Correlation of Morphological Appearance of Peritoneal Lesions at Laparotomy and Disease at Pathological Assessment in Patients Undergoing Cytoreductive Surgery for Peritoneal Malignancy: Results of Phase I of the PRECINCT Study in 707 Patients.

BACKGROUND: The PRECINCT (Pattern of peritoneal dissemination and REsponse to systemic Chemotherapy IN Common and uncommon peritoneal Tumors) is a prospective, multicenter, observational study. This report from phase I of PRECINCT outlines variations in recording the surgical peritoneal cancer index (sPCI) at experienced peritoneal malignancy centers and the incidence of pathologically confirmed disease in morphologically different peritoneal lesions (PL). METHODS: The sPCI was recorded in a prespecified format that included the morphological appearance of PL. Six prespecified morphological terms were provided. The surgical and pathological findings were compared. RESULTS: From September 2020 to December 2021, 707 patients were enrolled at 10 centers. The morphological details are routinely recorded at two centers, structure bearing the largest nodule, and exact size of the largest tumor deposit in each region at four centers each. The most common morphological terms used were normal peritoneum in 3091 (45.3%), tumor nodules in 2607 (38.2%) and confluent disease in 786 (11.5%) regions. The incidence of pathologically confirmed disease was significantly higher in 'tumor nodules' with a lesion score of 2/3 compared with a lesion score of 1 (63.1% vs. 31.5%; p < 0.001). In patients receiving neoadjuvant chemotherapy, the incidence of pathologically confirmed disease did not differ significantly from those undergoing upfront surgery [751 (47.7%) and 532 (51.4%) respectively; p = 0.069]. CONCLUSIONS: The sPCI was recorded with heterogeneity at different centers. The incidence of pathologically confirmed disease was 49.2% in 'tumor nodules'. Frozen section could be used more liberally for these lesions to aid clinical decisions. A large-scale study involving pictorial depiction of different morphological appearances and correlation with pathological findings is indicated.

A Synthetic Route to Tetrahydro-1H-azepino[4,3,2-cd]indoles via Ring-Opening Cyclization of Activated Azetidines with 4-Bromoindole: Toward a Vasopressin V2 Receptor Antagonist.

A simple one-pot, two-step strategy for the synthesis of tetrahydro-1H-azepino[4,3,2-cd]indoles via Lewis acid-catalyzed SN2-type ring opening of activated azetidines with 4-bromoindole, followed by a Pd-catalyzed intramolecular C-N cyclization reaction, with good to excellent yields is described. Utilizing this protocol, the vasopressin V2 receptor antagonist precursor has been synthesized easily. Enantioenriched tetrahydro-1H-azepino[4,3,2-cd]indoles were obtained by starting from enantiopure azetidine.

Ring-Opening Cyclization (ROC) of Aziridines with Propargyl Alcohols: Synthesis of 3,4-Dihydro-2H-1,4-oxazines.

Activated aziridines react with propargyl alcohols in the presence of Zn(OTf)2 as the Lewis acid catalyst following an SN2-type ring-opening mechanism to furnish the corresponding amino ether derivatives. Those amino ethers further undergo intramolecular hydroamination via 6-exo-dig cyclization in the presence of Zn(OTf)2 as the catalyst and tetrabutylammonium triflate salt as an additive under one-pot two-step reaction conditions. However, for nonracemic examples, ring-opening and cyclization steps were conducted under two-pot conditions. The reaction works well without any additional solvents. The final 3,4-dihydro-2H-1,4-oxazine products were obtained with 13 to 84% yield and 78 to 98% enantiomeric excess (for nonracemic examples).

Clinical and Radiologic Predictors of a Pathologic Complete Response to Neoadjuvant Chemotherapy (NACT) in Patients Undergoing Cytoreductive Surgery for Colorectal Peritoneal Metastases: Results of a Prospective Multi-center Study.

BACKGROUND: Patients undergoing cytoreductive surgery for colorectal peritoneal metastases who have a pathologic complete response (pCR) to neoadjuvant chemotherapy experience a significantly longer survival than those with residual disease. This response is known only after surgery. This study aimed to examine clinical and radiologic predictors of a pCR. METHODS: From July 2018 to December 2019, the study prospectively enrolled 120 patients. The clinical and radiologic findings were compared between patients with and without a pCR. A protocol for pathologic evaluation was followed. RESULTS: A pCR was observed in 34 patients (28.3%). Receiver operating characteristic (ROC) curves showed that patients with a surgical Peritoneal Cancer Index (sPCI) of 3 or lower had an 80% probability of experiencing a pCR, and that patients with a radiologic PCI (rPCI) of 2 or lower had a 70% probability of experiencing a pCR. A pCR was correctly predicted for 47% of the patients by imaging and for 44.4% of the patients by surgical evaluation. The site of primary tumor, the timing of peritoneal metastasis (PM), histology, tumor marker positivity, and mutations in known poor prognostic genes (KRAS) did not differ between the patients with and those without pCR. The primary tumor showed residual disease in 23.5% and regional nodes in 26.4% of the patients with pCR. CONCLUSIONS: The rPCI and sPCI concurred with a pCR in less than 50% of the patients. The patients with a lower PCI had greater concordance. An sPCI of 3 or lower was predictive of a pCR in 80% of the patients. The impact of KRAS mutations on pCR should be evaluated in a larger series. The predictors of pCR and response to systemic chemotherapy should be incorporated in prognostic scores used to select patients for surgery.

Mucormycosis and COVID-19: An epidemic within a pandemic in India.

IMPORTANCE: Coronavirus disease (COVID-19) causes an immunosuppressed state and increases risk of secondary infections like mucormycosis. We evaluated clinical features, predisposing factors, diagnosis and outcomes for mucormycosis among patients with COVID-19 infection. METHODS: This prospective, observational, multi-centre study included 47 consecutive patients with mucormycosis, diagnosed during their course of COVID-19 illness, between January 3 and March 27, 2021. Data regarding demography, underlying medical conditions, COVID-19 illness and treatment were collected. Clinical presentations of mucormycosis, imaging and biochemical characteristics and outcome were recorded. RESULTS: Of the 2567 COVID-19 patients admitted to 3 tertiary centres, 47 (1.8%) were diagnosed with mucormycosis. Mean age was 55 ± 12.8years, and majority suffered from diabetes mellitus (n = 36, 76.6%). Most were not COVID-19 vaccinated (n = 31, 66.0%) and majority (n = 43, 91.5%) had developed moderate-to-severe pneumonia, while 20 (42.6%) required invasive ventilation. All patients had received corticosteroids and broad-spectrum antibiotics while most (n = 37, 78.7%) received at least one anti-viral medication. Mean time elapsed from COVID-19 diagnosis to mucormycosis was 12.1 ± 4.6days. Eleven (23.4%) subjects succumbed to their disease, mostly (n = 8, 72.7%) within 7 days of diagnosis. Among the patients who died, 10 (90.9%) had pre-existing diabetes mellitus, only 2 (18.2%) had received just one vaccine dose and all developed moderate-to-severe pneumonia, requiring oxygen supplementation and mechanical ventilation. CONCLUSIONS: Mucormycosis can occur among COVID-19 patients, especially with poor glycaemic control, widespread and injudicious use of corticosteroids and broad-spectrum antibiotics, and invasive ventilation. Owing to the high mortality, high index of suspicion is required to ensure timely diagnosis and appropriate treatment in high-risk populations.

A synthetic route to 1,4-disubstituted tetrahydro-ß-carbolines and tetrahydropyranoindoles via ring-opening/Pictet-Spengler reaction of aziridines and epoxides with indoles/aldehydes.

A simple and efficient synthetic route to various 1,4-disubstituted tetrahydro-ß-carbolines and tetrahydropyrano[3,4-b]indoles in high yields and stereoselectivity via LiClO4-catalyzed SN2-type ring opening of aziridines and epoxides with indoles followed by p-toluenesulfonic acid (PTSA) catalyzed Pictet-Spengler reaction is described.

Synthesis of Nonracemic 1,4-Benzoxazines via Ring Opening/Cyclization of Activated Aziridines with 2-Halophenols: Formal Synthesis of Levofloxacin.

Novel 3,4-dihydro-1,4-benzoxazine derivatives have been synthesized by an efficient and simple method in excellent enantio- and diastereospecificity (ee > 99%, de > 99%). The reaction proceeds via Lewis acid-catalyzed SN2-type ring opening of activated aziridines with 2-halophenols followed by Cu(I)-catalyzed intramolecular C-N cyclization in a stepwise fashion under one-pot conditions to furnish the 3,4-dihydro-1,4-benzoxazine derivatives in excellent yields (up to 95%). The strategy offers a short and efficient synthesis to ( S)-3-methyl-1,4-benzoxazine ( S)-3v, a late stage intermediate in the synthesis of levofloxacin.

Memory of Chirality Concept in Asymmetric Intermolecular Michael Addition of α-Amino Ester Enolates to Enones and Nitroalkenes.

A highly stereoselective asymmetric intermolecular conjugate addition of α-amino ester derivatives to cyclic enones via the memory of chirality (MOC) concept in high yields with excellent diastereo- and enantioselectivity (dr >99:1, up to 99% ee) is reported. The applicability and the generality of the strategy was demonstrated by its further exploration to acyclic α,ß-unsaturated ketone and aromatic nitroalkenes, resulting in the formation of δ-keto-α-amino ester derivative and γ-nitro-α-amino ester derivatives, respectively, with excellent ee and dr.

Perioperative outcomes and platinum resistant recurrence in patients undergoing systematic, protocol-based, total parietal peritonectomy during interval cytoreductive surgery for advanced ovarian cancer: results of the TORPEDO study.

OBJECTIVE: The TORPEDO (CTRI/2018/12/016789) is the single-arm, prospective, interventional study evaluating the role of a total parietal peritonectomy (TPP) in patients undergoing interval cytoreductive surgery (iCRS). In this manuscript, we report the perioperative outcomes and platinum resistant recurrence (PRR) in 218 patients enrolled in the study. METHODS: A TPP was performed in all patients undergoing iCRS irrespective of the residual disease extent. hyperthermic intraperitoneal chemotherapy (HIPEC) was performed as per the clinician's discretion with 75 mg/m² of cisplatin. Maintenance therapy was also used at the discretion of the treating clinicians. RESULTS: From 9th December 2018 to 31st July 2022 (recruitment complete), 218 patients were enrolled at 4 medical centers in India. The median surgical peritoneal cancer index was 14 and a complete gross resection was achieved in 95.8%. HIPEC was performed in 130 (59.6%) patients. The 90-day major morbidity was 17.4% and 2.7% patients died within 90 days of surgery. Adjuvant chemotherapy was delayed beyond 6 weeks in 7.3%. At a median follow-up of 19 months (95% confidence interval [CI]=15.9-35 months), 101 (46.3%) recurrences and 19 (8.7%) deaths had occurred. The median progression-free survival was 22 months (95% CI=17-35 months) and the median overall survival (OS) not reached. Platinum resistant recurrence was observed in 6.4%. The projected 3-year OS was 81.5% and in 80 patients treated before may 2020, it was 77.5%. CONCLUSION: The morbidity and mortality of TPP with or without HIPEC performed during iCRS is acceptable. The incidence was of PRR is low. Early survival results are encouraging and warrant conduction of a randomized controlled trial comparing TPP with conventional surgery.

Randomized controlled trial of topical EMLA and breastfeeding for reducing pain during wDPT vaccination.

UNLABELLED: The primary objective was to evaluate the analgesic effect of a eutectic mixture of local anesthetics (EMLA) during whole cell DPT vaccination. The secondary objective was to evaluate if the analgesic effect of EMLA was synergistic to breastfeeding. A randomized, placebo-controlled trial was done to include infants of up to 3 months of age who came for their first DPT vaccination. The outcome variables were duration of cry, latency of onset of cry, and Modified Facial Coding Score. Thirty babies were enrolled in each of three groups. The groups did not differ significantly in baseline characteristics. Median (interquartile range) of duration of cry was least [34.6 (24.1-72.2) s] in babies receiving EMLA cream with breastfeeding (EB group), followed by 94.2 (46.1-180) s in babies receiving EMLA cream with oral distilled water (EW group), as compared to 180.0 (180-180) s in babies receiving placebo cream with oral distilled water (PCW group) (p < 0.05). Mean (SD) of latency of cry was significantly greater in EB group [2.4 (1.14) s] and EW group [1.9 (0.62) s] as compared to babies in PCW group [1.5 (0.47) s] (p < 0.05), but the difference between EB and EW groups was not significant. Modified Facial Coding Score was significantly lower in EB group as compared to the other groups (p < 0.05). CONCLUSIONS: Topical EMLA is effective in reducing pain and has a synergistic effect in analgesia when combined with breastfeeding during vaccination in infants.

DAMAD: Database, Attack, and Model Agnostic Adversarial Perturbation Detector.

Adversarial perturbations have demonstrated the vulnerabilities of deep learning algorithms to adversarial attacks. Existing adversary detection algorithms attempt to detect the singularities; however, they are in general, loss-function, database, or model dependent. To mitigate this limitation, we propose DAMAD-a generalized perturbation detection algorithm which is agnostic to model architecture, training data set, and loss function used during training. The proposed adversarial perturbation detection algorithm is based on the fusion of autoencoder embedding and statistical texture features extracted from convolutional neural networks. The performance of DAMAD is evaluated on the challenging scenarios of cross-database, cross-attack, and cross-architecture training and testing along with traditional evaluation of testing on the same database with known attack and model. Comparison with state-of-the-art perturbation detection algorithms showcase the effectiveness of the proposed algorithm on six databases: ImageNet, CIFAR-10, Multi-PIE, MEDS, point and shoot challenge (PaSC), and MNIST. Performance evaluation with nearly a quarter of a million adversarial and original images and comparison with recent algorithms show the effectiveness of the proposed algorithm.

Feasibility and Safety of Taxane-PIPAC in Patients with Peritoneal Malignancies-a Retrospective Bi-institutional Study.

Taxanes have a favorable pharmacokinetic profile for intraperitoneal application. We report our initial experience with taxane-PIPAC (pressurized intraperitoneal chemotherapy) for unresectable peritoneal metastases from different primary sites in terms of safety, feasibility, response rate, and conversion to resectability. In this retrospective study, PIPAC was performed alone or in combination with systemic chemotherapy. Paclitaxel was used as a single agent, whereas docetaxel was used in combination with cisplatin-adriamycin or oxaliplatin-adriamycin. From December 2019 to December 2021, 47 patients underwent 82 PIPAC procedures (1 PIPAC in 55.3%, 2 in 29.7%, 3 in 14.8%). The most common primary sites were ovarian cancer (31.9%), gastric cancer (23.4%), and colorectal cancer (21.2%). Docetaxel-cisplatin-adriamycin was used in 33 (70.2%) patients, docetaxel-oxaliplatin-adriamycin in 12 (25.5%), and paclitaxel alone in 2 (4.2%) patients. Grade 1-2 complications were observed in 24 (51%) and grade 3-4 complications in 6 (12.7%) patients (8.5% of 82 PIPACs). 16/47 (34.0%) patients had a clinical response to PIPAC. The mean PCI was 25.9 ± 9.2 for the first PIPACs and 22.4 ± 9 for the subsequent PIPACs with an average reduction of 3.6 points [change in PCI ranged from - 14 to + 8]. The PRGS was 1/2 in 4/47 (8.5%) patients (19.0% patients with > 1 PIPAC). A reduction in ascites was observed in 35.4% presenting with ascites. Nine (19.1%) patients had conversion to operability leading to a subsequent cytoreductive surgery in 8 (17%) patients. PIPAC with docetaxel is feasible and safe. The role of PIPAC with both docetaxel and paclitaxel either alone or in combination with other drugs should be investigated in prospective studies.

Greater-omentum lesion-score (GOLS) as a predictor of residual disease in different regions of the peritoneal cavity in patients undergoing interval cytoreductive surgery for advanced ovarian cancer and its potential clinical utility.

BACKGROUND AND AIM: The greater omentum(GO) is a common site of residual disease in patients receiving neoadjuvant chemotherapy for advanced epithelial ovarian cancer. The presence of tumor in the GO could predict presence of disease in other peritoneal regions. The goal of this study was to perform a correlation between the greater-omentum lesion-score(GOLS) and presence of disease in different peritoneal regions and determine its potential utility in guiding interval cytoreductive surgery(CRS). METHODS: This prospective study included 134 patients undergoing interval CRS from July 1, 2018 to June 30, 2020. Each region of Sugarbaker's Peritobneal Cancer Index(PCI) was given a lesion score(LS) from 0 to 3 according to the diameter of the largest tumor in the region. The GOLS was recorded separately from other structures in the region. Correlation between the GOLS and surgical and pathological LS in each region was performed. RESULTS: As the GOLS increased, the incidence of disease(surgical LS) in other regions of the peritoneal cavity increased. Receiver operating characteristic(ROC) curves showed area under curve more than 80% for regions 1-2 and 7-8 indicating a high probability of disease in these regions in patients with GOLS 1-3. The positive predictive value(PPV) of preoperative imaging for GOLS was 95.7%. No cut-off of the GOLS could predict presence of disease on pathology with more than 70% accuracy. CONCLUSIONS: Presence of disease in the GO warrants performing upper abdominal exploration and/or cytoreduction and interval CRS should be planned accordingly in these patients. Imaging has a high PPV in detecting disease in the GO.

Patterns of peritoneal dissemination and response to systemic chemotherapy in common and rare peritoneal tumours treated by cytoreductive surgery: study protocol of a prospective, multicentre, observational study.

INTRODUCTION: Despite optimal patient selection and surgical effort, recurrence is seen in over 70% of patients undergoing cytoreductive surgery (CRS) for peritoneal metastases (PM). Apart from the Peritoneal Cancer Index (PCI), completeness of cytoreduction and tumour grade, there are other factors like disease distribution in the peritoneal cavity, pathological response to systemic chemotherapy (SC), lymph node metastases and morphology of PM which may have prognostic value. One reason for the underutilisation of these factors is that they are known only after surgery. Identifying clinical predictors, specifically radiological predictors, could lead to better utilisation of these factors in clinical decision making and the extent of peritoneal resection performed for different tumours. This study aims to study these factors, their impact on survival and identify clinical and radiological predictors. METHODS AND ANALYSIS: There is no therapeutic intervention in the study. All patients with biopsy-proven PM from colorectal, appendiceal, gastric and ovarian cancer and peritoneal mesothelioma undergoing CRS will be included. The demographic, clinical, radiological, surgical and pathological details will be collected according to a prespecified format that includes details regarding distribution of disease, morphology of PM, regional node involvement and pathological response to SC. In addition to the absolute value of PCI, the structures bearing the largest tumour nodules and a description of the morphology in each region will be recorded. A correlation between the surgical, radiological and pathological findings will be performed and the impact of these potential prognostic factors on progression-free and overall survival determined. The practices pertaining to radiological and pathological reporting at different centres will be studied. ETHICS AND DISSEMINATION: The study protocol has been approved by the Zydus Hospital ethics committee (27 July, 2020) and Lyon-Sud ethics committee (A15-128). TRIAL REGISTRATION NUMBER: CTRI/2020/09/027709; Pre-results.

Accuracy of CT Scan in Predicting the Surgical PCI in Patients Undergoing Cytoreductive Surgery with/without HIPEC-a Prospective Single Institution Study.

Our aim was to study the accuracy of CT scan in predicting the peritoneal cancer index (PCI) and the impact of neoadjuvant chemotherapy (NACT), abdominal region, disease volume, and primary tumor site on it. This was a prospective single-center study that included patients undergoing cytoreductive surgery ± HIPEC. The CT-PCI was calculated and compared to the surgical PCI. The accuracy of CT-PCI in predicting the surgical PCI and the difference between the two was evaluated. From January 2018 to August 2018, 50 patients were included. The median CT PCI was 6 (range 0-35) and median surgical PCI was 17 (range 2-35). CT-PCI was more than the surgical PCI in 12 (24%), less in 23 (46%), and same in 15 (30%) with an accuracy of 30%. The highest accuracy was in region 10 and lowest in region 3. It was 15% in patients with ovarian cancer, 30% in PMP, 21% in patients receiving NACT, 35% in high-volume disease, and 42.1% in low volume disease. The CT and surgical PCI varied significantly in patients with ovarian cancer (p < 0.001), following NACT (p = 0.01) and those with moderate volume disease (p < 0.001). CT has a low accuracy in predicting the surgical PCI in both high and low volume disease. The CT-PCI can differ significantly from the surgical PCI in patients with ovarian cancer and in patients who have received NACT for peritoneal disease. The impact of NACT on accuracy of CT-PCI in non-ovarian peritoneal metastases should be evaluated further.

Synthetic route to chiral indolines via Cu(OAc)2-catalyzed ring-opening/C(sp2)-H activation of activated aziridines.

A simple strategy for the synthesis of highly functionalized indolines via Lewis acid catalyzed ring-opening of activated aziridines with various nucleophiles followed by Cu(OAc)2-mediated intramolecular C-H amination in one-pot has been developed with excellent enantio- and diastereospecificity (ee 99%; de >99%). The reaction proceeds via Cu(OAc)2-catalyzed SN2-type ring-opening of 2-phenyl-N-(2-pyridinesulfonyl)aziridine with alcohols and arene, followed by copper-mediated pyridine-2-sulfonamide directed intramolecular C(sp2)-H activation/cyclization in a stepwise fashion to furnish the indoline derivatives in excellent yields (up to 91%).

FR-CAPTCHA: CAPTCHA based on recognizing human faces.

A Completely Automated Public Turing test to tell Computers and Humans Apart (CAPTCHA) is designed to distinguish humans from machines. Most of the existing tests require reading distorted text embedded in a background image. However, many existing CAPTCHAs are either too difficult for humans due to excessive distortions or are trivial for automated algorithms to solve. These CAPTCHAs also suffer from inherent language as well as alphabet dependencies and are not equally convenient for people of different demographics. Therefore, there is a need to devise other Turing tests which can mitigate these challenges. One such test is matching two faces to establish if they belong to the same individual or not. Utilizing face recognition as the Turing test, we propose FR-CAPTCHA based on finding matching pairs of human faces in an image. We observe that, compared to existing implementations, FR-CAPTCHA achieves a human accuracy of 94% and is robust against automated attacks.

Comparison of analgesic effect of direct breastfeeding, oral 25% dextrose solution and placebo during 1st DPT vaccination in healthy term infants: a randomized, placebo controlled trial.

OBJECTIVE: To compare analgesic effect of direct breast feeding, 25% dextrose solution and placebo as we give 1st intramuscular whole cell DPT injection to 6week - 3month old infants. DESIGN: Randomized, placebo controlled trial. SETTINGS: Immunization clinic of Department of Pediatrics, LLRM Medical College. PARTICIPANTS: Infants coming for their 1st DPT vaccination were randomized in to three groups of 40 each. OUTCOME MEASURES: The primary outcome variable was the duration of cry after vaccination. Secondary outcome variables were Modified Facial Coding Score (MFCS) and latency of onset of cry. RESULTS: 120 babies were equally enrolled in breast feed group, 25% dextrose fed group and distilled water fed group. Median (interquartile range) of duration of cry was significantly lower in breast fed (33.5 (17-54) seconds) and 25% dextrose fed babies (47.5 (31-67.5) seconds) as compared to babies given distilled water (80.5 (33.5-119.5) seconds) (P<0.001). MFCS at 1 min and 3 min was significantly lower in direct breast fed and dextrose fed babies. CONCLUSION: Direct breastfeeding and 25% dextrose act as analgesic in young infants undergoing DPT vaccination in young infants less than 3 month of age.