A modular phage vector platform for targeted photodynamic therapy of Gram-negative bacterial pathogens.

Growing antibiotic resistance has encouraged the revival of phage-inspired antimicrobial approaches. On the other hand, photodynamic therapy (PDT) is considered a very promising research domain for the protection against infectious diseases. Yet, very few efforts have been made to combine the advantages of both approaches in a modular, retargetable platform. Here, we foster the M13 bacteriophage as a multifunctional scaffold, enabling the selective photodynamic killing of bacteria. We took advantage of the well-defined molecular biology of M13 to functionalize its capsid with hundreds of photo-activable Rose Bengal sensitizers and contemporarily target this light-triggerable nanobot to specific bacterial species by phage display of peptide targeting moieties fused to the minor coat protein pIII of the phage. Upon light irradiation of the specimen, the targeted killing of diverse Gram(-) pathogens occurred at subnanomolar concentrations of the phage vector. Our findings contribute to the development of antimicrobials based on targeted and triggerable phage-based nanobiotherapeutics.

Short-Term Outcomes in Patients Undergoing Virtual/Ghost Ileostomy or Defunctioning Ileostomy after Anterior Resection of the Rectum: A Meta-Analysis.

BACKGROUND AND OBJECTIVES: Anterior rectal resection (ARR) represents one of the most frequently performed methods in colorectal surgery, mainly carried out for rectal cancer (RC) treatment. Defunctioning ileostomy (DI) has long been chosen as a method to "protect" colorectal or coloanal anastomosis after ARR. However, DI does not rule out risks of more or less serious complications. A proximal intra-abdominal closed-loop ileostomy, the so-called virtual/ghost ileostomy (VI/GI), could limit the number of DIs and the associated morbidity. MATERIALS AND METHODS: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines. Meta-analysis was performed by use of RevMan [Computer program] Version 5.4. RESULTS: The five included comparative studies (VI/GI or DI) covering an approximately 20-year study period (2008-2021). All included studies were observational ones and originated from European countries. Meta-analysis indicated VI/GI as significantly associated with lower short-term morbidity rates related to VI/GI or DI after primary surgery (RR: 0.21, 95% CI: 0.07-0.64, p = 0.006), fewer dehydration (RR: 0.17, 95% CI: 0.04-0.75, p = 0.02) and ileus episodes after primary surgery (RR: 0.20, 95% CI: 0.05-0.77, p = 0.02), fewer readmissions after primary surgery (RR: 0.17, 95% CI: 0.07-0.43, p = 0.0002) and readmissions after primary surgery plus stoma closure surgery (RR: 0.14, 95% CI: 0.06-0.30, p < 0.00001) than the DI group. On the contrary, no differences were identified in terms of AL after primary surgery, short-term morbidity after primary surgery, major complications (CD ≥ III) after primary surgery and length of hospital stay after primary surgery. Conclusions: Given the significant biases among meta-analyzed studies (small overall sample size and the small number of events analyzed, in particular), our results require careful interpretation. Further randomized, possibly multi-center trials may be of paramount importance in confirming our results.

Local excision of T1 colorectal cancer: good differentiation, absence of lymphovascular invasion, and limited tumor radial infiltration (≤4.25 mm) may allow avoiding radical surgery.

BACKGROUND: Early colorectal cancer (ECC) is defined as T1NXM0 colorectal cancer (CRC). Although a non-negligible number of T1-CRCs presents metastatic lymph-nodes, local excision is increasingly proposed as alternative to radical resection. Several criteria have been suggested to identify low-risk T1-CRC, but recommendations on this topic are still heterogeneous. This study aims to identify criteria associated with N+ T1-CRC, to select patients to undergo (or not) local excision. METHODS: A retrospective analysis of demographic, clinical, and histology criteria of 122 consecutive T1-CRC patients undergoing radical resection at Parma University Hospital between 2000 and 2018 has been performed. RESULTS: Lymph-node metastasis (LNM) was observed in 15/122 patients (12.3%). No LNM was observed among well-differentiated (G1) tumors (0/37), while 10/65 (15.4%) G2 cases as well as 5/20 (25%) G3 patients presented LNM. G1 was associated with absence of LNM (p = 0.013). After excluding G1 patients, the rate of N + T1-CRC was 17.6% (15/85). LNM was observed in 4/8 (50%) patients with lymphovascular invasion (LVI) and in 11/77 (14.2%) without LVI. LVI resulted being associated with LNM (p < 0.042). LNM was reported in 28.3% of cases with a tumor infiltration >4.25 mm (13/46), compared to 5.1% in cases with an infiltration ≤4.25 mm (2/39) (p = 0.012). In Cox regression analysis, the higher hazard ratio (HR) was reported for the LVI + and infiltration >4.25 mm (HR 24.849). CONCLUSIONS: In patients with ECC (pT1NXM0), good differentiation (G1), absence of lymphovascular invasion (LVI-), and tumor radial infiltration ≤4.25 mm may allow performing local resection and avoiding radical surgery.

Gastrectomy with or without Complete Omentectomy for Advanced Gastric Cancer: A Meta-Analysis.

Background and Objectives: Surgery remains the only possible curative treatment for advanced gastric cancer (AGC). Peritoneal metastases are estimated to occur in approximately 55-60% AGC patients. Greater omentum is the most common metastatic area in AGC. At present, omentectomy alone or bursectomy are usually carried out during gastric cancer surgery. We performed a meta-analysis in order to evaluate long-term and short-term outcomes among AGC patients, who have undergone radical gastrectomy with or without complete omentectomy (CO). Materials and Methods: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Meta-analysis was performed by use of RevMan (Computer program) Version 5.4. Results: The eight included studies covered an approximately 20 years long study period (2000-2018). Almost all included studies were retrospective ones and originated from Asian countries. Meta-analysis indicated gastrectomy without CO as significantly associated with longer 3-year (RR: 0.94, 95% CI: 0.90-0.98, p = 0.005) and 5-year overall survivals (OS) (RR: 0.93, 95% CI: 0.88-0.98, p = 0.007). Moreover, we found longer operative time (MD: 24.00, 95% CI: -0.45-48.45, p = 0.05) and higher estimated blood loss (MD: 194.76, 95% CI: 96.40-293.13, p = 0.0001) in CO group. Conclusions: Non-complete omentectomy (NCO) group had a statistically greater rate in 3-year and 5-year OSs than the CO group, while the CO group had significantly longer operative time and higher estimated blood loss than the NCO group. Further randomized, possibly multi-center trials may turn out of paramount importance in confirming our results.

Robotic versus Laparoscopic Gastrectomy for Gastric Cancer: An Updated Systematic Review.

Background and Objectives: Gastrectomy with D2 lymphadenectomy is the standard surgical treatment with curative intent for patients with gastric cancer (GC). Over the last three decades, surgeons have been increasingly adopting laparoscopic surgery for GC, due to its better short-term outcomes. In particular, laparoscopic gastrectomy (LG) has been routinely used for early gastric cancer (EGC) treatment. However, LG suffers from technical limitations and drawbacks, such as a two-dimensional surgical field of view, limited movement of laparoscopic tools, unavoidable physiological tremors and discomfort for operating surgeon. Therefore, robotic surgery has been developed to address such limitations. Materials and Methods: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines in order to investigate the benefits and harms of robotic gastrectomy (RG) compared to the LG. PubMed/MEDLINE, Scopus, Cochrane Library (Cochrane Database of Systematic Re-views, Cochrane Central Register of Controlled Trials-CENTRAL) and Web of Science (Science and Social Science Citation Index) databases were used to search all related literature. Results: The 7 included meta-analyses covered an approximately 20 years-study period (2000-2020). Almost all studies included in the meta-analyses were retrospective ones and originated from Asian countries (China and Korea, in particular). Examined overall population ranged from 3176 to 17,712 patients. If compared to LG, RG showed both operative advantages (operative time, estimated blood loss, number of retrieved lymph nodes) and perioperative ones (time to first flatus, time to restart oral intake, length of hospitalization, overall complications, Clavien-Dindo (CD) ≥ III complications, pancreatic complications), in the absence of clear differences of oncological outcomes. However, costs of robotic approach appear significant. Conclusions: It is impossible to make strong recommendations, due to the statistical weakness of the included studies. Further randomized, possibly multicenter trials are strongly recommended, if we want to have our results confirmed.

The double challenge (preoperative diagnosis and surgical approach) of primary leiomyosarcoma of the sigmoid colon.

BACKGROUND AND AIM: Primary colonic leiomyosarcoma (cLMS) is a rare malignancy of muscularis mucosae or muscularis propria showing highly aggressive behaviour and poor prognosis. To date, making a preoperative diagnosis and performing the most appropriate treatment represent laborious tasks for the clinicians. On the one hand, in fact, cLMS diagnosis is often difficult to achieve preoperatively because of the low specificity of clinical, radiological and bioptical features: for these motives, the diagnosis is usually obtained at postoperative histology/immune-histochemistry. On the other hand, although surgery represents the mainstay of multi-modal treatment, in the current era of minimally invasive surgery the optimal approach to cLMS is debated: in the absence of a standardized and unanimous algorithm, in fact, laparoscopy is usually proposed for small tumors, whereas laparotomy for masses exceeding 4 cm in diameter. Our aim was to elucidate such two aspects by reporting our experience. METHODS: We present the case of a 51-year-old man affected with a 6-cm LMS of the sigmoid colon. RESULTS: Preoperative diagnosis was achieved through a preoperative echo-endoscopic biopsy. The lesion was successfully and safely managed by laparoscopic surgery. CONCLUSIONS: Our case suggests that a preoperative diagnosis of cLMS is possible in an appropriate setting. Moreover, laparoscopy seems to be a safe and successful approach to resect cancers even larger than the common 4 centimetres proposed by the current literature.

Three distinct outcomes in patients with colorectal adenocarcinoma and lymphovascular invasion: the good, the bad, and the ugly.

PURPOSE: In colorectal cancer (CRC), lymphovascular invasion (LVI) is a predictor of poor outcome and its analysis is nowadays recommended. Literature is still extremely heterogeneous, and we hypothesize that, within such a group of patients, there are any further predictors of survival. METHODS: A total of 2652 patients with I-III-stage CRC undergoing resection between 2002 and 2018 were included in a retrospective analysis of demographic, clinical, and histology with the aim of defining the impact of LVI on overall survival (OS) and its relationship with other prognostic factors. RESULTS: Overall, 5-year-OS was 62.6% (77-month-median survival). LVI was found in 558 (21%) specimens and resulted associated with 44.9%-5-year-OS (44 months) vs. 64.1% (104 months) of LVI cases. At multivariate analysis, LVI (p = 0.009), T3-4 (p < 0.001), and N ≠ 0 (p < 0.001) resulted independent predictors of outcome. LVI resulted as being associated with older age (p < 0.013), T3-4 (p < 0.001), lower grading (p < 0.001), N ≠ 0 (p < 0.001), mucinous histology (p < 0.001), budding (p < 0.001), and PNI (p < 0.001). Within the LVI + patients, T3-4 (p = 0.009) and N ≠ 0 (p < 0.001) resulted as independent predictors of shortened OS. In particular, N-status impacted the prognosis of patients with T3-4 tumors (p = 0.020), whereas it did not impact the prognosis of patients with T1-2 tumors (p = 0.393). Three groups (T1-2anyN, T3-4N0, T3-4 N ≠ 0), with distinct outcome (approximately 70%-, 52%-, and 35%-5-year-OS, respectively), were identified. CONCLUSIONS: LVI is associated with more aggressive/more advanced CRC and is confirmed as predictor of poor outcome. By using T- and N-stage, a simple algorithm may easily allow re-assessing the expected survival of patients with LVI + tumors.

The Holocaust Is a Significant and Independent Risk Factor of Late-Onset Cancers: A Systematic Review of the Literature and Original Data on Jewish Israeli, Jewish Non-Israeli and Non-Jewish Non-Israeli Survivors.

BACKGROUND/AIM: Seventy-six years after Auschwitz Liberation, the Holocaust keeps on persecuting its surviving victims. As witnessed by the psychiatric and medical literature in the last decades, in fact, the Holocaust survivors (HS) appear to suffer from several Shoah-related late-onset diseases impacting their survival, such as internal illnesses and post-traumatic stress disorder (PTSD). Cancer represents a further severe pathology which seems to be connected with the Holocaust experience. Our aim was to review the existing knowledge of Holocaust-related cancer in HS in order to assess its real incidence and clinicoprognostic significance. MATERIALS AND METHODS: We systematically reviewed the literature dealing with Israeli Jewish and non-Jewish non-Israeli HS developing cancer. We also reviewed and analyzed the cancer data of noted Jewish HS not resident or having resided in Israel available as public information. RESULTS: We found 16 and 15 studies on Israeli Jews and non-Jewish non-Israeli survivors, respectively. A statistically significant association between the Holocaust and development of late-onset cancer in HS was seen in most studies with cancer adversely impacting the survival. We also selected 330 noted Jewish non-Israeli HS: genocide-related late-onset cancer resulted to be a significant and independent risk factor of poor prognosis (p<0.0001) imparting shorter survival in affected versus non-cancer subjects (57 versus 64 years, respectively, p=0.0001). CONCLUSION: Although 76 years have passed, our review shows how the Holocaust keeps on burdening its survivors. Moreover, we offered the first analysis of Jewish HS not resident or having resided in Israel in terms of genocide-related late-onset diseases focusing on cancer. Further studies on Jewish non-Israeli HS are needed in order to corroborate our findings on late-onset cancer occurring in this targeted population.

Laparoscopic Partial Splenectomy: A Critical Appraisal of an Emerging Technique. A Review of the First 457 Published Cases.

Background: Laparoscopic partial splenectomy (LPS) may allow avoiding total splenectomy (TS) complications and maximizing the advantages of mini-invasive approach. The objective of this review is to assess feasibility and safety of LPS, to compare this approach with alternative options. Materials and Methods: A literature review of articles reporting LPS is performed. Several parameters, including age, indication, surgical technique, devices used for splenic section/hemostasis, adverse outcomes, including morbidity/mortality, conversions to open surgery, conversions to TS, operative time (OT), and hospital stay (HS), are analyzed. Articles comparing LPS' results with those of open partial splenectomy and laparoscopic TS are also analyzed. Results: Fifty-nine articles reporting 457 LPS were included. Patients' characteristics varied widely, concerning age and indications, including hematological disease (hereditary spherocytosis, drepanocytosis), splenic focal masses, and trauma. Several technical options are reported. Mean OT and HS are 128 ± 43.7 minutes and 4.9 ± 3.8 days, respectively. No mortality and 5.7% morbidity are reported. Conversion rates to open surgery and to TS are 3.9% and 3.7%, respectively. Conclusions: In conclusion LPS is feasible and safe, with no mortality, low morbidity, and low conversion rates to laparotomy and to TS. LPS may be accomplished by various techniques and tools. Major complications are sporadically reported, thus potential risks should not be underestimated.

Inguinal GIST: A Systematic Literature Review of Primary and Metastatic Cases.

BACKGROUND/AIM: Gastrointestinal stromal tumor (GIST) has a wide spectrum of clinical manifestations. Involvement of the groin region can cause interesting presentations but, as of 2020, has rarely been investigated. Our aim was to assess the clinicopathological and prognostic features of GIST appearing in this specific part of the body. MATERIALS AND METHODS: We investigated the world literature dealing with primary or metastatic GIST appearing in the inguinal region (IGIST). A case of metastatic IGIST from our clinical records was also included. RESULTS: We found only six cases of primary and nine of metastatic IGIST. All were of male gender, and most aged 60 years or more (10 cases). Inguinal hernia (11 cases) was the patient type most frequently affected. The association between metastatic IGIST and inguinal lymphadenopathy was statistically significant (p=0.049). CONCLUSION: IGIST is a rare entity with particular clinical manifestations. Inguinal hernia and inguinal lymphadenopathy should be carefully investigated in patients with a history of GIST.

Retrospective survival analysis of stage II-III rectal cancer: tumour regression grade, grading and lymphovascular invasion are the only predictors.

BACKGROUND: Tumour regression grade is gaining interest as a prognostic factor of patients undergoing neoadjuvant chemoradiotherapy and surgery for locally advanced rectal cancer. METHODS: A series of 68 consecutive patients with locally advanced rectal cancer treated by neoadjuvant chemoradiotherapy and surgery between 2010 and 2016 was retrospectively studied. The impact on disease-free survival (DFS) and overall survival (OS) of several criteria was analysed. Univariate analysis was performed through Kaplan-Meier statistics. Multivariate analysis was performed through Cox regression model. Using criteria found to be related to long-term outcomes, a predictive model of patient's OS was calculated. RESULTS: Poor tumour regression grade - TRG3 (P = 0.010), poor grading - G3 (P = 0.001) and lymphovascular invasion (LVI; P = 0.030) were associated with short OS at univariate analysis. OS was associated with TRG3 and G3 at multivariate analysis (P = 0.016 and P = 0.027, respectively). DFS was associated with LVI (P = 0.001), G3 tumours (P = 0.046) and TRG3 (P = 0.045) at univariate analysis. At multivariate analysis, only LVI was associated with DFS (P = 0.041). A score, pondering the impact of three parameters (2 points for TRG3, 2 for G3 and 1 for LVI), was created and resulted to predict patient OS (P = 0.008), ranging from 94.5 months (score = 0-1) to 32 months (score = 3-5). CONCLUSION: TRG3 and G3 were associated with poor OS, and LVI was the most significant predictor of DFS. An easy-to-use score may allow for a more accurate prediction of OS.