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Purpose: Targeted axillary dissection (TAD) for the axillary staging of clinically node-positive (cN +) breast cancer patients converting to clinically node negative post neoadjuvant chemotherapy (NAC), has gained popularity due to its minimal false negative rate and low arm morbidity. The aim of this study is to shed more light on the variation in the clinical practice globally in terms of indications and perceived limitations of TAD. Methods: A panel of expert breast surgeons constructed a structured questionnaire comprising of 18 questions and asked surgeons worldwide for their opinions and routine practice on TAD. The questionnaire was electronically distributed and answers were collected between May 1st and August 1st 2022. Results: Responses included 137 entries from 36 countries. Of them, 73.7% consider TAD for cN + patients planned to receive NAC. Among them, the greatest number of respondents (45%) perform the procedure for tumours up to T3, whereas 27% regardless of T-stage. The majority (42%) perform TAD on patients with 1–3 positive nodes and only 30% consider TAD when matted nodes are present. HER2 positive and Triple Negative subtypes are more likely to undergo TAD than Luminal A and B (86%, 79.1%, 39.5%, and 62.8%, respectively). Maximum acceptable lymph node burden is median 3 nodes for any subtype with a tendency to accept more positive nodes for Triple Negative. Conclusion: This study demonstrates the differences in current practice regarding TAD as well as the fact that the biology of the tumour heavily affects the method of axillary staging. [ABSTRACT FROM AUTHOR]

Constipation, obstructed defecation, and fecal incontinence are frequent complaints in multiple sclerosis. The literature on the pathophysiological mechanisms underlying these disorders is scant. Using anorectal manometry, we compared the anorectal function in patients with and without multiple sclerosis.

An abstract of the research paper "Wound defects in the elderly: our experience," presented at the 23rd annual meeting of the Italian Society of Geriatric Surgery, held in Lecce, Italy during December 2-4, 2010, is presented.

An abstract of the research paper "Elective and emergency laparoscopic cholecystectomy in the elderly: early or delayed approach," presented at the 23rd annual meeting of the Italian Society of Geriatric Surgery, held in Lecce, Italy during December 2-4, 2010, is presented.

Src family kinases (SFKs) are evolutionarily conserved proteins acting downstream of receptors and regulating cellular processes including proliferation, adhesion, and migration. Elevated SFK expression and activity correlate with progression of a variety of cancers. Here, using the Drosophila melanogaster border cells as a model, we report that localized activation of a Src kinase promotes an unusual behavior: engulfment of one cell by another. By modulating Src expression and activity in the border cell cluster, we found that increased Src kinase activity, either by mutation or loss of a negative regulator, is sufficient to drive one cell to engulf another living cell. We elucidate a molecular mechanism that requires integrins, the kinases SHARK and FAK, and Rho family GTPases, but not the engulfment receptor Draper. We propose that cell cannibalism is a result of aberrant phagocytosis, where cells with dysregulated Src activity fail to differentiate between living and dead or self versus non-self, thus driving this malignant behavior., (© 2023 Torres et al.)

Proteotoxic stress drives numerous degenerative diseases. In response to misfolded proteins, cells adapt by activating the unfolded protein response (UPR), including endoplasmic reticulum-associated protein degradation (ERAD). However persistent stress triggers apoptosis. Enhancing ERAD is a promising therapeutic approach for protein misfolding diseases. From plants to humans, loss of the Zn 2+ transporter ZIP7 causes ER stress, however the mechanism is unknown. Here we show that ZIP7 enhances ERAD and that cytosolic Zn 2+ is limiting for deubiquitination of client proteins by the Rpn11 Zn 2+ metalloproteinase as they enter the proteasome in Drosophila and human cells. ZIP7 overexpression rescues defective vision caused by misfolded rhodopsin in Drosophila. Thus ZIP7 overexpression may prevent diseases caused by proteotoxic stress, and existing ZIP inhibitors may be effective against proteasome-dependent cancers., Competing Interests: Competing interests: The authors have organizational affiliations, stock ownership, and research support to disclose. D.J.M. is a member of the Board of Scientific Counselors for the National Cancer Institute; has 5% equity in Mór Bio, a subsidiary of Inceptor Bio, which is a cellular immunotherapy company; and has 20% equity in Anastasis Biotechnology Corporation. The authors have patent filings to disclose: Modulation of Anastasis, UCSB Case Number 2020–062-2, US Patent found in United States Provisional Patent Application Number 63/029,380, entitled “Methods of Modulating Anastasis,” filed May 22, 2020; Detection of Anastasis, UCSB Case Number 2020–62-1, found in US Patent United States Provisional Patent Application Number 63/029,358, entitled “Methods of Detecting Anastasis,” filed May 22, 2020; US provisional application no. 63/014,049 entitled “Stimulating US Patent Phagocytosis of Cancer Cells by Activating Rac in Macrophages” filed on April 23, 2020, with docket number P2495-USP; and US provisional application no. 63/126,379 entitled “Genetically US Patent Engineered Phagocytes and Related Compositions Methods and Systems” filed on December 16, 2020, with docket number P2495-USP2. D.J.M. has received research funds in the form of unrestricted gifts from the Anastasis Biotechnology Corporation and from Inceptor Bio.

Executioner-caspase activation has been considered a point-of-no-return in apoptosis. However, numerous studies report survival from caspase activation after treatment with drugs or radiation. An open question is whether cells can recover from direct caspase activation without pro-survival stress responses induced by drugs. To address this question, we engineered a HeLa cell line to express caspase-3 inducibly and combined it with a quantitative caspase activity reporter. While high caspase activity levels killed all cells and very low levels allowed all cells to live, doses of caspase activity sufficient to kill 15 to 30% of cells nevertheless allowed 70 to 85% to survive. At these doses, neither the rate, nor the peak level, nor the total amount of caspase activity could accurately predict cell death versus survival. Thus, cells can survive direct executioner-caspase activation, and variations in cellular state modify the outcome of potentially lethal caspase activity. Such heterogeneities may underlie incomplete tumor cell killing in response to apoptosis-inducing cancer treatments.

Diploid and stable karyotypes are associated with health and fitness in animals. By contrast, whole-genome duplications-doublings of the entire complement of chromosomes-are linked to genetic instability and frequently found in human cancers 1-3 . It has been established that whole-genome duplications fuel chromosome instability through abnormal mitosis 4-8 ; however, the immediate consequences of tetraploidy in the first interphase are not known. This is a key question because single whole-genome duplication events such as cytokinesis failure can promote tumorigenesis 9 . Here we find that human cells undergo high rates of DNA damage during DNA replication in the first S phase following induction of tetraploidy. Using DNA combing and single-cell sequencing, we show that DNA replication dynamics is perturbed, generating under- and over-replicated regions. Mechanistically, we find that these defects result from a shortage of proteins during the G1/S transition, which impairs the fidelity of DNA replication. This work shows that within a single interphase, unscheduled tetraploid cells can acquire highly abnormal karyotypes. These findings provide an explanation for the genetic instability landscape that favours tumorigenesis after tetraploidization., (© 2022. The Author(s).)

Ploidy variations such as genome doubling are frequent in human tumors and have been associated with genetic instability favoring tumor progression. How polyploid cells deal with increased centrosome numbers and DNA content remains unknown. Using Drosophila neuroblasts and human cancer cells to study mitotic spindle assembly in polyploid cells, we found that most polyploid cells divide in a multipolar manner. We show that even if an initial centrosome clustering step can occur at mitotic entry, the establishment of kinetochore-microtubule attachments leads to spatial chromosome configurations, whereby the final coalescence of supernumerary poles into a bipolar array is inhibited. Using in silico approaches and various spindle and DNA perturbations, we show that chromosomes act as a physical barrier blocking spindle pole coalescence and bipolarity. Importantly, microtubule stabilization suppressed multipolarity by improving both centrosome clustering and pole coalescence. This work identifies inhibitors of bipolar division in polyploid cells and provides a rationale to understand chromosome instability typical of polyploid cancer cells., (© 2020 Goupil et al.)

Insomnia, i.e., difficulties initiating and/or maintaining sleep, is one of the most common sleep disorders. To study underlying mechanisms for insomnia, we studied autonomic activity changes around sleep onset in participants without clinical insomnia but with varying problems with initiating or maintaining sleep quantified as increased sleep onset latency (SOL) and wake after sleep onset (WASO), respectively. Polysomnography and electrocardiography were simultaneously recorded in 176 participants during a single night. Cardiac autonomic activity was assessed using frequency domain analysis of RR intervals and results show that the normalized spectral power in the low frequency band ( LF nu ) after sleep onset was significantly higher in participants with long SOL compared to participants with short SOL. Furthermore, the normalized spectral power in the high frequency band ( HF nu ) was significantly lower in participants with long SOL as compared to participants with short SOL over 3 time periods (first 10 min in bed intending to sleep, 10 min before, and 10 min after sleep onset). These results suggest that participants with long SOL are more aroused in all three examined time periods when compared to participants with short SOL, especially for young adults (20-40 years). As there is no clear consensus on the cutoff for an increased WASO, we used a data-driven approach to explore different cutoffs to define short WASO and long WASO groups. LF nu , HF nu , and LF / HF differed between the long and the short WASO groups. A higher LF nu and LF / HF and a lower HF nu was observed in participants with long WASO for most cutoffs. The highest effect size was found using the cutoff of 66 min. Our findings suggest that autonomic cardiac activity has predictive value with respect to sleep characteristics pertaining to sleep onset and maintenance., (Copyright © 2020 Nano, Fonseca, Overeem, Vullings and Aarts.)

Polyploidy arises from the gain of complete chromosome sets [1], and it is known to promote cancer genome evolution. Recent evidence suggests that a large proportion of human tumors experience whole-genome duplications (WGDs), which might favor the generation of highly abnormal karyotypes within a short time frame, rather than in a stepwise manner [2-6]. However, the molecular mechanisms linking whole-genome duplication to genetic instability remain poorly understood. Using repeated cytokinesis failure to induce polyploidization of Drosophila neural stem cells (NSCs) (also called neuroblasts [NBs]), we investigated the consequences of polyploidy in vivo. Surprisingly, we found that DNA damage is generated in a subset of nuclei of polyploid NBs during mitosis. Importantly, our observations in flies were confirmed in mouse NSCs (mNSCs) and human cancer cells after acute cytokinesis inhibition. Interestingly, DNA damage occurs in nuclei that were not ready to enter mitosis but were forced to do so when exposed to the mitotic environment of neighboring nuclei within the same cell. Additionally, we found that polyploid cells are cell-cycle asynchronous and forcing cell-cycle synchronization was sufficient to lower the levels of DNA damage generated during mitosis. Overall, this work supports a model in which DNA damage at mitotic entry can generate DNA structural abnormalities that might contribute to the onset of genetic instability., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Defects in mitotic spindle orientation (MSO) disrupt the organization of stem cell niches impacting tissue morphogenesis and homeostasis. Mutations in centrosome genes reduce MSO fidelity, leading to tissue dysplasia and causing several diseases such as microcephaly, dwarfism, and cancer. Whether these mutations perturb spindle orientation solely by affecting astral microtubule nucleation or whether centrosome proteins have more direct functions in regulating MSO is unknown. To investigate this question, we analyzed the consequences of deregulating Plk4 (the master centriole duplication kinase) activity in Drosophila asymmetrically dividing neural stem cells. We found that Plk4 functions upstream of MSO control, orchestrating centriole symmetry breaking and consequently centrosome positioning. Mechanistically, we show that Plk4 acts through Spd2 phosphorylation, which induces centriole release from the apical cortex. Overall, this work not only reveals a role for Plk4 in regulating centrosome function but also links the centrosome biogenesis machinery with the MSO apparatus., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Development requires cell proliferation, differentiation and spatial organization of daughter cells to occur in a highly controlled manner. The mode of cell division, the extent of proliferation and the spatial distribution of mitosis allow the formation of tissues of the right size and with the correct structural organization. All these aspects depend on cell cycle duration, correct chromosome segregation and spindle orientation. The centrosome, which is the main microtubule-organizing centre (MTOC) of animal cells, contributes to all these processes. As one of the most structurally complex organs in our body, the brain is particularly susceptible to centrosome dysfunction. Autosomal recessive primary microcephaly (MCPH), primordial dwarfism disease Seckel syndrome (SCKS) and microcephalic osteodysplastic primordial dwarfism type II (MOPD-II) are often connected to mutations in centrosomal genes. In this chapter, we discuss the consequences of centrosome dysfunction during development and how they can contribute to the etiology of human diseases.

Introduction: Acute appendicitis is the most common cause of acute abdomen in adolescents, with an overall incidence of 7%. Two such tools are used to diagnose acute appendicitis: ultrasound and Computer Tomography imaging. End point of this study was to verify the accuracy of ultrasound imaging in the diagnosis of acute appendicitis with respect to intraoperative observations and the respective clinical and laboratory findings in young and in the elderly., Methods: We considered all the appendectomies for acute appendicitis performed between 1 January 2010 and 1 January 2015. We evaluated clinical symptoms, laboratory findings, ultrasound findings, intraoperative signs, and anatomical and pathological findings. In the study we compared the ultrasound and intraoperative findings and then compared these with the respective clinical and laboratory data., Results: In a comparison of diagnostic accuracy, the difference between clinical and ultrasound examinations was not significant. The differences between the diagnostic accuracy of clinical and laboratory findings and between ultrasound and laboratory investigations were statistically significant., Conclusion: We defined white blood cells and C protein levels as non-diagnostic of the type of acute inflammation but rather as indicators of the severity of the inflammatory process. We also agree with the authors who proposed the incorporation of ultrasonography into routine practice in the diagnosis of acute appendicitis, but only and exclusively to support other diagnostic procedures and preferably within emergency departments. A thorough clinical examination of patients with suspected acute appendicitis is still the best diagnostic procedure available to us., (Copyright © 2016. Published by Elsevier Ltd.)

Venous ulceration is a complex and serious problem that affects 1-2% of the global elderly population (>65 years), and its incidence is constantly increasing. The population group with higher risk of development of venous ulceration is the elderly. These lesions have a significant negative impact on patients' quality of life. Our aim was to analyze the state of the art, starting with the medical literature review. The evidence supports that managing chronic wounds with a multidisciplinary wound care team significantly increases wound healing and reduces the severity of wound-associated pain and the required daily wound treatments compared with persons who are not managed by such a team., (Copyright © 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: The laparoscopic repair of non-midline ventral hernia (LNM) has been debated. The aim of this study is to analyze our experience performing the laparoscopic approach to non-midline ventral hernias (NMVHs) in Northwest Italy for 6 years., Methods: A total of 78 patients who underwent LNM between March 2008 and March 2014 in the selected institutions were analyzed. We retrospectively analyzed the peri- and postoperative data and the recurrence rate of four subgroups of NMVHs: subcostal, suprapubic, lumbar, and epigastric. We also conducted a literature review., Results: No difference was found between the four subgroups in terms of demographic data, defect characteristics, admission data, and complications. Subcostal defects required a shorter operating time. Obesity was found to be a risk factor for recurrence., Conclusions: In our experience, subcostal defects were easier to perform, with a lower recurrence rate, lesser chronic pain, and faster surgical performance. A more specific prospective randomized trial with a larger sample is awaited. Based on our experience, however, the laparoscopic approach is a safe treatment for NMVHs in specialized centers., (Copyright © 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

The centrosome is the main microtubule organizing center of animal cells. It contributes to spindle assembly and orientation during mitosis and to ciliogenesis in interphase. Numerical and structural defects in this organelle are known to be associated with developmental disorders such as dwarfism and microcephaly, but only recently, the molecular mechanisms linking centrosome aberrations to altered physiology are being elucidated. Defects in centrosome number or structure have also been described in cancer. These opposite clinical outcomes--arising from reduced proliferation and overproliferation respectively--can be explained in light of the tissue- and developmental-specific requirements for centrosome functions. The pathological outcomes of centrosome deficiencies have become clearer when considering its consequences. Among them, there are genetic instability (mainly aneuploidy, a defect in chromosome number), defects in the symmetry of cell division (important for cell fate specification and tissue architecture) and impaired ciliogenesis. In this review, we discuss the origins and the consequences of centrosome flaws, with particular attention on how they contribute to developmental diseases.

Centrosome amplification has severe consequences during development and is thought to contribute to a variety of diseases such as cancer and microcephaly. However, the adverse effects of centrosome amplification in epithelia are still not known. Here, we investigate the consequences of centrosome amplification in the Drosophila wing disc epithelium. We found that epithelial cells exhibit mechanisms of clustering but also inactivation of extra centrosomes. Importantly, these mechanisms are not fully efficient, and both aneuploidy and cell death can be detected. Epithelial cells with extra centrosomes generate tumors when transplanted into WT hosts and inhibition of cell death results in tissue over-growth and disorganization. Using SILAC-fly, we found that Moesin, a FERM domain protein, is specifically upregulated in wing discs with extra centrosomes. Moesin localizes to the centrosomes and mitotic spindle during mitosis, and we show that Moesin upregulation influences extra-centrosome behavior and robust bipolar spindle formation. This study provides a mechanistic explanation for the increased aneuploidy and transformation potential primed by centrosome amplification in epithelial tissues., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

It has been established that there is a relationship between chronic inflammation and cancer development. The constant colonic inflammation typical of inflammatory bowel diseases is now considered a risk factor for colorectal carcinoma (CRC) development. The inflammatory network of signaling molecules is also required during the late phases of carcinogenesis, to enable cancer cells to survive and to metastasize. Oxidative reactions are an integral part of the inflammatory response, and are generally associated with CRC development. However, when the malignant phenotype is acquired, increased oxidative status induces antioxidant defenses in cancer cells, favoring their aggressiveness. This contradictory behavior of cancer cells toward redox status is of great significance for potential anticancer therapies. This paper summarizes the essential background information relating to the molecules involved in regulating oxidative stress and inflammation during carcinogenesis. Understanding more of their function in CRC stages might provide the foundation for future developments in CRC treatment., (© 2015 New York Academy of Sciences.)

Background: Abdominal compartment syndrome (ACS) is defined as an increase of intra-abdominal pressure (IAH) to values higher than 20 mmHg, associated with reduced perfusion and organ dysfunction., Materials and Methods: There is a classification of open abdomen which stratifies patients according to the natural history of improvement or clinical deterioration. The aim of treatment is to maintain the open abdomen at the lowest level and to prevent progression to a more complex level., Discussion: Surgical treatment essentially consists in abdominal decompression by leaving the abdomen open. Analysis of the literature shows that negative pressure increases the rate of primary fascial closure; entero-cutaneous fistulas are seen in a minority of cases, without seeming consequence of the application of the dressing. Open abdomen management consists of three treatment stages: acute (24-48 hours), intermediate (from 48 hours to 10 days) and late or reconstruction (from 10 days to the final closure)., Conclusion: It's important to recognize patients at risk of IAH and the first signs of ACS and intervene early with abdominal decompression if this will establish itself. Management of the open abdomen is now facilitated by negative pressure devices, which positively affect the morbidity and mortality of patients with ACS.

Introduction: Inguinal hernia surgery is one of the most common surgical procedures performed worldwide. Some studies demonstrated clear advantages of laparoscopic approach in terms of chronic pain, recurrence rate and daily life activities Aim of this study was to compare short and long-terms outcome of tacks and fibrin glue used during laparoscopic transabdominal hernioplasty (TAPP)., Methods: This is a retrospective study conducted by our division of General Surgery. From May 2008 to May 2013 we performed 116 hernioplasty with TAPP technique. We compared two groups of patients: a group of 59 patients treated with fibrin glue and a group of 57 patients treated with conventional tacks and the two subgroups of patients over 65 years old. We evaluated: perioperative outcomes, early and late complications., Results: There were no significative difference about length of postoperative stay, time to return to work, recurrence rate and complications., Discussion: This study demonstrates that fibrin glue are same tolerated than tacks by patients and that the glues lead to the same good results during initial follow-up and in long term data also in the elderly. Meticulous preparation of the groin with preservation of spermatic sheet is in our opinion necessary to provide effective pain reduction and a good result in every TAPP procedure., (Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

We present the case of a 29-years-old male patient, affected by a voluminous post-traumatic mesenteric cyst, a rare abdominal disease; our patient represents a rarely affected age group. Treatment was based on interventional radiology with an US-guided drainage and sclerosis by ethyl alcohol of the lesion. The intervention performed on this patient represents the application of a standardized radiological technique to a new contest, mesenteric cysts, whose gold-standard treatment is represented in literature by surgery. In our case we obtained an optimal result, with complete regression of the treated cyst: it proved to be an effective, feasible, safe and minimally invasive procedure., (Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

Introduction: Incidence of neuroendocrine tumor (NET) is increased in the last thirty years from 1.1 to 5.2 cases per 100,000 people in the United States. They can originate from the pancreatic gland and for the majority of cases are not functioning (80%). A small percentage of functioning may produce adrenocorticotropic hormone (ACTH) and lead to ectopic ACTH Syndrome (EAS), responsible of Cushing-Syndrome., Results: We present a case of a 30 year-old woman suffering from EAS due to a neoformation of the pancreatic tail of the maximum diameter of 4 cm. The lesion was resectable at preoperatory imaging. The patient was subjected to distal splenopancreasectomy. Histological examination showed a well-differentiated neuroendocrine carcinoma pT3N0. The postoperative course was regular. At two years of follow-up patient is almost completely asymptomatic for Cushing's but she has developed multiple liver metastases, for which she began chemotherapy., Discussion: p-NET responsible for EAS is usually malignant and the radical treatment of excision of the lesion is not possible because they occur at the time of diagnosis with liver metastases or unresectable. Our patient had a mass at the time of diagnosis resectable but despite radical surgery, she has developed multiple liver metastases at two years and she was undergoing chemotherapy., Conclusions: In agreement with previous literature we confirm the aggressive nature of pancreatic tumors secreting ACTH, despite radical surgery. Conversely, surgical treatment is effective on the resolution of clinical symptoms., (Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

Laparoscopic cholecystectomy (LC) is currently the gold standard treatment for symptomatic cholelithiasis. LC is actually condidered a medium complexity surgical operation. LC could be technically hard, especially if patient underwent previous surgical operation. These difficulties increase in outcome of previous operation in right upper quadrant (RUQ): in this case laparoscopic access is defined as an "hard access". We present two cases in which an unconventional access was performed: laparoscopic cholecistectomy is a safe and feasible procedure, although a careful assessment preoperative is indispensable. In particular, caution is required in both the triangulation of the trocar, which in pneumoperitoneum induction., (Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

Introduction: Endorectal ultrasound (ERU) is used for locoregional staging of rectal cancer. Our work compares the data in the literature regarding diagnostic accuracy of the technique and results of routine use of the technique in two centers in Piedmont., Material and Methods: 77 reports ultrasound with the final diagnosis of rectal cancer from the period 2008-2012 were examined. The echographies were performed by two experienced operators, using two ultrasound device with the same technical characteristics., Results: Sensitivity levels are high, with the exception of stage T3. Specificity is always high. The relationships of verisimilitude, both negative and positive, showing that the accuracy of the test is still high. The risk of overstaging is higher for pT1, while most important the risk of understaging concerns the stage T3 (23.5%); on the contrary the ERU is able to exclude infiltration of perirectal organs with a good accuracy (NPV of 99.3%)., Conclusion: Although our study was a retrospective study, likewise some literature's reports, the interpretation of our analysis results shows a significant risk of downstaging T3 and N+ tumors. ERU represents in our experience a very important radiological staging methods to evaluate T1 and T2 rectal cancer., (Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)