Impact of Perioperative Systemic Chemotherapy on Survival for Patients Who have Diffuse Malignant Peritoneal Mesothelioma Treated with CRS-HIPEC.

BACKGROUND: The available data on the role of perioperative systemic chemotherapy (SC) for diffuse malignant peritoneal mesothelioma (DMPM) patients undergoing (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is heterogeneous and unstandardized. This study aimed to evaluate the impact of SC on the survival outcomes of DMPM patients undergoing CRS-HIPEC and to identify prognostic factors that affect the decision to administer SC. METHODS: Patients who underwent CRS-HIPEC in the National Cancer Institute Milan (1995-2020) were retrospectively analyzed using propensity score-matching of known covariates. The patients were grouped into three groups: group A (neoadjuvant chemotherapy [NACT] and no-SC), group B (no-SC and adjuvant chemotherapy [ACT]), and group C (NACT and ACT). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meir method, and prognostic factors were calculated using the Cox-regression method. RESULTS: After a median follow-up period of 45 months (95% confidence interval [CI], 6.348-83.652 months) for group A, 115 months (95% CI, 44.379-185.621 months) for group B, and 88 months (95% CI, 3.296-172.704 months) for group C, the study analyzed 154 DMPM patients consisting of matched group A (NACT: 60 + no-SC: 52 = 112), group B (ACT: 38 + no-SC: 38 = 76), and group C (NACT: 31 + ACT: 31 = 62). The patients undergoing ACT had better 5-year OS and PFS than the patients undergoing NACT. In the multivariate analysis, ACT was significantly associated with improved OS by 48% (hazard ratio [HR], 0.52; 95% CI, 0.280-0.965, p = 0.038). For PFS, the association of ACT did not reach statistical significance (HR, 0.531; 95% CI, 0.266-1.058; p = 0.072). CONCLUSION: The optimum treatment sequence for DMPM is CRS-HIPEC followed by adjuvant chemotherapy for high-risk patients. Upfront surgery appears preferable to NACT for patients amenable to complete CRS.

Delayed onset of fatal encephalitis in a COVID-19 positive patient.

BACKGROUND: The SARS-nCoV-2019 epidemic has spread since December 2019, quickly gaining worldwide attention. Symptoms consist of fever, cough and breathing difficulties. An increasing number of studies are focusing on neurological manifestations. In addition to the typical ageusia and anosmia, up to 30% of cases can present headache, nausea and vomiting. More serious neurological manifestations, such as encephalitis, thrombosis and cerebral haemorrhage have been reported. CASE DESCRIPTION: We described the case of a 47-year-old man who tested positive for COVID-19 virus in early March 2020. After two negative nasopharyngeal swabs, 41 days after the diagnosis of COVID-19 infection, he developed intense headache with fever, and he was hospitalized. He had subsequent generalized epileptic seizures and intubation was necessary. Contrast Head MRI was negative for brain abscesses or tumours but detected severe vasogenic oedema of the white matter with 10 mm shift of the midline and compression of the right lateral ventricle. Massive cortisone support therapy was ineffective. We diagnosed brain death on day 43 from the infection diagnosis. DISCUSSION: COVID-19 virus can reach the brain, penetrating into the neuronal cells through the interaction between the spike protein S1 and the host ACE-2 receptor, expressed in the capillary endothelium. We believe that in this infection, the pro-inflammatory state induced by the cytokine storm can cause a cerebral cell-mediated response, with subsequent vasodilatation and brain oedema. CONCLUSION: To our knowledge, this is the first description of a delayed onset cell-mediated encephalitis caused by COVID-19 virus after more than 40 days from the diagnosis.

Pathologic complete response after neoadjuvant chemotherapy/(re)chemoradiation for pelvic relapse of rectal cancer undergoing complex pelvic surgery: more frequent than expected?

PURPOSE: To estimate the rate of pathologic complete response (pCR) after neoadjuvant chemotherapy/(re)chemoradiation and its impact on survival in locally recurrent rectal cancer (LRRC) and to identify predictors of pCR or differences between neoadjuvant treatments. METHODS: Among 394 LRRC patients treated at the National Cancer Institute of Milan (Italy), 74 (27.8%) were treated with neoadjuvant chemotherapy with or without (re)chemoradiation before surgery. The pCR rate was estimated, and its impact on 5-year survival was evaluated with the Kaplan-Meier survival method. Univariate analysis was performed to find pre-treatment predictors of pCR. RESULTS: After surgery, in 12 (16.2%) patients, a pCR was observed. All patients who reached pCR had R0 margins after surgery; among the 62 non-pCR patients, R0 margins were obtained in 29 (46.8%) cases only (p = 0.0004). pCR patients showed a significantly higher 5-year overall survival compared to non-pCR cases (33.3% vs. 21.0%, p = 0.045) and a trend toward better 5-year re-local recurrence-free survival. On univariate analysis, no predictor of pCR was found in the present study based on pre-treatment features. CONCLUSION: Since pCR is significantly associated to R0 resection and 5-year overall survival, pCR could be a target for LRRC cure. However, pCR is currently unpredictable based on pre-treatment features.

Impact of Previous Gynecologic Surgical Procedures on Outcomes of Non-Gynecologic Peritoneal Malignancies Mimicking Ovarian Cancer: Less Is More?

BACKGROUND: Non-gynecologic rare peritoneal surface malignancies (PSMs) often are misdiagnosed as disseminated ovarian cancer and initially treated by gynecologic surgeons. This study aimed to assess whether these previous maneuvers (i.e., full surgical staging and/or cytoreductive attempts) affect outcomes after the definitive surgery performed in a tertiary center. METHODS: The study reviewed 298 women affected by non-gynecologic PSM who underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) after previous gynecologic surgery. Prior surgery was categorized as limited surgery (pLS: abdominal exploration with biopsy plus adnexectomy and/or appendectomy) or extended surgery (pES: full surgical staging or cytoreductive attempts including hysterectomy with bilateral salpingo-oophorectomy). RESULTS: Of the 298 patients, 143 had pLS and 153 had pES. Morbidity was similar between the groups (P = 0.143), but the pES group had more severe urinary tract injuries (19 vs. 3; P < 0.001), longer operating time (585.9 vs. 506.7; P = 0.027), and more patients needing more than two anastomoses (41 vs. 26; P = 0.033). Age older than 55 years (odds ratio [OR] 2.42; P = 0.009) and number of anastomoses (OR 3.17; P = 0.002) correlated with severe morbidity; pES correlated with urinary tract grades 3 and 4 injuries (OR 7.9; P = 0.001). The 5-year cumulative incidence of locoregional relapse was significantly higher in the pES group (0.41 vs. 0.27; P = 0.012; median follow-up period, 69 months). The multivariate analysis identified a Peritoneal Carcinomatosis Index (PCI) higher than 20 and pES as independent risk factors. CONCLUSION: For women undergoing CRS±HIPEC for non-gynecologic PSM, the risk for locoregional relapse and severe postsurgical urinary tract complications is increased by pES. Therefore, prior full surgical staging or cytoreductive attempts without definitive gynecologic histology should be avoided. Prophylactic ureteral stenting and stricter oncologic follow-up assessment must be considered in this scenario.

Glargine insulin loaded lipid nanoparticles: Oral delivery of liquid and solid oral dosage forms.

BACKGROUND AND AIMS: The oral administration of insulin has so far been precluded by gastro-intestinal enzyme degradation and poor intestinal absorption. Preliminary evidence for peptide uptake by the gut has recently been obtained, by our research group, following the administration of nanostructured lipid-carrier suspensions loaded with glargine insulin in healthy animal models. METHODS AND RESULTS: In this experimental study, glargine insulin-loaded nanostructured lipid carriers have been converted into solid oral dosage forms (tablets, capsules), that are more suitable for administration in humans and have prolonged shelf-life. The liquid and solid oral dosage forms were tested for glargine insulin uptake and glucose responsivity in healthy and streptozotocin-induced diabetic rats (6 animals in each group). A suitable composition gave redispersible solid oral dosage forms from glargine insulin-loaded carriers, using both spray-drying and freeze-drying. It was observed that the liquid and solid formulations had relevant hypoglycaemic effects in healthy rats, while only capsules were efficacious in diabetic rats; probably because of gut alterations in these animal models. Detected glargine insulinaemia was consistent with a glycaemic profile. CONCLUSION: The formulations under study showed their potential as oral glucose-lowering agents, particularly when used as capsules. However, further study is needed to produce a useful orally-active insulin preparation.

Validation of Thiosemicarbazone Compounds as P-Glycoprotein Inhibitors in Human Primary Brain-Blood Barrier and Glioblastoma Stem Cells.

P-glycoprotein (Pgp) is highly expressed on blood-brain barrier (BBB) and glioblastoma (GB) cells, particularly on cancer stem cells (SC). Pgp recognizes a broad spectrum of substrates, limiting the therapeutic efficacy of several chemotherapeutic drugs in eradicating GB SC. Finding effective and safe inhibitors of Pgp that improve drug delivery across the BBB and target GB SC is open to investigation. We previously identified a series of thiosemicarbazone compounds that inhibit Pgp with an EC50 in the nanomolar range, and herein, we investigate the efficacy of three of them in bypassing Pgp-mediated drug efflux in primary human BBB and GB cells. At 10 nM, the compounds were not cytotoxic for the brain microvascular endothelial hCMEC/D3 cell line, but they markedly enhanced the permeability of the Pgp-substrate doxorubicin through the BBB. Thiosemicarbazone derivatives increased doxorubicin uptake in GB, with greater effects in the Pgp-rich SC clones than in the differentiated clones derived from the same tumor. All compounds increased intratumor doxorubicin accumulation and consequent toxicity in GB growing under competent BBB, producing significant killing of GB SC. The compounds crossed the BBB monolayer. The most stable derivative, 10a, had a half-life in serum of 4.2 h. The coadministration of doxorubicin plus 10a significantly reduced the growth of orthotopic GB-SC xenografts, without eliciting toxic side effects. Our work suggests that the thiosemicarbazone compounds are able to transform doxorubicin, a prototype BBB-impermeable drug, into a BBB-permeable drug. Bypassing Pgp-mediated drug efflux in both BBB and GB SC, thiosemicarbazones might increase the success of chemotherapy in targeting GB SC, which represent the most aggressive and difficult components to eradicate.

Neoadjuvant chemo-radiotherapy for cT3N0 rectal cancer: any benefit over upfront surgery? A propensity score-matched study.

PURPOSE: Benefits of neoadjuvant chemo-radiotherapy (CRT) are well known for locally advanced and/or node-positive rectal cancer, but the best timing for CRT has been less explored for cT3N0 patients. The aim of the present study was to compare the 5-year disease-free survival (DFS) probability between neoadjuvant CRT and upfront surgery in patients affected by cT3N0 rectal cancer. METHODS: A retrospective review of 105 patients affected by cT3N0 rectal cancer, staged by pelvic magnetic resonance imaging and treated at the National Cancer Institute of Milan between 2011 and 2017, was performed: 42 (40.0%) were treated by neoadjuvant CRT and 63 (60.0%) by upfront surgery. Propensity score matching was performed to avoid selection bias, and Cox multivariate regression was used to analyze outcomes. RESULTS: The 5-year DFS probability was 87.5% in neoadjuvant CRT patients vs. 90.0% in upfront surgery cases (Log-rank p = 0.76). The 5-year loco-regional recurrence-free survival probability was respectively 96.8% vs. 96.3% (Log-rank p = 0.954). On multivariate analysis, neoadjuvant CRT had no impact on DFS when compared to upfront surgery (adjusted HR 0.71, 95%CI 0.18-2.70, p = 0.613), but 61.9% of upfront surgery cases were treated by adjuvant chemo-radiation (adjusted HR 0.41, 95%CI 0.11-1.57, p = 0.196). The only independent predictor of improved DFS was age at diagnosis (adjusted HR 0.95, p = 0.017). CONCLUSION: CRT should be considered for cT3N0 patients, but its timing (neoadjuvant vs. adjuvant) seems not to affect the disease-free survival in the present cohort of patients.

Correction to: Clinical Surveillance After Macroscopically Complete Surgery for Low-Grade Appendiceal Mucinous Neoplasms (LAMN) with or Without Limited Peritoneal Spread: Long-Term Results in a Prospective Series.

In the original article Massimo Milione's last name was spelled incorrectly. It is correct as reflected here. The original article has also been updated.

Clinical Surveillance After Macroscopically Complete Surgery for Low-Grade Appendiceal Mucinous Neoplasms (LAMN) with or Without Limited Peritoneal Spread: Long-Term Results in a Prospective Series.

BACKGROUND: Low-grade appendiceal mucinous neoplasm (LAMN) is the most common primary lesion of pseudomyxoma peritonei, a disease whose standard treatment is cytoreduction and hyperthermic intraperitoneal chemotherapy. The optimal management of LAMN is not well defined. This study prospectively assessed a clinical surveillance strategy for LAMN with or without limited peritoneal spread. METHODS: During 2003-2017, the study prospectively enrolled 41 patients treated by macroscopically complete surgery for LAMN with or without limited peritoneal spread (pelvis and right lower quadrant). Follow-up assessment included thoracic-abdomino-pelvic computed tomography scan and serum tumor markers scheduled after surgery, then every 6 months for 5 years, and yearly thereafter. All specimens were reviewed by a dedicated pathologist. RESULTS: Appendectomy and five right colectomies were performed for 36 patients. Nine patients also underwent macroscopically complete cytoreduction of mucinous peritoneal disease, and four patients had hysterectomy plus bilateral salphingo-oophorectomy. Appendiceal rupture was evaluable in 38 of the 41 patients, being present in 21 patients (51.2%). Mucin, cells, or both outside the appendix were observed in 24 patients (58.5%). The median follow-up period was 58 months (range 9.3-162 months). The 5-year recurrence-free survival rate was 95.1%. Only two patients experienced peritoneal recurrences (4.9%), respectively 18 and 22 months after appendectomy. Their primary lesions were LAMNs with and without appendix wall rupture or extra-appendiceal mucin, respectively. No death occurred. CONCLUSION: These findings strongly suggest that radically resected LAMN, even with limited peritoneal spread, carries a low recurrence risk. Furthermore, appendix wall perforation and the presence of mucin, cells, or both outside the appendix were not associated with a higher risk of metachronous peritoneal dissemination. In this setting, clinical and radiologic surveillance is a viable choice.

Early detection of colorectal adenocarcinoma: a clinical decision support tool based on plasma porphyrin accumulation and risk factors.

BACKGROUND: An increase in naturally-occurring porphyrins has been described in the blood of subjects bearing different kinds of tumors, including colorectal, and this is probably related to a systemic alteration of heme metabolism induced by tumor cells. The aim of our study was to develop an artificial neural network (ANN) classifier for early detection of colorectal adenocarcinoma based on plasma porphyrin accumulation and risk factors. METHODS: We measured the endogenous fluorescence of blood plasma in 100 colorectal adenocarcinoma patients and 112 controls using a conventional spectrofluorometer. Height, weight, personal and family medical history, use of alcohol, red meat, vegetables and tobacco were all recorded. An ANN model was built up from demographic data and from the integral of the fluorescence emission peak in the range 610-650 nm. We used the Receiver Operating Characteristic (ROC) curve to assess performance in distinguishing colorectal adenocarcinoma patients and controls. A liquid chromatography-high resolution mass spectrometry (LC-HRMS) analytical method was employed to identify the agents responsible for native fluorescence. RESULTS: The fluorescence analysis indicated that the integral of the fluorescence emission peak in the range 610-650 nm was significantly higher in colorectal adenocarcinoma patients than controls (p < 0.0001) and was weakly correlated with the TNM staging (Spearman's rho = 0.224, p = 0.011). LC-HRMS measurements showed that the agents responsible for the fluorescence emission were mainly protoporphyrin-IX (PpIX) and coproporphyrin-I (CpI). The overall accuracy of our ANN model was 88% (87% sensitivity and 90% specificity) with an area under the ROC curve of 0.83. CONCLUSIONS: These results confirm that tumor cells accumulate a diagnostic level of endogenous porphyrin compounds and suggest that plasma porphyrin concentrations, indirectly measured through fluorescence analysis, may be useful, together with risk factors, as a clinical decision support tool for the early detection of colorectal adenocarcinoma. Our future efforts will be aimed at examining how plasma porphyrin accumulation correlates with survival and response to therapy.

Should a History of Extraperitoneal Disease Be a Contraindication to Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Cancer Peritoneal Metastases?

BACKGROUND: Survival improvements have been reported in selected patients affected by colorectal peritoneal metastases who were undergoing cytoreductive surgery with intraperitoneal hyperthermic chemotherapy. Treatment of peritoneal metastases associated with extraperitoneal disease is still controversial. OBJECTIVE: We assessed the prognostic impact of a history of extraperitoneal disease that was curatively treated either at the same time as or before the onset of peritoneal metastases. DESIGN: We reviewed 2 prospective databases. Peritoneal involvement was scored by Peritoneal Cancer Index. SETTINGS: Our study was conducted in 2 high-volume peritoneal malignancy management institutions. PATIENTS: A total of 148 patients with peritoneal metastases were included. In 27 patients, extraperitoneal disease involving the liver (n = 23), lung (n = 1), both lung and liver (n = 2), or inguinal lymph nodes and liver (n = 1) was curatively treated either simultaneously with peritoneal metastases (n = 22) or before their onset (n = 5). INTERVENTIONS: All of the macroscopic tumors were removed by means of peritonectomy procedures and visceral resections. Microscopic residual disease was treated by mitomycin C/cisplatin-based hyperthermic intraperitoneal chemotherapy. MAIN OUTCOME MEASURES: Overall survival was the primary outcome measure. RESULTS: After a median follow-up of 34.6 months (95% CI, 22.6-65.7 mo), 5-year survival of patients treated for both peritoneal and extraperitoneal disease versus peritoneal metastases alone was 16.5% versus 52.0% (p = 0.019). After multivariate analysis, reduced survival correlated with extraperitoneal disease (p = 0.001), Peritoneal Cancer Index >19 (p = 0.004), and peritoneal residual disease >2.5 mm (p = 0.018). Three prognostic groups were defined, and median survival was not reached for group 1 (Peritoneal Cancer Index ≤19 and no extraperitoneal disease), reached in 27.0 months for group 2 (Peritoneal Cancer Index ≤9 and extraperitoneal disease), and reached in 11.6 months for group 3 (Peritoneal Cancer Index >19 and no extraperitoneal disease or Peritoneal Cancer Index >9 and extraperitoneal disease). LIMITATIONS: The main study limitation is its observational nature. CONCLUSIONS: A history of extraperitoneal disease is associated with poorer prognosis. However, survival benefit may be obtained in selected patients with limited peritoneal involvement. See Video Abstract at http://links.lww.com/DCR/A655.

Lipophilic Prodrug of Floxuridine Loaded into Solid Lipid Nanoparticles: In Vitro Cytotoxicity Studies on Different Human Cancer Cell Lines.

Floxuridine is a very effective drug with high potency in the treatment of various tumors but its utility is limited by its low efficiency of cellular uptake. In order to improve the floxuridine efficiency of cellular uptake, lipophilic prodrug of floxuridine (3',5'-distearoyl-5-fluoro-2'-deoxyuridine) was synthetized and loaded into behenic acid nanoparticles produced by fatty acid coacervation technique. Generally, spherical shaped SLN with mean diameters below 300 nm were obtained. Distearoyl-floxuridine was loaded in SLN with high entrapment efficiency (from 70.8 to 82.8%). In Vitro cytotoxicity studies on different human cancer cell lines (M14, HT-29 and MDA-MB231) were performed in order to test the ability of distearoyl-floxuridine-SLN to inhibit the cancer cell growth. In MTT test distearoyl floxuridine SLN showed a greater efficacy than floxuridine on all cancer cell lines revealing an efficiency about 100 times higher. Also clonogenic assay showed a higher cytotoxicity of distearoyl-floxuridine-SLN compared to floxuridine but the difference between the formulations was only about 10 times. In conclusion, SLN proved to be a promising vehicle to increase the floxuridine efficacy in cancer therapy.

Solid Lipid Nanoparticles Carrying Temozolomide for Melanoma Treatment. Preliminary In Vitro and In Vivo Studies.

AIM: To develop an innovative delivery system for temozolomide (TMZ) in solid lipid nanoparticles (SLN), which has been preliminarily investigated for the treatment of melanoma. MATERIALS AND METHODS: SLN-TMZ was obtained through fatty acid coacervation. Its pharmacological effects were assessed and compared with free TMZ in in vitro and in vivo models of melanoma and glioblastoma. RESULTS: Compared to the standard free TMZ, SLN-TMZ exerted larger effects, when cell proliferation of melanoma cells, and neoangiogeneis were evaluated. SLN-TMZ also inhibited growth and vascularization of B16-F10 melanoma in C57/BL6 mice, without apparent toxic effects. CONCLUSION: SLN could be a promising strategy for the delivery of TMZ, allowing an increased stability of the drug and thereby its employment in the treatment of aggressive malignacies.

Solid lipid nanoparticles carrying lipophilic derivatives of doxorubicin: preparation, characterization, and in vitro cytotoxicity studies.

Doxorubicin (DOXO) lauroyl ester and amide were proposed as lipophilic derivatives and entrapped in SLNs. DOXO derivatives-loaded SLNs were spherical shaped, had 200-300 nm mean diameters and showed 80-94% w/w drug entrapment efficiencies. The effect of DOXO derivatives-loaded SLNs and free DOXO on cell growth was examined by MTT and colony-forming assays on four different tumour cell lines: a pancreatic, CFPAC-1, a lung, A549, and two ovarian, A2780 and A2780res (DOXO-resistant). The results obtained with MTT and colony-forming assay show that although DOXO displayed an inhibition of cell proliferation greater or similar to DOXO lauroyl amide-loaded SLNs on all cell types, the effect induced by DOXO lauroyl ester-loaded SLNs was higher and concentration-dependent, and it was the only one maintained at 10(-5 )mM concentration. Only DOXO lauroyl ester-loaded SLNs were able to induce a 40% inhibitory effect on A2780 res cell line up to 10(-4 )mM concentration.

Bevacizumab loaded solid lipid nanoparticles prepared by the coacervation technique: preliminary in vitro studies.

Glioblastoma, the most common primary brain tumor in adults, has an inauspicious prognosis, given that overcoming the blood-brain barrier is the major obstacle to the pharmacological treatment of brain tumors. As neoangiogenesis plays a key role in glioblastoma growth, the US Food and Drug Administration approved bevacizumab (BVZ), an antivascular endothelial growth factor antibody for the treatment of recurrent glioblastoma in patients whose the initial therapy has failed. In this experimental work, BVZ was entrapped in solid lipid nanoparticles (SLNs) prepared by the fatty-acid coacervation technique, thanks to the formation of a hydrophobic ion pair. BVZ activity, which was evaluated by means of four different in vitro tests on HUVEC cells, increased by 100- to 200-fold when delivered in SLNs. Moreover, SLNs can enhance the permeation of fluorescently labelled BVZ through an hCMEC/D3 cell monolayer-an in vitro model of the blood brain barrier. These results are promising, even if further in vivo studies are required to evaluate the effective potential of BVZ-loaded SLNs in glioblastoma treatment.

Cilostazol prevents foot ulcers in diabetic patients with peripheral vascular disease.

Diabetic patients are at high risk of foot ulcerations that may lead to limb amputations with important socio-economic impact. Peripheral vascular disease may be frequently associated in diabetes mellitus type II with its main symptom, intermittent claudication. Many studies reported the known efficacy of cilostazol in treating vascular claudication. Metalloproteinase-9 (MMP-9) seems to be a biochemical marker implicated in chronic wounds and in particular in diabetic foot ulcers. Cilostazol appears to have a lowering effect on MMP-9 levels and this may suggest a beneficial effect in order to prevent or retard the onset of foot ulcer in diabetic patients. In our study, two groups of diabetic patients with peripheral vascular disease were divided into two groups according to the presence of claudication in order to receive cilostazol. Group A (31 patients without claudication) were not eligible to receive cilostazol whereas Group B (47 patients with claudication) received cilostazol administration for 24 weeks (100 mg orally twice daily). Median follow up was of 16 months. During the follow up, 4·25% of patients of Group B and 35·48% of patients of Group A (P < 0·01) showed onset of foot ulceration. Although further randomised and controlled studies are required cilostazol seems to show beneficial effects for primary prevention of diabetic foot ulcers.