Group with the PVAG regimen. Recently, the Scotland and Newcastle Lymphoma Study Group published the SHIELD program associating a prospective phase 2 trial with VEPEMB and a prospective registration of others patients. Patients over 60y with early-stage disease received three cycles plus radiotherapy and had 81% of 3-year overall survival (OS). Those with advanced-stage disease received six cycles, with 3-year OS of 66%. The role of geriatric and comorbidity assessment in the treatment's choice for HL in the elderly is a major challenge. The combination of loss of activities of daily living combined with the age stratification more or less 70y has been shown as a simple and effective survival model. Hopes come from promising new agents like brentuximab-vedotin (BV) a novel antibody-drug conjugate. The use of TEP to adapt the combination of chemotherapy and radiotherapy according to the metabolic response could also be way for prospective studies.
Background: Bing-Neel syndrome (BNS) is a rare complication of Waldenström Macroglobulinemia (WM) defined as the direct involvement of central nervous system (CNS) by neoplastic cells. Because of its ...rarity, few data are currently available in the literature, which is mostly based on case-reports descriptions. The management of these patients is challenging with no consensus about the best treatment strategies to use.
Patients and Methods: We retrospectively analyzed 37 patients out of 15 French centers databases, treated for a BNS between 1995 and 2014.
Results: At the time of BNS diagnosis, the median age was 64 years. In 13 cases (35%), BNS was the first manifestation of WM. In others cases, median time between WM diagnosis and BNS was 96 months (range 2-300).BNS occurrence was correlated with a systemic progression of WM in 30% of cases. For the others patients with no systemic progression of WM, median time between the end of the last treatment of WM and BNS diagnosis was 30 months (range 10-72). The median IgM level was 11.25 g/L (range 0.35-60.8) at the time of BNS onset.
Clinical manifestations: the most frequent symptoms at the time of BNS diagnosis were cognitive impairment (32%), motor or sensory deficits (30% and 16% respectively), pain (16%), cranial nerves involvement (30%), headache (21%), poor performance status (32%) and cauda equina syndrome (18%). The median interval between appearance of neurological symptoms and diagnosis of BNS was 4 months.
Cerebrospinal fluid (CSF) analysis showed a lymphocytic meningitis in 81% of cases with a median of 33 cells/mm3 (range 7-3900), all with monoclonal B-cell population when phenotyping was available (except one case). Protein level was elevated in 94% (1,77 g/L in median, range 0,52-7,23).
Magnetic resonance imaging (MRI) showed abnormalities in 83% (n=29/35) of cases. Meningeal enhancement was present in 52% of cases with conus medullaris infiltration in half of these patients. Cerebral enhancement was present in 45 % of cases and a normal pressure hydrocephalus in 3 cases. In 17% of cases, MRI was normal.
Based on MRI results and CSF analysis, the majority of patients (81%, n=30/37) had an infiltrative form with only 7 patients presenting with a pseudotumoral involvement of brain parenchyma. The diagnosis was made on CSF analysis in the majority of cases (82%, n= 28/34). In four cases the diagnosis required a brain biopsy.
First-line treatment comprised systemic chemotherapy in 89% (n=33/37) of cases. Treatment of CNS involvement was based on high-dose chemotherapy in 17 cases (methotrexate and/or aracytine). Intra-thecal chemotherapy was used in 70% of cases, and rituximab in 58% of cases. Autologous stem-cell transplantation (ASCT) in first-line was performed in 4 cases. 4 patients were treated up-front by whole-brain radiotherapy (in combination with systemic chemotherapy by fludarabine, cyclophosphamide and rituximab in 1 case).
Outcome: 31 patients were assessable for first-line treatment response: overall response rate (ORR) was 68% (n=21/31) including 7 complete remissions; 7 patients had a progressive disease. 9 patients died. Median follow-up of alive patients was 23 months. At 5 years after BNS diagnosis, 79% of the patients were alive.
Conclusion: Up to now, this is the most important retrospective cohort of patients presenting with Bing-Neel syndrome. In more than one third of the cases, BNS was the first manifestation of WM disease. Noteworthy is the late occurrence of some cases, up to 25 years. No correlation was observed between systemic progression of WM and BNS occurrence. BNS should be considered even in the context of a stable WM disease. In order to define the best treatment strategies, collection of additional cases is currently ongoing, and data will be up-dated at time of the meeting.
No relevant conflicts of interest to declare.
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Background:
Azacitidine (AZA) is the reference treatment for higher-risk MDS patients ineligible for intensive chemotherapy (IC) (Lancet Oncol 2009). It also improves overall survival (OS) in ...elderly AML patients with more than 30% marrow blasts ineligible for IC over conventional care (Dombret et al., EHA 2014). To date, no reliable biological marker predictive of AZA response has been reported. In a preliminary retrospective work in 32 patients, we found that quantification of BCL2L10 (an anti-apoptotic member of the Bcl-2 family of proteins) bone marrow mononuclear cells (BMMC) positive cells by flow cytometry (FCM) in HR-MDS patients represents a new potential biomarker for AZA response (Cluzeau et al. Oncotarget 2012). The aim of the present study was to validate those preliminary findings in a larger prospective multicenter cohort, analyzed blindly in 2 different laboratories.
Methods:
FCM was performed on fresh BMMC obtained at different times during AZA treatment: at treatment onset, after 3 or 6 cycles of AZA and at relapse, as previously described (Cluzeau et al., Oncotarget 2012) after several steps of fixation, permeabilization, and consecutive treatment with i) an anti-BCL2L10 antibody (Cell Signaling) and ii) a donkey anti-Rabbit FITC-antibody (Santa Cruz). All assays were performed in two different laboratories with two kinds of cytometers: Paris (Canto Becton Dickinson), Nice (Miltenyi Biotec). MDS and AML patients treated with AZA were prospectively included from 6 centers in this correlative study (clinicaltrial.gov: NCT 01210274). Response was assessed by IWG 2006 criteria for MDS or by Cheson et al (2003) for AML.
Results:
75 MDS or AML patients were included. Median age was 73 years (range 35-91) and M/F was 37/38. 20%, 19%, 36% and 25% patients had RA, RAEB-1, RAEB-2 and AML respectively. IPSS was low, int-1, int-2 and high in 2%, 26%, 35% and 37% respectively. IPSS-R was very low, low, int, high and very high in 3%, 2%, 16%, 20% and 59% respectively. Patients were treated by AZA (75mg/m²/day, 7 days every 4 weeks) for a median number of 6 cycles (range 1-50). Overall response rate (ORR) was 60%, including 28% CR, 17% marrow (m) CR, 7% PR and 8% stable disease (SD) with hematologic improvement (HI). In MDS, the ORR was 57% (33 % CR, 11% mCR, 7% PR and 6% SD with HI). In AML, the ORR was 62% (23% CR, 23% mCR, 8% PR and 8% and SD with HI, based on MDS criteria).
The median % of BCL2L10 positive cells was 9.5% (range 0-95) and no correlation was observed between % of BCL2L10 positive cells and marrow blasts. The median % of BCL2L10 positive cells was 30% (range 0-95) in non-responders and 10% (range 0-56) in responders (p=0.01). The response rate was 7% and 64% in patients with ≥ 50% vs < 50% BCL2L10 positive cells, respectively (p<0.0001). Median OS after FCM analysis performed before or during AZA treatment was 5.8 months in the 11 patients with more than 50% versus 11.7 months in the 64 patients with less than 50% of BCL2L10 positive cells (p=0.03). In 8 patients studied sequentially before, during AZA treatment and at relapse, the % of BCL2L10 positive cells remained stable below 50% and increased above 50% few months before relapse. The best prognostic cut off value for BCL2L10 positive cells was 50%. Flow cytometry results were reproducible in the two laboratories, with two different cytometers.
Conclusion:
We confirmed in this larger prospective multicenter cohort that the percentage of BCL2L10 positive cells, analyzed in 2 different labs, is inversely correlated with response and survival after AZA treatment in both MDS and AML patients, the best prognostic cut-off value for BCL2L10 positive cells being 50%. Our flow cytometry assay is reproducible in different laboratories and can be performed routinely at diagnosis and during AZA treatment. A multivariate analysis including other prognostic factors of response and OS with AZA will be presented.
No relevant conflicts of interest to declare.
Central nervous system involvement by malignant cells is a rare complication of Waldenström macroglobulinemia, and this clinicopathological entity is referred to as the Bing-Neel syndrome. There is ...currently no consensus on the diagnostic criteria, therapeutic approaches and response evaluation for this syndrome. In this series, we retrospectively analyzed 44 French patients with Bing-Neel syndrome. Bing-Neel syndrome was the first manifestation of Waldenström macroglobulinemia in 36% of patients. When Waldenström macroglobulinemia was diagnosed prior to Bing-Neel syndrome, the median time interval between this diagnosis and the onset of Bing-Neel syndrome was 8.9 years. This study highlights the possibility of the occurrence of Bing-Neel syndrome without any other evidence of progression of Waldenström macroglobulinemia. The clinical presentation was heterogeneous without any specific signs or symptoms. Biologically, the median lymphocyte count in the cerebrospinal fluid was 31/mm(3). Magnetic resonance imaging revealed abnormalities in 78% of the cases. The overall response rate after first-line treatment was 70%, and the overall survival rate after the diagnosis of Bing-Neel syndrome was 71% at 5 years. Altogether, these results suggest that Bing-Neel syndrome should be considered in the context of any unexplained neurological symptoms associated with Waldenström macroglobulinemia. The diagnostic approach should be based on cerebrospinal fluid analysis and magnetic resonance imaging of the brain and spinal axis. It still remains difficult to establish treatment recommendations or prognostic factors in the absence of large-scale, prospective, observational studies.
Conjunctival-pigmented tumors are rare, but they are one of the most commonly encountered by the pathologist working with the department of ophthalmology. Nevus and melanoma can be encountered and ...have some histological difference compared to their cutaneous counterpart. Primary acquired melanosis (PAM) is a conjunctival specific entity. This clinical term includes several histological lesions ranging from benignity to melanoma precursor lesion. Histologic examination determines the therapy and the risk of progression to melanoma. We present here a histopathological, clinical and therapeutic synthesis of conjunctival-pigmented lesions, emphasizing the importance of a good understanding between clinicians and pathologists.
Metastasis to unusual sites Olivier, Timothée; Gastaud, Lauris; Maschi, Celia ...
Bulletin du cancer
101, Številka:
2
Journal Article
Recenzirano
Metastases are responsible for the majority of deaths from solid cancers. Metastatic phenomenon, complex, is a multi-step process where interactions between cells and with the microenvironment are ...essential. The organ tropism, that is the propensity of a cancer to metastasize to specific organs, can be explained by several mechanisms that we have described. Apart from the usual metastases, unusual sites can appear with heterogeneous clinical presentations. We describe known to date mechanisms that can explain these unusual metastasis. A summary of these locations has been realized. A rare location should always be considered in front of any atypical symptom.
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