Cytoreductive Surgery Combined With Hyperthermic Intraperitoneal Intraoperative Chemotherapy for Peritoneal Carcinomatosis Arising From Colon Adenocarcinoma

Background: Hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) has been recently proposed to treat peritoneal carcinomatosis arising from colon adenocarcinoma, which is usually regarded as a lethal clinical entity. The purpose of this study was to evaluate the clinical outcome of this combined treatment.Methods: A retrospective study of 46 patients treated for peritoneal carcinomatosis from colon adenocarcinoma was performed. Thirty-four patients were treated with complete cytoreductive surgery immediately followed by intraoperative HIIC with mitomycin C and cisplatin. The clinical outcome of these 34 patients was analyzed; the median follow-up period was 14.5 months.Results: No postoperative deaths were reported. The postoperative morbidity rate was 35%. No severe locoregional or systemic toxicity was observed. The 2-year overall survival was 31%, and the median survival time and the median time to local disease progression were 18 and 13 months, respectively. Survival and local disease control in patients with well- and moderately differentiated colon adenocarcinoma were significantly better than in those with poorly differentiated tumors.Conclusions: Considering the dismal prognosis of this condition, HIIC seems to achieve encouraging results in a selected group of patients affected with resectable peritoneal carcinomatosis arising from colon adenocarcinoma. These findings support the conduction of formal phase III randomized trials.     

Impact of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy on Systemic Toxicity

Introduction The purpose of this study was to analyze the postoperative systemic toxicity and procedure-related mortality (PRM) of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal surface malignancies (PSMs). Patients and methods A total of 242 (84 males/158 females) patients with PSM underwent 247 consecutive procedures. The mean age was 52 years (range 22–79). CRS was performed using peritonectomy procedures. The HIPEC technique through the closed abdomen was conducted with cisplatin (CDDP 25 mg/m²/l of perfusate)+mitomycin C (MMC 3.3 mg/m²/l perfusate) or CDDP (43 mg/l perfusate)+doxorubicin (Dx 15.25 mg/l perfusate) at 42.5°C. These dosages were reduced by 30% when the patient had received systemic chemotherapy before the CRS+HIPEC. Systemic toxicities were graded according to the NCI CTCAE v3 criteria. Results G3-5 systemic toxicity rate was 11.7 % and adverse events were bone marrow suppression, 13; nephrotoxicity, 14; neutropenic infection, 2 and pulmonary toxicity, 1. Independent risk factors for G3-5 systemic toxicity after multivariate analysis were a dose of CDDP for HIPEC of 240 mg or more (OR 2.78, CI 95% 1.20–6.45) and CDDP+Dx schedule for HIPEC (OR 2.36, CI 95% 1.02–5.45). PRM was 1.2%. Conclusions CRS+HIPEC presented acceptable systemic toxicity and PRM rates. Independent risk factors for systemic toxicity were the CDDP+Dx schedule and CDDP dose for HIPEC.     

Peritoneal Mesothelioma Treated by Cytoreductive Surgery and Intraperitoneal Hyperthermic Chemotherapy: Results of a Prospective Study

Background Peritoneal mesothelioma is a rare disease with few therapeutic options. Recently, the combination of cytoreductive surgery with intraperitoneal hyperthermic chemotherapy (HIPEC) has shown promising results. Methods Fifteen patients with peritoneal mesothelioma who were treated by cytoreductive surgery and HIPEC between 1989 and 2004 were identified from a prospective database. HIPEC was performed with cisplatin and mitomycin C for 90 minutes by using the closed-abdomen technique. Results All patients but one (multicystic) had malignant disease of the following pathologic types: 12 epithelial and 2 biphasic. After surgical resection, 11 patients were considered to have a CC-0 or CC-1 resection (macroscopic complete resection or diameter of residual nodules <2.5 mm). No postoperative death occurred, and six postoperative complications were recorded. All but one patient had resolution of ascites. The overall median survival for the 14 patients with malignant mesothelioma was 35.6 months. The median survival was 37.8 months for patients treated with a CC-0 or CC-1 resection, whereas it was 6.5 months for those treated with a CC-2 or CC-3 resection (diameter of residual nodules >2.5 mm; P < .001). In a univariate analysis, the only other significant prognostic factor was the carcinomatosis extent (P = .02). Conclusions A therapeutic strategy combining cytoreductive surgery with HIPEC seems to provide an adequate and efficient locoregional treatment for peritoneal mesothelioma. It is associated with acceptable morbidity when performed by an experienced surgical team. The completeness of cytoreduction is the major determinant of survival.     

胸腔内循环高温灌注化疗对恶性胸腔积液的作用

目的:总结胸腔内循环高温灌注化学治疗对恶性胸腔积液的作用及优点。方法:对40例恶性胸腔积液的患者,在全身麻醉胸腔镜下用体外循环机将43℃恒温液(生理盐水3000mL、顺铂300mg)持续灌注胸腔1h。结果:患者胸闷、气急等症状消失,胸水控制,KPS评分均在70分以上,毒副作用能耐受。胸水中CEA、CYFRA21-1、NSE浓度较治疗前明显下降(P<0.05),镜下观察胸膜癌结节中癌细胞大量坏死,电镜下可见染色质浓缩、凋亡小体形成,最终核碎裂、肿瘤细胞死亡。结论:胸腔内循环高温灌注化疗对恶性胸腔积液有较好的治疗作用,不良反应轻微,微创,对年老体弱患者也适用。     

Morbidity and Mortality Analysis of 200 Treatments With Cytoreductive Surgery and Hyperthermic Intraoperative Intraperitoneal Chemotherapy Using the Coliseum Technique

Background: Peritoneal carcinomatosis from gastrointestinal cancers is a fatal diagnosis without special combined surgical and chemotherapy interventions. Guidelines for cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) by using the Coliseum technique have been developed to treat patients with peritoneal carcinomatosis and other peritoneal surface malignancies. The purpose of this study was to analyze the morbidity and mortality of patients undergoing cytoreductive surgery and HIIC by using mitomycin C.Methods: Data were prospectively recorded on 183 patients who underwent 200 cytoreductive surgeries with HIIC between November 1994 and June 1998. Seventeen of the 183 patients returned for a second-look surgery plus HIIC. All HIIC administrations occurred after cytoreduction and used continuous manual separation of intra-abdominal structures to optimize drug and heat distribution. Origins of the tumors were as follows: appendix (150 patients), colon (20 patients), stomach (7 patients), pancreas (2 patients), small bowel (1 patient), rectum (1 patient), gallbladder (1 patient), and peritoneal papillary serous carcinoma (1 patient). Morbidity was organized into 20 categories that were graded 0 to IV by the National Cancer Institutes Common Toxicity Criteria. In an attempt to identify patient characteristics that may predispose to complications, each morbidity variable was analyzed for an association with the 25 clinical variables recorded.Results: Combined grade III/IV morbidity was 27.0%. Complications observed included the following: peripancreatitis (6.0%), fistula (4.5%), postoperative bleeding (4.5%), and hematological toxicity (4.0%). Morbidity was statistically linked with the following clinical variables: duration of surgery (P < .0001), the number of peritonectomy procedures and resections (P < .0001), and the number of suture lines (P = .0078). No HIIC variables were statistically associated with the presence of grade III or grade IV morbidity. Treatment-related mortality was 1.5%.Conclusions: HIIC may be applied to select patients with peritoneal carcinomatosis from gastrointestinal malignancies with 27.0% major morbidity and 1.5% treatment-related mortality. The frequency of complications was associated with the extent of the surgical procedure and not with variables associated with the delivery of heated intraoperative intraperitoneal chemotherapy. The technique has shown an acceptable frequency of adverse events to be tested in phase III adjuvant trials.Presented at the 52nd Annual Meeting of Society of Surgical Oncology, Orlando, Florida, March 4–7, 1999.     

Appendiceal Neoplasms With Peritoneal Dissemination: Outcomes After Cytoreductive Surgery and Intraperitoneal Hyperthermic Chemotherapy

Background Appendiceal neoplasms frequently present with peritoneal dissemination (PD) and have a clinical course marked by bowel obstruction and subsequent death. Few data have correlated outcome with appendiceal histology after cytoreductive surgery and intraperitoneal hyperthermic chemotherapy (IPHC). We have reviewed our experience with cytoreductive surgery and IPHC for PD from the appendix. Methods A total of 110 cases of PD from proven appendiceal neoplasms treated with IPHC were identified from a prospectively managed database. Tumor samples were classified on pathologic review as disseminated peritoneal adenomucinosis (n = 55), peritoneal mucinous carcinomatosis (PMCA) with intermediate features (n = 18), PMCA (n = 29), or high-grade nonmucinous lesions (n = 8). A retrospective review was performed with long-term survival as the primary outcome measure. Results A total of 116 IPHCs were performed on 110 patients for appendiceal PD between 1993 and 2004. The 1-, 3-, and 5-year survival rates for all cases were 79.9% ± 4.1%, 59.0% ± 5.7%, and 53.4% ± 6.5%, respectively. When stratified by histology, disseminated peritoneal adenomucinosis and intermediate tumors had better 3-year survival rates (77% ± 7% and 81% ± 10%) than PMCA and high-grade nonmucinous lesions (35% ± 10% and 15% ± 14%; P = .0032 for test of differences between groups). Age at presentation (P = .0134), performance status (P < .0001), time between diagnosis and IPHC (P = .0011), resection status (P = .0044), and length of hyperthermic chemoperfusion (P = .0193) were independently associated with survival. Conclusions The data show that long-term survival is anticipated in most patients who are treated with cytoreduction and IPHC for appendiceal PD. The findings presented herein underscore the important prognostic characteristics that predict outcome after IPHC in patients with PD. In all, this work establishes a framework for the consideration of IPHC in future trials for appendiceal PD.     

Cytoreductive Surgery with Intraperitoneal Hyperthermic Chemotherapy for Malignant Peritoneal Mesothelioma: Mitomycin Versus Cisplatin

Background  

Malignant peritoneal mesothelioma (MPM) is a rare, rapidly fatal disease. Because traditional treatments offer little benefit, there has been increasing interest in cytoreductive surgery (CS) with intraperitoneal hyperthermic chemotherapy (IPHC). The most efficacious chemotherapy regimen is not established. Herein we report clinical outcomes of MPM patients treated with CS and IPHC and contrast results using two chemoperfusates: mitomycin and cisplatin.     

Toxicity and Quality of Life after Cytoreductive Surgery Plus Hyperthermic Intraperitoneal Chemotherapy

Background The purpose of our study was to determine the toxicity and quality of life for patients with peritoneal metastases after cytoreductive surgery (CS) plus hyperthermic intraperitoneal chemotherapy (HIPC).Methods From 2001 to 2005, 35 consecutive patients with peritoneal metastases enrolled in a prospective trial approved by the University of Minnesota Institutional Review Board. Their primary cancer sites included the appendix (19 patients), colon (7), mesothelioma (3), stomach (2), small bowel (2), gallbladder (1), and unknown (1). We performed CS in an effort to remove all or nearly all peritoneal tumor nodules. Using a closed technique, we administered hyperthermic mitomycin C into the peritoneal cavity for 90 min. Before treatment and then at 4-month postoperative intervals, we used the functional assessment of cancer therapy-colon subscale (FACT-C) instrument to assess the patients’ quality of life.Results The median hospital stay was 9 days; 12 patients were hospitalized at least 30 days or required readmission within 30 days after treatment. The postoperative mortality rate was 0%; adverse events occurred in 18 (51%) patients. As of December 2005, 20 patients were alive; 14 had died of progressive disease and 1 of an unrelated cause. The median survival time was 21.4 months. Quality of life measurements, including trial outcome index (TOI), FACT-colon, and FACT-general, returned to baseline 4 months after treatment and were significantly improved at 8 and 12 months.Conclusions Despite early toxicity, CS plus HIPC may prolong the overall survival rate of patients with peritoneal metastases and improve quality of life measurements. Source of support: University of Minnesota Cancer Center. This original work was originally presented at the 2006 Gastrointestinal Cancer Symposium.     

胸腔持续灌注热化疗治疗癌性胸水

目的:研究胸腔持续灌注热化疗对癌性胸水的综合疗效及对机体免疫功能的影响.方法:对21例癌性胸水患者置胸管,向胸水中加入化疗药物顺铂200～250 mg/m2,保持胸水温度42～45℃,持续灌注60 min左右..结果:胸水控制有效率95.2%(CR 90.4% PR4.8%),平均胸水消失持续时间12.5个月,有5例肺部肿块缩小,2例发生远处转移死亡.中位存活期13.7个月.热化疗前、后CD 19、CD 25的表达率明显增高.结论:胸腔持续灌注热化疗使癌性胸水缓解率明显提高,使B淋巴细胞免疫功能及T淋巴细胞活化率明显提高.     

Limited Cardiotoxicity after Extensive Thoracic Surgery and Intraoperative Hyperthermic Intrathoracic Chemotherapy with Doxorubicin and Cisplatin

Background Recently, pleural mesothelioma has been treated by cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy with doxorubicin and cisplatin. The well-established cardiotoxicity of doxorubicin and distressing data from an animal study raised concern about its impact on cardiac function. In the present study, early cardiotoxicity of this treatment modality was prospectively analyzed. Patients and Methods In 13 pleural mesothelioma patients, cardiotoxicity was monitored by clinical examination, electrocardiography, Troponin levels, cardiac ultrasonography, and estimation of left ventricular ejection fraction (LVEF) by radionuclide ventriculography before and during the first 6 months after cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy with doxorubicin (25–54 mg/m²) and cisplatin (65–120 mg/m²). Results No clinical cardiac failure or treatment-related death was observed. In two patients transient atrial fibrillation was noted; one associated with pulmonary emboli. Early posttreatment Troponin release was not of predictive value. Ultrasonography did not reveal significant alterations. LVEF decreased significantly (mean 0.07 or 11%, P = .001) during the first 3 months and remained stable thereafter. In univariate analysis, the degree of LVEF reduction was statistically related to maximal intrathoracic doxorubicin concentration (P = .031) and total cisplatin dose (P = .029). Direct exposure of the heart to the drugs as a result of partial pericardectomy was not associated with greater LVEF decrease. On the contrary, partial pericardectomy seemed to be associated with a smaller LVEF decline than when the pericardium remained intact (P = .045). In this small series, no statistically significant correlation between other treatment or pharmacokinetic parameters and LVEF decline was found. Notably, higher doxorubicin plasma concentrations and exposure were not associated with increased LVEF reduction. Conclusions Early cardiotoxicity is limited after this treatment modality using substantial doses of doxorubicin and cisplatin. Hence, this study suggests that intrathoracic chemotherapy with doxorubicin and/or cisplatin may be used for primary and secondary pleural malignancies, even immediately after extensive thoracic surgery, without concern of severe early cardiotoxicity.     

细胞减灭术联合腹腔热灌注化疗治疗腹膜转移癌患者的护理

对21例发生腹膜转移癌患者行细胞减灭术加术中腹腔热灌注化疗,手术时间4～10 h,术后1 d出现低蛋白血症5例,术后5d发热1例,局部/全身性水肿2例,均经对症处理后好转;未出现切口感染、切口裂开、腹盆腔或全身感染,随访8～40个月,7例死亡,7例带瘤生存,7例无瘤生存.提出做好术前心理护理和准备;术后密切病情观察,做好引流管、营养支持和预防并发症的护理,可提高手术效果.     

高温隔离灌注化疗在下肢骨与软组织肉瘤保肢治疗中的价值与限度

为了减低肢体恶性肿瘤治疗中保肢手术的局部复发率，我们从１９９０年开始对５７例下肢ⅡＢ期骨与软组织肉瘤进行术前顺铂或卡铂高温（４１～４３°Ｃ）隔离灌注化疗，同时结合静脉滴注阿霉素。本组进行保肢手术４７例、截肢手术１０例。术前化疗后显示９１％患者局部疼痛完全消失；９５％肿块明显缩小；８９．５％关节活动度改善。术后病理检查肿瘤坏死率９０％～１００％为完全反应者４９例（８６％）；６０％～９０％为部分反应者５例（８．８％）；６０％以下为无反应者３例（５．２％）。术后随访２～５年的２６例保肢者中局部复发２例（７．７％）；术后３年以上随访者２６例，无病存活１６例（６１．５％）。作者认为本法局部效果非常良好，十分利于施行保肢术手，但无助于提高存活率，对截肢者不必应用。     

Cytoreductive Surgery and Intraperitoneal Hyperthermic Chemotherapy With Mitomycin C for Peritoneal Carcinomatosis from Nonappendiceal Colorectal Carcinoma

Background: Cytoreductive surgery (CS) and intraperitoneal hyperthermic chemotherapy (IPHC) are efficacious in patients with disseminated mucinous tumors of the appendix. We reviewed our experience using this approach for nonappendiceal colorectal cancer (NACC).Methods: We performed a retrospective chart review of a prospective database for patients undergoing CS and IPHC with mitomycin C for peritoneal carcinomatosis from colorectal primary lesions between December 1991 and April 2002.Results: There were 77 patients, with a median age of 54 years. Peritoneal carcinomatosis was synchronous and metachronous in 27% and 73% patients, respectively. Seventy-five percent of patients (n = 58) had received chemotherapy prior to IPHC. Complete resection of all gross disease was accomplished in 37 patients (48%). The mean carcinoembryonic antigen level decreased from a preoperative value of 31.2 to a postoperative value of 6.9 (P < .0001). Overall survival (OS) at 1, 3, and 5 years was 56%, 25%, and 17%, respectively. With a median follow-up of 15 months, the median OS was 16 months. Perioperative morbidity and mortality were 30% and 12%, respectively. Hematologic toxicity occurred in 15 patients (19%). Cox regression analysis identified poor performance status (P = .018), bowel obstruction (P = .001), malignant ascites (P = .001), and incomplete resection of gross disease (P = .011) as independent predictors of decreased survival. Patients with complete resection of all gross disease had a 5-year OS of 34%, with a median OS of 28 months.Conclusions: CS and IPHC with mitomycin C can improve outcomes for select patients with peritoneal spread from NACC. One third of patients who undergo complete resection of gross disease have long-term survival.     

The Role of Perioperative Systemic Chemotherapy in Diffuse Malignant Peritoneal Mesothelioma Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

Background

The aim of this study was to evaluate the effects of perioperative systemic chemotherapy (CT) on short-term surgical and long-term oncologic results in diffuse malignant peritoneal mesothelioma (DMPM) patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

Patients and Methods

We retrospectively analyzed data obtained from an institutional prospective database at NCI of Milan. The study group comprised 116 DMPM patients treated with CRS + HIPEC from August 1995 to October 2011. A total of 60 cases underwent preoperative CT (PRECT), 30 underwent postoperative CT (POSTCT), and 26 did not undergo any CT (NOCT). Also, 55 cases used the perioperative combination of platinum and pemetrexed. We tested whether covariates related to clinical, histologic, PRECT, and surgical treatment were correlated with completeness of cytoreduction (CC), postoperative G3-5 morbidity, and progression-free survival and overall survival (OS). Univariate and multivariate analyses were performed.

Results

Factors independently associated with CC were ECOG performance status (PF) of 0, and PCI <20. Factors independently associated with postoperative G3-5 morbidity were ECOG >1, bowel anastomosis, and number of peritonectomy procedures. Preoperative platelet count >400 × 103/mm³, histological subtype (biphasic and sarcomatoid vs epithelial), CC, and G3-5 morbidity were independent prognostic factors. PRECT was not associated with CC or G3-5 morbidity. There was no significant difference in terms of survival between the PRECT, POSTCT, and NOCT groups.

Conclusions

The CC, G3-5, and OS were not influenced by aspects related to perioperative CT. The present data warrants confirmation reconducting the comparative analysis in a larger multi-institutional series preferably using matching control techniques.     

Peritoneal Carcinomatosis in Digestive Cancers: Cytoreductive Surgery Combined with Intraperitoneal Chemohyperthermia. The Experience in Centre Hospitalier et Universitaire Lyon Sud (CHLS)

Intraperitoneal chemohyperthermia (IPCH) with Cytoreductive surgery (CS) has been used in Centre Hospitalier et Universitaire Lyon Sud (CHLS) since 1989. Up to 2005· 420 patients were involved in different phase II studies for peritoneal carcinomatosis (PC) from colorectal· gastric or ovarian origin· as well as for pseudomyxoma peritonei and peritoneal mesothelioma. Encouraging results were achieved in case of optimal PC cytoreduction. The CHLS experience· as well as the Dutch randomized trial and the international registration· underline the advantage of such an aggressive combined therapy for selected patients in experienced multidisciplinary centers.     

The Effects of Adjuvant Experimental Radioimmunotherapy and Hyperthermic Intraperitoneal Chemotherapy on Intestinal and Abdominal Healing after Cytoreductive Surgery for Peritoneal Carcinomatosis in the Rat

Background  Cytoreductive surgery (CS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) results in limited survival benefit and high morbidity and mortality rates in patients with peritoneal carcinomatosis (PC). Radioimmunotherapy (RIT) after CS of experimental PC has been shown to increase survival and compare favorably to HIPEC. The effects of RIT and HIPEC on wound healing after CS need to be determined. Methods  PC was induced by intraperitoneal inoculation of CC-531 colon carcinoma cells in Wag/Rij rats. Animals were subjected to CS and anastomotic construction only or followed by RIT or HIPEC. RIT consisted of 74 MBq ¹⁷⁷lutetium-labeled anti-CC531 antibody MG1. HIPEC was performed by a closed abdominal perfusion technique using mitomycin-C during 60 minutes. Anastomotic and abdominal wall strength measurements were performed 3 and 5 days after surgery. Results  At day 5, bursting pressure in ileum and colon anastomoses in the CS + HIPEC group, but not in the CS + RIT group, was lower (P < .01) than in the CS group. In the CS group, the colonic bursting site was more often outside the true anastomotic area (8 of 12 animals) than in the CS + HIPEC (1 of 12) and CS + RIT (5 of 12) groups. Abdominal wall strength in the CS + HIPEC group was significantly (P < .01) lower, at both measuring points, than that in both the CS group and the CS + RIT group. There was no difference between the latter. Conclusion  As adjuvant to CS, HIPEC showed a decrease in anastomotic and abdominal wall wound strength in a model of PC of CRC, whereas RIT did not.     

Prognostic Analysis of Clinicopathologic Factors in 49 Patients With Diffuse Malignant Peritoneal Mesothelioma Treated With Cytoreductive Surgery and Intraperitoneal Hyperthermic Perfusion

Background Diffuse malignant peritoneal mesothelioma (DMPM) is a subset of peritoneal mesothelioma with a poor clinical outcome. We performed a prognostic analysis in a cohort of DMPM patients treated homogeneously by cytoreductive surgery and intraperitoneal hyperthermic perfusion (IPHP). Methods Forty-nine DMPM patients who underwent 52 consecutive procedures were enrolled onto the study. Cytoreductive surgery was performed according to the peritonectomy technique, and the IPHP was performed with cisplatin plus doxorubicin or cisplatin plus mitomycin C. We assessed the correlation of the clinicopathologic variables (previous surgical score, age, sex, performance status, previous systemic chemotherapy, carcinomatosis extension, completeness of cytoreduction, IPHP drug schedule, mitotic count [MC], nuclear grade, and biological markers [epidermal growth factor receptor, p16, matrix metalloproteinase 2 and matrix metalloproteinase 9]) with overall and progression-free survival. Results The mean age was 52 years (range, 22–74 years). The mean follow-up was 20.3 months (range, 1–89 months). Regarding the biological markers, the rates of immunoreactivity of epidermal growth factor receptor, p16, matrix metalloproteinase 2, and matrix metalloproteinase 9 were 94%, 60%, 100%, and 85%, respectively. The strongest factors influencing overall survival were completeness of cytoreduction and MC, whereas those for progression-free survival were performance status and MC. No biological markers were shown to be of prognostic value. Conclusions Completeness of cytoreduction, performance status, and MC seem to be the best determinants of outcome. These data warrant confirmation by a further prospective formal trial. No biological markers presented a significant correlation with the outcome. The overexpression of epidermal growth factor receptor, matrix metalloproteinase 2, and matrix metalloproteinase 9 and absent or reduced expression of p16 might be related to the underlining tumor kinetics of DMPM and warrant further investigation with other methods.